WO2017182425A1 - Pharmaceutical dosage form mountable to a tooth - Google Patents

Pharmaceutical dosage form mountable to a tooth Download PDF

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Publication number
WO2017182425A1
WO2017182425A1 PCT/EP2017/059104 EP2017059104W WO2017182425A1 WO 2017182425 A1 WO2017182425 A1 WO 2017182425A1 EP 2017059104 W EP2017059104 W EP 2017059104W WO 2017182425 A1 WO2017182425 A1 WO 2017182425A1
Authority
WO
WIPO (PCT)
Prior art keywords
dosage form
pharmaceutical dosage
tooth
adjacent teeth
mounting unit
Prior art date
Application number
PCT/EP2017/059104
Other languages
French (fr)
Inventor
Carmen STOMBERG
Klaus WENING
Marcel Haupts
Original Assignee
Grünenthal GmbH
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Grünenthal GmbH filed Critical Grünenthal GmbH
Publication of WO2017182425A1 publication Critical patent/WO2017182425A1/en

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
    • A61K9/0063—Periodont
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61C—DENTISTRY; APPARATUS OR METHODS FOR ORAL OR DENTAL HYGIENE
    • A61C13/00—Dental prostheses; Making same
    • A61C13/0003—Making bridge-work, inlays, implants or the like
    • A61C13/0006—Production methods
    • A61C13/0019—Production methods using three dimensional printing
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61C—DENTISTRY; APPARATUS OR METHODS FOR ORAL OR DENTAL HYGIENE
    • A61C19/00—Dental auxiliary appliances
    • A61C19/06—Implements for therapeutic treatment
    • A61C19/063—Medicament applicators for teeth or gums, e.g. treatment with fluorides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61C—DENTISTRY; APPARATUS OR METHODS FOR ORAL OR DENTAL HYGIENE
    • A61C5/00—Filling or capping teeth
    • A61C5/80—Dental aids fixed to teeth during treatment, e.g. tooth clamps
    • A61C5/88—Wedges
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/485—Morphinan derivatives, e.g. morphine, codeine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/02—Stomatological preparations, e.g. drugs for caries, aphtae, periodontitis

Definitions

  • the invention relates to a three-dimensionally printed pharmaceutical dosage form comprising a mounting unit which is mountable to a tooth or two adjacent teeth of a patient, preferably into a dental interstice between two adjacent teeth; and a releasing unit comprising a pharmacologically active ingredient.
  • the invention also relates to a process for the preparation of said pharmaceutical dosage form comprising a three-dimensional printing step.
  • the oral route is one of the most preferred routes of drug administration, as it is more convenient, cost effective, and ease of administration lead to high level of patient compliance.
  • the oral route is problematic because of the swallowing difficulty for pediatric and geriatric patients who have fear of choking.
  • Patient convenience and compliance oriented research has resulted in the development of sophisticated drug delivery systems including e.g. fast dissolving drug delivery systems, buccal drug delivery systems, and the like.
  • buccal drug delivery has lately become an important route of drug administration.
  • Various bioadhesive mucosal pharmaceutical dosage forms have been developed, which includes adhesive tablets, gels, ointments, patches, and more recently the use of polymeric films for buccal delivery, also known as mouth dissolving films.
  • the buccal delivery serves as an excellent platform for parenteral absorption of molecules that have poor dermal penetration.
  • Known fast dissolve technologies can be divided in to three broad groups: (i) lyophilized systems, (ii) compressed tablet-based systems, and (iii) oral thin films (OTF).
  • Lyophilized systems involve taking a suspension or solution of drug with other structural excipients and, through the use of a mould or blister pack, forming tablet-shaped units. The units or tablets are then frozen and lyophilized in the pack or mould. The resulting units have a very high porosity, which allows rapid water or saliva penetration and very rapid disintegration. Dose handling capability for these systems differs depending on whether the active ingredients are soluble or insoluble drugs, with the dose capability being slightly lower for the former than for some tablet based systems. The units are capable of incorporating a range of taste masked materials and have more rapid disintegration than tablet-based systems.
  • Compressed tablet-based systems are produced using standard tablet technology by direct compression of excipients.
  • the tablet technologies have different levels of hardness and friability. These results in varying disintegration performance and packaging needs.
  • the speed of disintegration for fast dissolving tablets compared with a standard tablet is achieved by formulating using water soluble excipients, or superdisintegrate or effervescent components, to allow rapid penetration of water into the core of the tablet.
  • Oral thin films are a group of flat films which are administered into the oral cavity.
  • Dissolvable OTF have evolved over the past few years from confection and oral care markets in the form of breath strips and become a widely accepted form by consumers for delivering vitamins and personal care products.
  • OTF are useful technology for systemic delivery of APIs for over-the-counter (OTC) medications and for prescription drugs. For further details, it can be referred to R Bala, Int J Pharm Investig. 2013, 3(2), 67-76.
  • Further techniques for the oral administration of a drug include attaching a dosage form or a carrier device comprising a drug material to a patient's denture.
  • WO 2004/032785 discloses an applicator for applying a chemical or a medicament, which is applied on an absorbent portion of the applicator, such as a flocked end, sponge, foam or brush.
  • US 2005/0175959 relates to a system for the strategic controlled delivery of materials to the dental surfaces of the intraoral cavity.
  • the system is adapted for physical fixation onto the dental site by way of a physical property, shape, configuration and elasticity or with an adhering agent.
  • US 2012/0082950 discloses systems for intra-oral delivery of drugs, wherein said systems can be inter alia removable appliances adapted to fit over teeth on a jaw or bases and brackets and wires on both sides of the teeth.
  • US 2015/0125810 discloses a reshapable retention device for insertion at a dental site and contact with adjacent dental surfaces for the controlled delivery to the dental site of at least one material having a predetermined intraoral activity.
  • the retention device comprises at least one matrix containing the material and is adapted for physically affixing at the dental site by virtue of its shape, configuration and elasticity.
  • the retention device can be provided in form of a substrate which has the form of a sheet or a strip.
  • WO 99/60946 discloses a dental device including a matrix retainer band which comprises a translucent portion in the form of a strip of flexible translucent plastics material, the translucent portion being configured to be locatable around a tooth. Further, the band can be used in applying a medicament.
  • US 5,085,585 relates to a dental medicament applicator including a U-shaped body member having a base portion with an upstanding peripheral wall. The medicament is placed in the base portion of the applicator.
  • the pharmaceutical dosage forms of the prior art are not satisfactory in every respect and there is a demand for improved pharmaceutical dosage forms.
  • Such improved pharmaceutical dosage forms should provide improved compliance, be easy to manufacture, provide reliable and reproducible drug release and should principally be useful for local or systemic administration of a large variety of different drugs and combinations thereof.
  • Such improved pharmaceutical dosage forms should be suitable to remain in the mouth during drug delivery, i.e. for an extended period of time.
  • dosage forms which are to be fixed to the denture by means of volume expansion when being contacted with saliva.
  • volume expansion can be uncomfortable or even cause pain e.g. at the gingiva.
  • dosage form after a dosage form has been mounted to a tooth, it should not cause an unpleasant taste in the mouth of a patient, e.g. a bitter taste.
  • dosage forms which are to be fixed to the teeth by means of adhesives.
  • adhesives may contain ingredients having an unpleasant taste even when being released in minor amounts only.
  • dosage forms that are devoted to remain in the mouth during drug delivery should stay in the position to which they have been originally mounted and should not slip, shift, waggle or even fall off the tooth.
  • three-dimensional printing technology preferably fused deposition modeling, makes available pharmaceutical dosage forms comprising a mounting unit which is mountable into a dental interstice between two adjacent teeth; and a releasing unit comprising a pharmacologically active ingredient.
  • the pharmaceutical dosage form may be mounted to the teeth of the patient and may thus be positioned and remain in the oral cavity for a certain period of time providing immediate or prolonged release of the pharmacologically active ingredient.
  • Three-dimensional printing technology allows for individually adapting the shape of the pharmaceutical dosage forms to the shape of the denture (teeth and/or jar) of the individual patient by scanning said shape (negative) and by three-dimensionally printing the pharmaceutical dosage form (positive) so as to accurately fit and provide optimal patient compliance.
  • the thus preferably achieved custom-fit of the pharmaceutical dosage form according to the invention not only provides sufficient mechanical strength of the linkage and fixation to the denture in order to withstand mechanical impact e.g. by chewing or tongue movement, but additionally improves patient compliance.
  • the mounting procedure is quick and easy, as the dosage form preferably can be mounted by simply clamping the dosage form around a tooth or into a dental interstice. Once correctly positioned in the oral cavity and mounted to the dental interstice between two adjacent teeth, the patient preferably does not realize, feel or sense the pharmaceutical dosage form. Further, the dosage form preferably does not slip or shift from the position on a tooth it has been mounted to or even falls off the tooth.
  • a first aspect of the invention relates to a three-dimensionally printed pharmaceutical dosage form comprising, preferably consisting of a mounting unit which is mountable to a tooth or two adjacent teeth of a patient, preferably into a dental interstice between two adjacent teeth; and a releasing unit comprising a pharmacologically active ingredient.
  • the invention also relates to a process for the preparation of said pharmaceutical dosage form comprising a three-dimensional printing step.
  • teeth interstice is to be regarded as the space between two adjacent teeth, also referred to as "interproximal space".
  • the two adjacent teeth may be (i) both natural, (ii) both artificial or (iii) one natural the other artificial.
  • the interstice between the two adjacent (remaining) teeth may be enlarged, i.e. the denture may be deficient.
  • Teeth may be deciduous teeth, incisors, canine tooth or molars.
  • the pharmaceutical dosage form according to the invention comprises a mounting unit which is mountable to a tooth or two adjacent teeth.
  • the tooth or the two adjacent teeth may be natural or artificial or partly artificial.
  • the tooth or the two adjacent teeth may have a dental filling, an inlay or a tooth crown.
  • the mounting unit preferably serves the purpose of mounting the pharmaceutical dosage form in a manner that it may not slip or shift, such that the gingiva may not be damaged by the pharmaceutical dosage form.
  • Mounting of the pharmaceutical dosage form to a tooth or to a plurality of teeth, preferably two adjacent teeth, is preferably achieved mechanically, preferably as custom-fit which preferably functions as a form-fit, positive fitting, positive locking, form-lock fixing, or the like.
  • the mounting unit may be provided with adhesive properties, e.g. by manufacturing at least a surface of the mounting unit form a material that becomes adhesive when being contacted with saliva.
  • the mounting unit is mountable into a dental interstice between two adjacent teeth.
  • the two adjacent teeth may be (i) both natural, (ii) both artificial or (iii) one natural the other artificial.
  • the interstice between the two adjacent (remaining) teeth may be enlarged.
  • the shortest distance between the two adjacent teeth is not more than 2 mm.
  • the mounting unit exhibits a certain degree of flexibility and a shape such that a portion thereof, preferably a base, may be clamped into the dental interstice between two adjacent teeth. The thus achieved connection or linkage of the pharmaceutical dosage form to the denture of the patient provides sufficient strength such that the pharmaceutical dosage form may remain in this position within the oral cavity for an extended period of time, preferably for several hours.
  • the mounting unit comprises a material which is insoluble or poorly soluble in saliva.
  • the purpose of the mounting unit preferably is to ensure fixation of the pharmaceutical dosage form in the oral cavity for an extended period of time.
  • the mounting unit preferably remains intact for an extended period of time during which the releasing unit may release the pharmacologically active ingredient.
  • the mounting unit is composed of a material that can be three-dimensionally printed, preferably by fused deposition modeling. Methods to distinguish such dosage forms from other dosage forms that have been manufactured by conventional techniques such as direct compression, extrusion, wet granulation, dry granulation, and the like are known to the skilled person and include but are not limited to microscopy and electron microscopy.
  • the mounting unit is made from a different material as the releasing unit.
  • the mounting unit does not comprise the pharmacologically active ingredient.
  • the mounting unit is made from the same material as the releasing unit, with the only difference that the material from which the mounting unit is made does not contain pharmacologically active ingredient.
  • the mounting unit comprises or is composed of a rigid material.
  • rigidity of an object is its ability to resist deformation in response to an applied force, i.e. the shape of the object does not change when a force is applied to the object.
  • the mounting unit comprises a rigid material that can resist deformation in response to an applied force of at least 200 N, more preferably at least 250 N, still more preferably at least 300 N, yet more preferably at least 350 N, even more preferably at least 400 N, most preferably at least 450 N, and in particular at least 500 N.
  • the mounting unit comprises or is composed of a flexible material, preferably an elastic material.
  • a flexible material preferably an elastic material.
  • the preferred flexible and elastic property may facilitate and improve mounting of the mounting unit to the tooth or the two adjacent teeth.
  • the shape of the object before the expansion process may also differ from the shape of the object at the end of the expansion process.
  • the mounting unit comprises a material that maintains its shape upon contact with saliva.
  • the mounting unit is a longitudinally extended element, preferably like a thread, which is connected on one of its ends to a release unit (preferably the one facing the tongue) or which is connected on both of its ends to releasing units.
  • the mounting unit exhibits a certain degree of flexibility and elasticity so that it may be easily positioned into the interstice of two adjacent teeth, possibly by pushing, pressing, and/or pulling.
  • the dimensions of the mounting unit depend upon the location in the mouth of the patient where the pharmaceutical dosage form is to be positioned.
  • the length of the mounting unit is preferably within the range of not more than 0.5 cm.
  • the length of the mounting unit is preferably within the range of more than 0.5 cm, e.g. of about 1 cm.
  • the mounting unit is made from a flexible and elastic material and its length is shorter than the dental interstice between the two adjacent teeth where the pharmaceutical dosage form is to be mounted.
  • the length of the elastic mounting unit is not more than about 95%, more preferably not more than about 90%, still more preferably not more than about 85%>, yet more preferably not more than about 80%> of the distance that is needed in order to mount the pharmaceutical dosage form to the dental interstice between the two adjacent teeth.
  • the length of the mounting unit may transiently be extended by pulling, and once the pharmaceutical dosage form has been properly mounted, the restoring force of the elastic material provides additional fixation of the pharmaceutical dosage form to the denture.
  • the pharmaceutical dosage form according to the invention comprises a releasing unit comprising a pharmacologically active ingredient.
  • the releasing unit is connected to the mounting unit and serves the purpose of releasing the pharmacologically active ingredient in a well-defined, controlled and safe manner.
  • the releasing unit preferably has a predetermined surface that is exposed to saliva when the pharmaceutical dosage form is mounted to the denture. The release kinetics of the pharmacologically active ingredient into the saliva may then be controlled by adjustable factors, especially by the area of said surface and by the material from which the releasing unit is manufactured.
  • the releasing unit preferably provides comfort and a good mouth feeling.
  • the surface of the releasing unit is smooth, flexible and does not contain sharp edges, rims or flanges.
  • the gingiva may not be damaged by the pharmaceutical dosage form and the releasing unit, respectively.
  • the releasing unit comprises an erodible matrix material, preferably a material that is soluble in saliva, in which the pharmacologically active ingredient is embedded.
  • soluble in saliva preferably means at least slightly soluble (10 to 1 g/L), more preferably at least sparingly soluble (33 to 10 g/L), still more preferably at least soluble (100 to 33 g/L), yet more preferably at least freely soluble (1000 to 100 g/L), even more preferably at least very soluble (greater or equal to 1000 g/L), in each case according to USP 23.
  • Suitable erodible matrix materials are known to the skilled person and besides the pharmacologically active ingredient may comprise a mixture of excipients such as fillers, binders, disintegrants, gelling agents, plasticizers, and the like.
  • the releasing unit is composed of a material that can be three-dimensionally printed, preferably by fused deposition modeling.
  • the release unit provides release of the pharmacologically active ingredient to the teeth. This may be achieved by shaping the pharmaceutical dosage form such that the surface of the release unit which provides release of the pharmacologically active ingredient comes into contact with the surface of the teeth.
  • the release unit provides release of the pharmacologically active ingredient to the gingiva. This may be achieved by shaping the pharmaceutical dosage form such that the surface of the release unit which provides release of the pharmacologically active ingredient comes into contact with the gingiva, the cheek pouch, and/or the palate.
  • the release unit provides release of the pharmacologically active ingredient into the saliva which is then subsequently distributed in the oral cavity and finally swallowed by the patient. This may be achieved by shaping the pharmaceutical dosage form such that the surface of the release unit which provides release of the pharmacologically active ingredient comes into contact with saliva.
  • the release unit of the pharmaceutical dosage form has a predetermined surface that under physiological conditions comes into contact with the saliva and said predetermined surface preferably comprises two areas:
  • a passive area that comprises or is covered with a non-erodible material that is essentially insoluble in saliva.
  • the size of the drug releasing area can be adjusted to the desired release profile that is to be achieved by the pharmaceutical dosage form according to the invention.
  • the larger the drug releasing area the faster the release of the pharmacologically active ingredient.
  • Providing the pharmaceutical dosage form according to the invention with a drug releasing area and with a passive area is advantageous with respect to a reproducible, adjustable and controlled drug release.
  • the drug releasing area comprises an erodible matrix material in which the pharmacologically active ingredient is embedded.
  • the drug releasing area amounts to at most 99%, or at most 98%>, or at most 97%o, or at most 96%>, or at most 95%>; more preferably at most 94%>, or at most 93%>, or at most 92%>, or at most 91%, or at most 90%o; still more preferably at most 89%o, or at most 88%o, or at most 87%o, or at most 86%>, or at most 85%>; yet more preferably at most 84%>, or at most 83 %>, or at most 82%>, or at most 81%, or at most 80%o; even more preferably at most 89%o, or at most 88%o, or at most 87%o, or at most 86%>, or at most 85%>; most preferably at most 84%>, or at most 83%o, or at most 82%>, or at most 81%, or at most 80%o; and in particular at most 79%o, or at most 78%o, or at most 77%
  • the mounting unit comprises a material which is insoluble or poorly soluble in saliva.
  • the mounting unit comprises a material which is erodible in saliva, preferably soluble in saliva.
  • the mounting unit and the releasing unit are composed of different three-dimensionally printed materials.
  • the mounting unit is composed of a three-dimensionally printed material not containing the pharmacologically active ingredient and preferably the releasing unit is composed of a three- dimensionally printed material containing the pharmacologically active ingredient.
  • the mounting unit and the releasing unit are composed of the same three-dimensionally printed material, with the only difference that the three-dimensionally printed material from which the mounting unit is made does not contain the pharmacologically active ingredient.
  • the releasing unit is composed of a three-dimensionally printed material containing the pharmacologically active ingredient, which preferably is an analgesic.
  • the pharmaceutical dosage form according to the invention provides prolonged release of the pharmacologically active ingredient.
  • the pharmaceutical dosage form according to the invention provides immediate release of the pharmacologically active ingredient.
  • the pharmaceutical dosage form according to the invention provides prolonged release of the pharmacologically active ingredient.
  • the pharmaceutical dosage form according to the invention exhibits a release profile according to any of embodiments A 1 to A 8 as compiled in the table here below:
  • the pharmaceutical dosage form according to the invention provides immediate release of the pharmacologically active ingredient.
  • the embodiment is particularly preferred when the pharmaceutical dosage form provides simultaneous drug release for systemic as well as local administration.
  • the pharmaceutical dosage form according to the invention exhibits a release profile according to any of embodiments B 1 to B 8 as compiled in the table here below:
  • the administration of the pharmacologically active ingredient from the pharmaceutical dosage form according to the invention may proceed locally and/or systemically, in the latter case orally (perorally) or buccally or sublingually.
  • the pharmaceutical dosage form according to the invention is for local administration of the pharmacologically active ingredient. Administration may be topical.
  • the pharmaceutical dosage form according to the invention is for systemic administration of the pharmacologically active ingredient; preferably for peroral or buccal or sublingual administration of the pharmacologically active ingredient.
  • the pharmacologically active ingredient that is contained in the pharmaceutical dosage form is not particularly limited.
  • the pharmaceutical dosage form may contain a single pharmacologically active ingredient or a combination of two or more pharmacologically active ingredients or a combination of two or more derivatives of one and the same pharmacologically active ingredients such as different salts.
  • the pharmacologically active ingredient may be anyone for which buccal-systemic or local administration is desirable.
  • the pharmaceutical dosage form according to the invention provides local administration as well as systemic administration of one and the same pharmacologically active ingredient or of two different pharmacologically active ingredients.
  • the pharmaceutical dosage form may provide local administration of a local anesthetic (first pharmacologically active ingredient) and simultaneously - according to a corresponding or according to a different release kinetics - systemic administration of an analgesic.
  • the pharmaceutical dosage form comprises a single releasing unit
  • the two different pharmacologically active ingredients are contained both in the releasing unit.
  • the two different pharmacologically active ingredients may be distributed over the releasing units in various manners, e.g.
  • the entire amount of the first pharmacologically active ingredient may be contained in the first releasing unit, and the entire amount of the second pharmacologically active ingredient may be contained in the second releasing unit;
  • first pharmacologically active ingredient may be contained in the first releasing unit, and the remainder of the first pharmacologically active ingredient as well as the entire amount of the second pharmacologically active ingredient may be contained in the second releasing unit;
  • the entire amount of the first pharmacologically active ingredient as well as a portion of the second pharmacologically active ingredient may be contained in the first releasing unit, and the remainder of the second pharmacologically active ingredient may be contained in the second releasing unit;
  • first pharmacologically active ingredient as well as a portion of the second pharmacologically active ingredient may be contained in the first releasing unit, and the remainder of the first pharmacologically active ingredient as well as the remainder of the second pharmacologically active ingredient may be contained in the second releasing unit.
  • the pharmacologically active ingredient is selected from analgesics, stimulants, tranquilizers, narcotics and anesthetics.
  • the invention also relates to the pharmaceutical dosage form according to the invention for use in the treatment of a disease or disorder, preferably of pain.
  • the invention also relates to a method of treating a disease or disorder, preferably pain comprising the step of mounting a pharmaceutical dosage according to the invention into a dental interstice between two adjacent teeth of a patient in need of such treatment.
  • the pharmacologically active ingredient is for the treatment of diseases or disorders of the nervous system [ATC code N]; more preferably an analgesic [ATC code N02], or an antiepileptic [ATC code N03], or a psychoanaleptic [ATC code N06]; most preferably an opioid [ATC code N02A], an antiepileptic [ATC code N03A], or a psychostimulant [ATC code N06B].
  • Preferred pharmacologically active ingredients include but are not limited to asenapine, alfentanil, sufentanil, fentanyl, remifentanyl, bupreno hine, butorphanol, codeine, diphenoxylate, hydrocodone, hydromorphone, oxycodone, oxymorphone, levorphanol, levallorphan, loperamide, meperidine, morphine, naloxone, nalbuphine, nalmefene, ⁇ ⁇ , naltrexone, lidocaine, prochlorperazine, nitroglycerine, testosterone, nicotine, midazolam, and the like.
  • the total weight of the pharmaceutical dosage form according to the invention is not particularly limited.
  • the pharmaceutical dosage form according to the invention has a total weight within the range of 100 ⁇ 50 mg, or 200 ⁇ 100 mg, or 300 ⁇ 150 mg, or 400 ⁇ 200 mg, or 500 ⁇ 250 mg, or 600 ⁇ 300 mg, or 700 ⁇ 350 mg, or 800 ⁇ 400 mg, or 900 ⁇ 450 mg, or 1000 ⁇ 500 mg, or 1200 ⁇ 600 mg, or 1400 ⁇ 700 mg, or 1600 ⁇ 800 mg, or 1800 ⁇ 900 mg, or 2000 ⁇ 1000 mg, or 2500 ⁇ 1250 mg, or 3000 ⁇ 1500 mg.
  • the shape of the pharmaceutical dosage form according to the invention is not particularly limited, as long as it may be mounted to the dental interstice between two adjacent teeth, or to more than one dental interstice between several adjacent teeth, by means of the mounting unit.
  • the mounting is preferably accurate and flush fitted. This may principally be achieved by providing a variety of different shapes such that the patient may try which shape fits best at a given position in the denture.
  • the shape of the pharmaceutical dosage form is individually designed and adapted for an individual patient.
  • the pharmaceutical dosage form comprises a section having a shape that corresponds, preferably is individually adapted to correspond, to at least a section of the shape of the tooth or the two adjacent teeth.
  • the mounting unit or the releasing unit comprises a section having a shape that corresponds, preferably is individually adapted to correspond, to at least a section of the shape of the tooth or the two adjacent teeth.
  • a shape that corresponds is to be understood in the sense that the shape of a section of the dosage form is the complement or counterpart of the shape of a section of the tooth or the two adjacent teeth.
  • the section of the dosage form preferably of the mounting unit and/or of the releasing unit, preferably has a concave shape that matches with the convex shape of the section of the tooth.
  • the pharmaceutical dosage form preferably the mounting unit and/or the releasing unit, comprises a section having a surface that provides, preferably is individually adapted to provide, an intimate contact area with a surface of a section of at least one side of the tooth.
  • the dosage form comprises a section that is individually formed and shaped such that its surface preferably provides a maximal contact interface with the surface of at least a section of the tooth or the two adjacent teeth.
  • the surface of the section of the tooth has a convex shape
  • the surface of the section of the dosage form, preferably of the mounting unit and/or of the releasing unit is preferably a concave complement or counterpart to fit in intimate contact therewith.
  • a tooth can be described by the five sides on the surface of the tooth which are:
  • the mesial (anterior) side which is the side closest to the middle line of the face (mandibular symphysis),
  • distal (posterior) side which is the side furthest from to the middle line of the face (mandibular symphysis);
  • the surface of the section of the pharmaceutical dosage form preferably of the mounting unit and/or of the releasing unit, provides, preferably is individually adapted to provide, an intimate contact area with a surface of a section of the inner (lingual, palatal) side, and/or the mesial (anterior) side, and/or the outer (buccal, labial, vestibular) side, and/or the distal (posterior) side of the tooth.
  • the intimate contact area is at least 2.0 mm 2 , preferably at least 3.0 mm 2 , more preferably at least 4.0 mm 2 , still more preferably at least 5.0 mm 2 , yet more preferably at least 6.0 mm 2 , even more preferably at least 7.0 mm 2 , most preferably at least 8.0 mm 2 , and in particular at least 9.0 mm 2 .
  • the pharmaceutical dosage form preferably the mounting unit and/or the releasing unit, comprises
  • first section having a first surface that provides, preferably is individually adapted to provide, a first intimate contact area with a surface of a section of at least one side of the tooth;
  • a second section having a second surface that provides, preferably is individually adapted to provide, a second intimate contact area with a surface of a section of at least one side of the adjacent tooth.
  • the first surface of the first section provides, preferably is individually adapted to provide, a first intimate contact area with the inner (lingual, palatal) side, and/or the mesial (anterior) side, and/or the outer (buccal, labial, vestibular) side, and/or the distal (posterior) side of the tooth; and
  • the second surface of the second section provides, preferably is individually adapted to provide, a second intimate contact area with the inner (lingual, palatal) side, and/or the mesial (anterior) side, and/or the outer (buccal, labial, vestibular) side and/or the distal (posterior) side of the adjacent tooth.
  • the first intimate contact area together with the second intimate contact area is at least 2.0 mm 2 , preferably at least 3.0 mm 2 , more preferably at least 4.0 mm 2 , still more preferably at least 5.0 mm 2 , yet more preferably at least 6.0 mm 2 , even more preferably at least 7.0 mm 2 , most preferably at least 8.0 mm 2 , and in particular at least 9.0 mm 2 .
  • a custom-fit of the pharmaceutical dosage form according to the invention to the denture (teeth and/or jar), i.e. the tooth or the two adjacent teeth, of the patient can be achieved.
  • said custom-fit functions as a form-fit, positive fitting, positive locking, form-lock fixing, or the like.
  • the mounting unit is mechanically mountable to the tooth or the two adjacent teeth.
  • the mounting unit is mechanically mountable to the tooth or the two adjacent teeth without the employment of adhesives, or wires, or brackets, or tapes, or elastic bands, which in each case would provide for fixation or adhesion on the tooth or the two adjacent teeth.
  • the mounting unit is mountable to the tooth or the two adjacent teeth by a custom-fit.
  • custom-fit means personalized with regard to shape and size.
  • the custom-fit dosage form is modified with regard to some of its characteristics according to the patients' requirements, especially its geometric characteristics.
  • the custom-fit dosage form offers one-of-a-kind dosage forms that, due to their intrinsic characteristics and medical use, can be totally adapted to geometric characteristics in order to meet the patients' requirements.
  • custom-fit means that the shape of at least a portion of the pharmaceutical dosage form, particularly at least a portion of the shape of the mounting unit, is individually adapted to the shape of at least a portion of the tooth or the two adjacent teeth of a patient so that the pharmaceutical dosage form fits accurately at the determined tooth or two adjacent teeth.
  • a custom-fit of the pharmaceutical dosage form is achieved by a section of the dosage form having a shape that corresponds, preferably is individually adapted to correspond, to at least a section of the shape of the tooth or the two adjacent teeth.
  • the mounting unit is mountable to the tooth by clamping the mounting unit around the tooth, preferably by clamping the mounting unit around at least two sides of the tooth.
  • the mounting unit is mountable to the tooth by clamping the mounting unit around the tooth, wherein the mounting unit is clamped around
  • the mounting unit is mountable to the tooth by clamping the mounting unit into a dental interstice between the two adjacent teeth.
  • dental interstice is also referred to as “interproximal space” and describes the space between two adjacent teeth, i.e. the space between the distal side of one tooth and the mesial side of the adjacent other tooth or the mesial side of one tooth and the distal side of the adjacent other tooth, respectively.
  • the mounting unit is mountable to the tooth by clamping the mounting unit into a dental interstice between the two adjacent teeth and at least one outer side or at least one inner side of one of the two adjacent teeth.
  • the mounting unit is clamped into a dental interstice between two adjacent teeth and the two outer sides or the two inner sides of the two adjacent teeth.
  • the mounting unit is clamped into a dental interstice between the two adjacent teeth and one outer side of one of the two adjacent teeth and one inner side of the other of the two adjacent teeth.
  • clamping of the mounting unit is achievable by pressing (pushing, pinching, shifting, slipping) the mounting unit in a vertical direction around the tooth or into the dental interstice between the two adjacent teeth.
  • horizontal or vertical refers to directions of a patient sitting in an upright position.
  • a vertical directions means in a direction upwards to the upper jaw or downward to the lower jaw, respectively.
  • a horizontal direction means from the inside of the lips or cheek in the direction of the tongue or from the tongue in the direction of the lips or cheek, respectively.
  • clamping of the mounting unit is achievable by pressing the mounting unit in a vertical direction when the mounting unit is clamped around
  • clamping of the mounting unit is achievable by pressing (pushing, pinching, shifting, slipping) the mounting unit in a horizontal direction around the tooth or into the dental interstice between the two adjacent teeth.
  • clamping of the mounting unit is achievable by pressing the mounting unit in a horizontal direction when the mounting unit is clamped around
  • Conventional dosage forms are mounted to a tooth by means of volume expansion, often upon contact with saliva, of the conventional dosage form or of a part of said dosage form such that the expanded volume provides for fixing of the dosage form on the tooth or in a dental interstice.
  • Other mounting mechanisms for conventional dosage forms to a tooth involve the employment of adhering agents, or wires, or brackets, or tapes, or elastic bands, which provide for fixation or adhesion on a tooth.
  • the details of such conventional mounting mechanisms for mounting a conventional dosage form to a tooth are known to a skilled person.
  • the mounting unit is mountable to the tooth or the two adjacent teeth by a mounting mechanism which does not involve volume expansion of the pharmaceutical dosage form or of an element thereof.
  • the mounting mechanism does not involve volume expansion of the pharmaceutical dosage form or an element thereof such that the expanded volume provides for fixing the mounting unit in the dental interstice or provides for fixing the mounting around the tooth.
  • the mounting mechanism does not involve volume expansion of the pharmaceutical dosage form or of an element thereof upon contact with saliva.
  • the pharmaceutical dosage form does not substantially swell upon contact with saliva in the oral cavity.
  • "not substantially swell” means that upon contact with saliva, the volume of the pharmaceutical dosage form does not increase by more than 1.0 vol.-%, or more than 1.2 vol.-%, or more than 1.4 vol.-%, or more than 1.6 vol.-%, or more than 1.8 vol.-%, or more than 2.0 vol.-%, or more than 2.2 vol.-%, or more than 2.4 vol.-%, or more than 2.6 vol.-%, or more than 2.6 vol.-%, in each case compared to its original volume prior to contact with saliva.
  • the pharmaceutical dosage form maintains its volume upon contact with saliva.
  • the mounting unit is mountable to the tooth or the two adjacent teeth by a mounting mechanism which does not involve adhesion of the pharmaceutical dosage form to the tooth, to the two adjacent teeth, or to gingiva.
  • the mounting mechanism does not involve applying an adhesive to the tooth, to the two adjacent teeth or to the gingiva or to the dosage form prior to mounting of the mounting unit.
  • the mounting mechanism does not involve applying an adhesive prior to mounting of the mounting unit.
  • the mounting unit is mountable to the tooth or the two adjacent teeth by a mounting mechanism which does not involve a material which has not been three-dimensionally printed.
  • said material which has not been three-dimensionally printed is selected form the group consisting of elastomers, rubber and metal.
  • the mounting unit comprises a distal element, a proximal element, and a base, wherein the base connects the distal element with the proximal element.
  • the two adjacent teeth to which the mounting unit is mountable each have an inner (lingual, palatal) side, an mesial (anterior) side, an outer (buccal, labial, vestibular) side, and a distal (posterior) side
  • the base preferably is mountable to the dental interstice between the two adjacent teeth in a manner such that the distal element is positioned at the outer side of the adjacent teeth, the proximal element is positioned at the inner side of the adjacent teeth, and the base is positioned at the dental interstice between the adjacent teeth.
  • the base of the mounting unit is mountable to the dental interstice between the two adjacent teeth in a manner such that the distal element is in intimate contact with the outer (buccal, labial, vestibular) side of the teeth.
  • the distal element comprises a section having a surface that provides an intimate contact area of the distal element with the surface of a section of the outer side of the two adjacent teeth.
  • said intimate contact area of the distal element is at least 2.0 mm 2 , preferably at least 3.0 mm 2 , more preferably at least 4.0 mm 2 , still more preferably at least 5.0 mm 2 , yet more preferably at least 6.0 mm 2 , even more preferably at least 7.0 mm 2 , most preferably at least 8.0 mm 2 , and in particular at least 9.0 mm 2 .
  • the base of the mounting unit is mountable to the dental interstice between the two adjacent teeth in a manner such that the proximal element is in intimate contact with the inner (lingual, palatal) side of the teeth.
  • the proximal element comprises a section having a surface that provides an intimate contact area of the proximal element with the surface of a section of the inner side of the two adjacent teeth.
  • said intimate contact area of the proximal element is at least 2.0 mm 2 , preferably at least 3.0 mm 2 , more preferably at least 4.0 mm 2 , still more preferably at least 5.0 mm 2 , yet more preferably at least 6.0 mm 2 , even more preferably at least 7.0 mm 2 , most preferably at least 8.0 mm 2 , and in particular at least 9.0 mm 2 .
  • the base of the mounting unit is mountable to the dental interstice between the two adjacent teeth in a manner such that the base intimately fills the dental interstice between the adjacent teeth.
  • the dental interstice - also referred to as interproximal space - is the space between two adjacent teeth, which is usually bathed with saliva or any other liquid which is in the oral cavity.
  • the base of the mounting unit is not a hollow object and has a shape that corresponds to at least a section of the shape of at least one of the two sides of the adjacent teeth which flank the dental interstice, i.e. the mesial (anterior) side of the tooth and/or the distal (posterior) side of the adjacent other tooth or the distal (posterior) side of the tooth and/or the mesial (anterior) side of the adjacent other tooth.
  • the base of the mounting unit comprises a section having a surface that provides an intimate contact area of the proximal element with the surface of a section of the mesial (anterior) side of the tooth and/or the distal (posterior) side of the adjacent tooth or with the surface of a section of the distal (posterior) side of the tooth and/or the mesial (anterior) side of the adjacent tooth.
  • said intimate contact area of the base is at least 2.0 mm 2 , preferably at least 3.0 mm 2 , more preferably at least 4.0 mm 2 , still more preferably at least 5.0 mm 2 , yet more preferably at least 6.0 mm 2 , even more preferably at least 7.0 mm 2 , most preferably at least 8.0 mm 2 , and in particular at least 9.0 mm 2 .
  • the distal element and/or the proximal element and/or the base has a shape that is adapted, preferably individually adapted to, at least a section of the shape of the two adjacent teeth and to at least a section of the shape of the dental interstice, respectively.
  • a shape that is adapted in this context preferably is a shape which is the complement or counterpart of another shape.
  • the section of the distal element and/or the proximal element and/or the base preferably has/have a concave shape that matches with the convex shape of the section of the two adjacent teeth.
  • the distal element, the proximal element and the base may comprise the same material or different materials.
  • the distal element as well as the proximal element of the mounting unit may comprise a material that is softer than the material from which the base is formed.
  • the distal element, the proximal element and the base are composed of three-dimensionally printed materials.
  • the distal element and/or the proximal element are composed of a different three-dimensionally printed material than the base.
  • the distal element, the proximal element and the base are composed of the same three-dimensionally printed materials.
  • the pharmaceutical dosage form according to the invention comprises a distal releasing unit connected to the distal element; and/or a proximal releasing unit connected to the proximal element.
  • the distal releasing unit and the proximal releasing unit may comprise different pharmacologically active ingredients and/or may provide different release kinetics of the pharmacologically active ingredient.
  • the distal releasing unit and/or the proximal releasing unit are composed of three-dimensionally printed materials.
  • the distal releasing unit and/or the proximal releasing unit are composed of a different three-dimensionally printed material than the distal element and/or the proximal element and/or the base.
  • the distal releasing unit and/or the proximal releasing unit are composed of a three- dimensionally printed material containing a pharmacologically active ingredient.
  • said pharmacologically active ingredient is an analgesic.
  • the distal releasing unit and/or the distal element and/or the proximal releasing unit and/or the proximal element are composed of the same three-dimensionally printed materials, with the only difference that the three-dimensionally printed material from which the distal element and/or the proximal element is/are made does not contain pharmacologically active ingredient.
  • the pharmaceutical dosage form comprises no element selected from flexible films, flexible sheets, and discs.
  • films or sheets have uniformly flat surfaces.
  • the surfaces of said films or sheets do not correspond to or are not individually adapted to correspond, to the surface of a section of at least one side of a tooth and/or the surface of a section of at least one side of the adjacent tooth.
  • the surface of discs may have a concave or convex shape, but the surface does also not individually correspond to the individual surface of at least one side of a tooth and/or the surface of at least one side of the adjacent tooth.
  • the pharmaceutical dosage form does not assume the shape of a dental brace or dental bracket or a mouthgard (the latter term is synonymous to mouth protector, or mouth piece, or gumshield, or gumguard, or nightguard, or occlusal splint, or bite splint, or bite plane).
  • a mouthgard preferably is made of a hard polymeric material and covers all teeth of the upper jaw or lower jaw, respectively.
  • Dental braces or dental brackets are devices used in orthodontics that may help to position teeth.
  • the pharmaceutical dosage form does not assume the shape of a dental brace or dental bracket which is permanently attached to the teeth.
  • the pharmaceutical dosage form does not assume the shape of a dental brace or dental bracket which is not permanently attached to the teeth, preferably the shape of a dental brace or dental bracket which is made of metal hooks that surround the teeth and are enclosed by a plate, preferably made of a polymeric material, shaped to fit the patient's palate.
  • the pharmaceutical dosage form according to the invention is for use in therapy, wherein the pharmaceutical dosage form is mounted to one or more dental interstices or adjacent teeth and thus positioned in the oral cavity for at least 3 hours, or for at least 3.5 hours, or for at least 4 hours, or for at least 4.5 hours, or for at least 5 hours, or for at least 5.5 hours, or for at least 6 hours, or for at least 6.5 hours, or for at least 7 hours, or for at least 7.5 hours, or for at least 8 hours, or for at least 8.5 hours, or for at least 9 hours, or for at least 9.5 hours, or for at least 10 hours, or for at least 10.5 hours, or for at least 11 hours, or for at least 11.5 hours, or for at least 12 hours, or for at least 14 hours, or for at least 16 hours, or for at least 18 hours, or for at least 20 hours, or for at least 22 hours, or for at least 24 hours.
  • Figure 1 schematically illustrates a comparatively simple embodiment of the pharmaceutical dosage form (1) according to the invention comprising mounting unit (2) and releasing unit (3).
  • Figure 2 schematically illustrates the part of a denture of a jaw comprising a tooth (4) and an adjacent tooth (5).
  • Five sides of the tooth (4) are schematically illustrated in Figure 2, said five sides are:
  • the mesial side (4b) which is synonymous to the anterior side, which is the side closest to the middle line of the face (mandibular symphysis),
  • distal side (4d) which is synonymous to the posterior side, which is the side furthest from to the middle line of the face (mandibular symphysis);
  • Figure 2 schematically illustrates five sides of the adjacent tooth (5), said five sides are:
  • the mesial side (5b) which is synonymous to the anterior side, which is the side closest to the middle line of the face (mandibular symphysis),
  • distal side which is synonymous to the posterior side, which is the side furthest from to the middle line of the face (mandibular symphysis);
  • Figure 2 schematically illustrates a dental interstice (6) between two adjacent teeth, said dental interstice (6) is flanked by the distal side (4d) of the tooth and the mesial side (5b) of the adjacent tooth.
  • Figure 3 schematically illustrates how the pharmaceutical dosage form (1) according to Figure 1 can be mounted to the dental interstice (6) between two adjacent teeth (4) and (5) by clamping the mounting unit (2) therein.
  • Figure 4 schematically illustrates other preferred embodiments of the pharmaceutical dosage form (1) according to the invention.
  • Figure 4A shows a pharmaceutical dosage form (1), wherein the mounting unit (2) comprises a distal element (21), a proximal element (22), and a base (23), wherein the base (23) connects the distal element (21) with the proximal element (22).
  • a distal releasing unit (31) is connected to the distal element (21) .
  • Figure 4B shows an embodiment where a proximal releasing unit (32) is connected to the proximal element
  • Figure 4C shows an embodiment comprising two release units where a distal releasing unit (31) is connected to the distal element (21) and a proximal releasing unit (32) is connected to the proximal element (22).
  • Figure 5 schematically illustrates how the pharmaceutical dosage form (1) according to Figure 4 can be mounted to the dental interstice (6) between two adjacent teeth (4) and (5) by clamping the mounting unit (2) therein.
  • FIG. 6 schematically illustrates an alternative shape of the pharmaceutical dosage form (1) where the mounting unit (2) comprises two opposite bases (23 a) and (23b) that are each clamped into the dental interstices (6) of two adjacent teeth (4) and (5).
  • Figure 7 illustrates an alternative shape of the pharmaceutical dosage form (1) where the denture of the patient is deficient, as one tooth is missing.
  • the mounting unit (2) is nonetheless mounted into a dental interstice (6) between two adjacent teeth (4) and (5) thereby bridging the gap that is left by the missing tooth.
  • Figure 8 illustrates an alternative shape of the pharmaceutical dosage form (1) where the mounting unit (2) is not mounted into a dental interstice (6) between two adjacent teeth, but to a single tooth (4) at the end of the jar.
  • the mounting unit (2) assumes a shape that resembles a horseshoe and can be clamped around the tooth (4).
  • Mechanical mounting is achieved by a custom-fit (form-fit).
  • Figure 9 illustrates an alternative shape of the pharmaceutical dosage form comprising two mounting units (2a) and (2b) which are each mountable into a dental interstice (6) between two adjacent teeth (4) and (5). Mechanical mounting is achieved by a custom-fit (form-fit).
  • Another aspect of the invention relates to a process for the preparation of a pharmaceutical dosage form according to the invention as described above, said process comprising a three-dimensional printing step. It has been surprisingly found that pharmaceutical dosage forms according to the invention can be manufactured by three-dimensional printing technologies.
  • the process comprises the step of
  • step (b) three-dimensionally printing the pharmaceutical dosage form with a shape that accurately fits into the dental interstice as scanned in step (a).
  • Scanning step (a) may involve the use of a laser. Suitable techniques are known to the skilled person and are commercially available. Preferably, the scanning step (a) involves employing cone beam computed tomography. The result of scanning step (a) is preferably used in order to calculate the appropriate shape of the pharmaceutical dosage form to be printed in step (b). Suitable computer software is also commercially available. [0129] Preferably, the scanning step (a) involves determining at least a section of the shape and/or the surface of a tooth or two adjacent teeth of a patient, to which the pharmaceutical dosage form is to be mounted.
  • the scanning step (a) involves determining at least a section of the shape and/or the surface of the distal side of a tooth and the mesial side of the other adjacent tooth or the mesial side of a tooth and the distal side of the other adjacent tooth, respectively.
  • the pharmaceutical dosage form is designed and/or printed such that it comprises a section having a shape that corresponds to at least a section of the shape of the tooth or the two adjacent teeth determined in the scanning step (a).
  • the three-dimensional printing step involves fused deposition modeling.
  • Machines for fused deposition modeling are commercially available.
  • the machines may dispense multiple materials to achieve different goals: For example, one material may be used to build up the pharmaceutical dosage form and another material may be used to build up a soluble support structure.
  • one material may be used to build up the pharmaceutical dosage form and another material may be used to build up a soluble support structure.
  • the pharmaceutical dosage form is produced by extruding small flattened strings of molten material to form layers as the material hardens immediately after extrusion from the nozzle.
  • a thermoplastic filament is unwound from a coil and supplies material to an extrusion nozzle which can turn the flow on and off.
  • a worm-drive may push the filament into the nozzle at a controlled rate.
  • the nozzle is heated to melt the material.
  • the thermoplastic material is heated above its glass transition temperature and is then deposited by an extrusion die.
  • the nozzle can be moved in both horizontal and vertical directions by a numerically controlled mechanism.
  • the nozzle follows a tool-path controlled by a computer-aided manufacturing (CAM) software package, and the pharmaceutical dosage form is built from the bottom up, one layer at a time.
  • Stepper motors or servo motors are typically employed to move the extrusion die.
  • the mechanism used is often an X-Y-Z rectilinear design, although other mechanical designs such as deltabot have been employed.
  • Myriad materials are commercially available, such as polylactic acid (PLA), polyamide (PA), among many others (see Ursan et al., J Am Pharm Assoc (2003) 2013, 53(2), 136.44; Prasad et al., Drug Dev Ind Pharm 2015, 1-13).
  • the three-dimensional printing step involves a powder-based three-dimensional printing technology.
  • Typical powder-based three-dimensional printing technologies include, but are not limited to, Binder Jet Technique or Selective Laser Sintering.
  • Selective Laser Sintering is a three-dimensional printing technique that involves sintering powdered forms of e.g. thermoplastic materials by a high-power laser beam layer-by- layer.
  • a first step of a three-dimensional printing step involving selective laser sintering a thin layer of powder is deposited on a build tray.
  • the laser which is levelled with a roller, heats the powder particles and fuses them to a solid layer.
  • the build tray moves downward and a new layer of powder is deposited and sintered. This procedure is repeated until the object to be printed is completed.
  • the three-dimensional printing step involves Binder Jet Technique.
  • the Binder Jet Technique employs a print head to disperse a continuous jet of a binder solution onto powder layers.
  • the binder solution binds the powder particles as it touches them.
  • a first step of the three-dimensional printing process involving Binder Jet Technique a thin layer of powder is spread over a tray, which can be moved with a roller system. Then the print head selectively disperses a continuous jet of a binder solution onto the powder on the tray, which is moved so that the powder particles are bound according to the structure that is to be printed.
  • the three-dimensional printing step involves a liquid-based three-dimensional printing technology.
  • Typical liquid-based three-dimensional printing technologies include, but are not limited to stereolithography (SL or SLA) or PolyJet (Multijet) printing technology.
  • Poly Jet printing technology is performed by jetting photopolymer materials in ultra-thin layers onto a build tray layer-by-layer, wherein each layer is cured by UV light immediately after it has been jetted.
  • the three-dimensional printing step involves stereolithography printing technology.
  • Stereolithography is a three-dimensional printing technique where liquid photopolymer in a vat is cured sequentially layer-by-layer by a low-power UV-laser. The laser is guided by a mirror to focus onto the surface of the liquid photopolymer in the vat.
  • the three-dimensional printing step involves printing the pharmaceutical dosage form, according to the resolution of the printing device, by depositing individual three-dimensional microstructures having an individual volume of at most 1.5 mm 3 , or of at most 1.4 mm 3 , or of at most 1.3 mm 3 , or of at most 1.2 mm 3 , or of at most 1.1 mm 3 , or of at most
  • the three-dimensional printing step comprises printing at least two different three- dimensionally printable materials, which preferably are provided each in form of filaments useful for fused deposition modeling.
  • compositions preferably three-dimensionally printable materials, that are suitable to be employed in the three-dimensional printing step according to the invention, preferably in fused deposition modeling, are preferably identical to or at least similar with pharmaceutical compositions that have been known to be suitable for processing by conventional hot melt extrusion technology.
  • Fused deposition modeling has many similarities with conventional hot melt extrusion.
  • the pharmaceutical dosage form is prepared by three-dimensionally printing at least two different pharmaceutical compositions, preferably two different three-dimensionally printable materials, that preferably are provided each in form of filaments useful for fused deposition modeling.
  • one pharmaceutical composition preferably one three-dimensionally printable material
  • the other pharmaceutical composition preferably the other three- dimensionally printable material
  • Both compositions, preferably both three-dimensionally printable materials preferably contain pharmaceutical excipients that are conventionally employed in the manufacture of pharmaceutical dosage forms, preferably in the course of three-dimensional printing technology, especially fused deposition modeling.
  • the following preferred embodiments apply to both pharmaceutical compositions, preferably both three- dimensionally printable materials, (in the following referred to as "pharmaceutical composition"), irrespective of whether they contain a pharmacologically active ingredient or not.
  • the pharmaceutical composition preferably the three-dimensionally printable material, comprises a plasticizer.
  • plasticizers are known to the skilled person. Examples include but are not limited to polyethylene glycols, such as PEG 1500 or PEG 4000 or PEG 6000; citrates, phthalates, glycerin, sugar alcohols, various contents of copolymers (e.g. ethylene vinyl acetate (EVA) / vinyl acetate (VA)), and mixtures of any of the foregoing.
  • PEG 1500 or PEG 4000 or PEG 6000 citrates, phthalates, glycerin, sugar alcohols, various contents of copolymers (e.g. ethylene vinyl acetate (EVA) / vinyl acetate (VA)), and mixtures of any of the foregoing.
  • EVA ethylene vinyl acetate
  • VA vinyl acetate
  • the content of plasticizer is preferably within the range of from 0.1 to 20 wt.-%, more preferably 5.0 to 17.5 wt.-%, still more preferably 7.5 to 15 wt.-%, relative to the total weight of the pharmaceutical composition, preferably the three-dimensionally printable material.
  • the pharmaceutical composition preferably the three-dimensionally printable material, comprises one or more matrix polymers.
  • Suitable matrix polymers are known to the skilled person. Examples include but are not limited to polylactic acid (PLA); cellulose ethers such as methylcellulose (MC), ethyl- cellulose (EC), hydroxypropylcellulose (HPC) and hydroxypropylmethylcellulose (HPMC); vinyl polymers such as polyvinylpyrrolidone (e.g. Kollidon ® PF 12) or blends thereof such as polyvinyl acetate/polyvinylpyrrolidone (e.g. Kollidon ® SR).
  • PLA polylactic acid
  • cellulose ethers such as methylcellulose (MC), ethyl- cellulose (EC), hydroxypropylcellulose (HPC) and hydroxypropylmethylcellulose (HPMC)
  • vinyl polymers such as polyvinylpyrrolidone (e.g. Kollidon ® PF 12) or blends thereof such as polyvinyl
  • Suitable polymers include ethylene vinyl acetate copolymers (EVA), polyvinyl chloride, polyethylene terephthalate (PET), polyurethanes (PU), polyamides (PA), polyacrylates and mixtures of any of the foregoing.
  • EVA ethylene vinyl acetate copolymers
  • PET polyethylene terephthalate
  • PU polyurethanes
  • PA polyamides
  • the pharmaceutical composition may consist of one or more matrix polymers.
  • the total content of matrix polymers is preferably within the range of from 5.0 to 95 wt.-%, more preferably 10 to 90 wt.-%, still more preferably 25 to 85 wt.-%, relative to the total weight of the pharmaceutical composition, preferably the three-dimensionally printable material.
  • compositions preferably three-dimensionally printable materials, that are useful for the purpose of the invention are compiled in the table here below:
  • a matrix polymer or a mixture of various matrix polymers may be stored 24 h in oven at 40 °C ; when required it may be mixed in a mortar with PEG 1500 or PEG 4000 (2 %, 5 %, 10 % by weight calculated with respect to the dry polymer).
  • Hot-melt extrusion (HME) may be carried out in a twin-screw extruder (Haake MiniLab II, Thermo Scientific , USA) equipped with an aluminum rod - shaped die ( ⁇ 2.00 mm) . Extruded rods may be calibrated and rolled up on a spool.
  • Another aspect of the invention relates to a pharmaceutical dosage form that is obtainable by the process according to the invention as described above.

Abstract

The invention relates to a three-dimensionally printed pharmaceutical dosage form comprising a mounting unit which is mountable to a tooth or two adjacent teeth of a patient, preferably into a dental interstice between two adjacent teeth; and a releasing unit comprising a pharmacologically active ingredient. The invention also relates to a process for the preparation of said pharmaceutical dosage form comprising a three-dimensional printing step.

Description

Pharmaceutical Dosage Form Mountable To a Tooth
[0001] The invention relates to a three-dimensionally printed pharmaceutical dosage form comprising a mounting unit which is mountable to a tooth or two adjacent teeth of a patient, preferably into a dental interstice between two adjacent teeth; and a releasing unit comprising a pharmacologically active ingredient. The invention also relates to a process for the preparation of said pharmaceutical dosage form comprising a three-dimensional printing step.
[0002] The oral route is one of the most preferred routes of drug administration, as it is more convenient, cost effective, and ease of administration lead to high level of patient compliance. The oral route is problematic because of the swallowing difficulty for pediatric and geriatric patients who have fear of choking. Patient convenience and compliance oriented research has resulted in the development of sophisticated drug delivery systems including e.g. fast dissolving drug delivery systems, buccal drug delivery systems, and the like.
[0003] Recently, fast dissolving drug delivery systems have started gaining popularity and acceptance as one such example with increased consumer choice, for the reason of rapid disintegration or dissolution, self- administration even without water or chewing. Fast dissolving drug delivery systems were first invented in the late 1970s as to overcome swallowing difficulties associated with tablets and capsules for pediatric and geriatric patients.
[0004] Buccal drug delivery has lately become an important route of drug administration. Various bioadhesive mucosal pharmaceutical dosage forms have been developed, which includes adhesive tablets, gels, ointments, patches, and more recently the use of polymeric films for buccal delivery, also known as mouth dissolving films. The buccal delivery serves as an excellent platform for parenteral absorption of molecules that have poor dermal penetration.
[0005] Known fast dissolve technologies can be divided in to three broad groups: (i) lyophilized systems, (ii) compressed tablet-based systems, and (iii) oral thin films (OTF).
[0006] Lyophilized systems involve taking a suspension or solution of drug with other structural excipients and, through the use of a mould or blister pack, forming tablet-shaped units. The units or tablets are then frozen and lyophilized in the pack or mould. The resulting units have a very high porosity, which allows rapid water or saliva penetration and very rapid disintegration. Dose handling capability for these systems differs depending on whether the active ingredients are soluble or insoluble drugs, with the dose capability being slightly lower for the former than for some tablet based systems. The units are capable of incorporating a range of taste masked materials and have more rapid disintegration than tablet-based systems.
[0007] Compressed tablet-based systems are produced using standard tablet technology by direct compression of excipients. Depending on the method of manufacture, the tablet technologies have different levels of hardness and friability. These results in varying disintegration performance and packaging needs. The speed of disintegration for fast dissolving tablets compared with a standard tablet is achieved by formulating using water soluble excipients, or superdisintegrate or effervescent components, to allow rapid penetration of water into the core of the tablet. These systems can theoretically accommodate relatively high doses of drug material, including taste masked coated particles.
[0008] Oral thin films are a group of flat films which are administered into the oral cavity. Dissolvable OTF have evolved over the past few years from confection and oral care markets in the form of breath strips and become a widely accepted form by consumers for delivering vitamins and personal care products. OTF are useful technology for systemic delivery of APIs for over-the-counter (OTC) medications and for prescription drugs. For further details, it can be referred to R Bala, Int J Pharm Investig. 2013, 3(2), 67-76.
[0009] Further techniques for the oral administration of a drug include attaching a dosage form or a carrier device comprising a drug material to a patient's denture.
[0010] WO 2004/032785 discloses an applicator for applying a chemical or a medicament, which is applied on an absorbent portion of the applicator, such as a flocked end, sponge, foam or brush.
[0011] US 2005/0175959 relates to a system for the strategic controlled delivery of materials to the dental surfaces of the intraoral cavity. The system is adapted for physical fixation onto the dental site by way of a physical property, shape, configuration and elasticity or with an adhering agent.
[0012] US 2012/0082950 discloses systems for intra-oral delivery of drugs, wherein said systems can be inter alia removable appliances adapted to fit over teeth on a jaw or bases and brackets and wires on both sides of the teeth.
[0013] US 2015/0125810 discloses a reshapable retention device for insertion at a dental site and contact with adjacent dental surfaces for the controlled delivery to the dental site of at least one material having a predetermined intraoral activity. The retention device comprises at least one matrix containing the material and is adapted for physically affixing at the dental site by virtue of its shape, configuration and elasticity. The retention device can be provided in form of a substrate which has the form of a sheet or a strip.
[0014] WO 99/60946 discloses a dental device including a matrix retainer band which comprises a translucent portion in the form of a strip of flexible translucent plastics material, the translucent portion being configured to be locatable around a tooth. Further, the band can be used in applying a medicament.
[0015] US 5,085,585 relates to a dental medicament applicator including a U-shaped body member having a base portion with an upstanding peripheral wall. The medicament is placed in the base portion of the applicator.
[0016] The pharmaceutical dosage forms of the prior art are not satisfactory in every respect and there is a demand for improved pharmaceutical dosage forms. Such improved pharmaceutical dosage forms should provide improved compliance, be easy to manufacture, provide reliable and reproducible drug release and should principally be useful for local or systemic administration of a large variety of different drugs and combinations thereof. Such improved pharmaceutical dosage forms should be suitable to remain in the mouth during drug delivery, i.e. for an extended period of time.
[0017] When a dosage form is to be mounted to a tooth by means of an adhesive or mechanical fixation means such as wires, the mounting procedure can be complicated and hence uncomfortable for the patient. Mounting may be time consuming and most patients find it unpleasant to undergo long-lasting dental procedures. Further, such complicated mounting procedures may require assistance by other persons, e.g. dentists nursing staff, and the like. Thus, there is a demand for dosage forms which can be mounted to a tooth without complicated and time consuming procedures.
[0018] Further, after a dosage form has been mounted to a tooth, it should not cause an unpleasant sensation or feel in the mouth of a patient, e.g. a feeling of pressure. For example, dosage forms are known which are to be fixed to the denture by means of volume expansion when being contacted with saliva. However, such volume expansion can be uncomfortable or even cause pain e.g. at the gingiva.
[0019] Still further, after a dosage form has been mounted to a tooth, it should not cause an unpleasant taste in the mouth of a patient, e.g. a bitter taste. For example, dosage forms are known which are to be fixed to the teeth by means of adhesives. However, in order to achieve adhesiveness and tackiness, such adhesive may contain ingredients having an unpleasant taste even when being released in minor amounts only.
[0020] Yet further, dosage forms that are devoted to remain in the mouth during drug delivery, i.e. for an extended period of time, should stay in the position to which they have been originally mounted and should not slip, shift, waggle or even fall off the tooth.
[0021] It is an object of the invention to provide pharmaceutical dosage forms having advantages over the pharmaceutical dosage forms of the prior art.
[0022] This object has been achieved by the subject-matter of the patent claims.
[0023] It has been surprisingly found that three-dimensional printing technology, preferably fused deposition modeling, makes available pharmaceutical dosage forms comprising a mounting unit which is mountable into a dental interstice between two adjacent teeth; and a releasing unit comprising a pharmacologically active ingredient. The pharmaceutical dosage form may be mounted to the teeth of the patient and may thus be positioned and remain in the oral cavity for a certain period of time providing immediate or prolonged release of the pharmacologically active ingredient.
[0024] Three-dimensional printing technology allows for individually adapting the shape of the pharmaceutical dosage forms to the shape of the denture (teeth and/or jar) of the individual patient by scanning said shape (negative) and by three-dimensionally printing the pharmaceutical dosage form (positive) so as to accurately fit and provide optimal patient compliance. The thus preferably achieved custom-fit of the pharmaceutical dosage form according to the invention not only provides sufficient mechanical strength of the linkage and fixation to the denture in order to withstand mechanical impact e.g. by chewing or tongue movement, but additionally improves patient compliance.
[0025] The mounting procedure is quick and easy, as the dosage form preferably can be mounted by simply clamping the dosage form around a tooth or into a dental interstice. Once correctly positioned in the oral cavity and mounted to the dental interstice between two adjacent teeth, the patient preferably does not realize, feel or sense the pharmaceutical dosage form. Further, the dosage form preferably does not slip or shift from the position on a tooth it has been mounted to or even falls off the tooth.
[0026] A first aspect of the invention relates to a three-dimensionally printed pharmaceutical dosage form comprising, preferably consisting of a mounting unit which is mountable to a tooth or two adjacent teeth of a patient, preferably into a dental interstice between two adjacent teeth; and a releasing unit comprising a pharmacologically active ingredient. The invention also relates to a process for the preparation of said pharmaceutical dosage form comprising a three-dimensional printing step.
[0027] For the purpose of specification, "dental interstice" is to be regarded as the space between two adjacent teeth, also referred to as "interproximal space". The two adjacent teeth may be (i) both natural, (ii) both artificial or (iii) one natural the other artificial. Further, when the subject has lost a tooth, the interstice between the two adjacent (remaining) teeth may be enlarged, i.e. the denture may be deficient. Teeth may be deciduous teeth, incisors, canine tooth or molars.
[0028] The pharmaceutical dosage form according to the invention comprises a mounting unit which is mountable to a tooth or two adjacent teeth. The tooth or the two adjacent teeth may be natural or artificial or partly artificial. The tooth or the two adjacent teeth may have a dental filling, an inlay or a tooth crown.
[0029] The mounting unit preferably serves the purpose of mounting the pharmaceutical dosage form in a manner that it may not slip or shift, such that the gingiva may not be damaged by the pharmaceutical dosage form.
[0030] Mounting of the pharmaceutical dosage form to a tooth or to a plurality of teeth, preferably two adjacent teeth, is preferably achieved mechanically, preferably as custom-fit which preferably functions as a form-fit, positive fitting, positive locking, form-lock fixing, or the like. Alternatively or additionally, the mounting unit may be provided with adhesive properties, e.g. by manufacturing at least a surface of the mounting unit form a material that becomes adhesive when being contacted with saliva.
[0031] In a preferred embodiment, the mounting unit is mountable into a dental interstice between two adjacent teeth. The two adjacent teeth may be (i) both natural, (ii) both artificial or (iii) one natural the other artificial. Further, when the subject has lost a tooth, the interstice between the two adjacent (remaining) teeth may be enlarged. Typically and preferably, the shortest distance between the two adjacent teeth is not more than 2 mm. [0032] Typically, the mounting unit exhibits a certain degree of flexibility and a shape such that a portion thereof, preferably a base, may be clamped into the dental interstice between two adjacent teeth. The thus achieved connection or linkage of the pharmaceutical dosage form to the denture of the patient provides sufficient strength such that the pharmaceutical dosage form may remain in this position within the oral cavity for an extended period of time, preferably for several hours.
[0033] Preferably, the mounting unit comprises a material which is insoluble or poorly soluble in saliva. The purpose of the mounting unit preferably is to ensure fixation of the pharmaceutical dosage form in the oral cavity for an extended period of time. Thus, the mounting unit preferably remains intact for an extended period of time during which the releasing unit may release the pharmacologically active ingredient. Preferably, the mounting unit is composed of a material that can be three-dimensionally printed, preferably by fused deposition modeling. Methods to distinguish such dosage forms from other dosage forms that have been manufactured by conventional techniques such as direct compression, extrusion, wet granulation, dry granulation, and the like are known to the skilled person and include but are not limited to microscopy and electron microscopy.
[0034] In a preferred embodiment, the mounting unit is made from a different material as the releasing unit. Preferably, the mounting unit does not comprise the pharmacologically active ingredient.
[0035] In a preferred embodiment, the mounting unit is made from the same material as the releasing unit, with the only difference that the material from which the mounting unit is made does not contain pharmacologically active ingredient.
[0036] In a preferred embodiment, the mounting unit comprises or is composed of a rigid material. For the purpose of specification, rigidity of an object is its ability to resist deformation in response to an applied force, i.e. the shape of the object does not change when a force is applied to the object. Preferably, the mounting unit comprises a rigid material that can resist deformation in response to an applied force of at least 200 N, more preferably at least 250 N, still more preferably at least 300 N, yet more preferably at least 350 N, even more preferably at least 400 N, most preferably at least 450 N, and in particular at least 500 N.
[0037] In another preferred embodiment, the mounting unit comprises or is composed of a flexible material, preferably an elastic material. As a result of the flexibility and the elasticity of a material, the shape of an object comprising the flexible and elastic material changes when the object is compressed, but the object gains back its original shape when it is not compressed anymore. The preferred flexible and elastic property may facilitate and improve mounting of the mounting unit to the tooth or the two adjacent teeth.
[0038] For the purpose of the specification, flexibility/elasticity of the material is not to be confused with expansion of the material or swelling of the material. Objects comprising a material that expands or swells increase their volume under certain conditions, usually when being brought into contact with a fluid, and at the end of the expansion process said objects remain at a volume that is bigger than their original volume, i.e. their volume before the expansion process started. Thus, the shape of the object before the expansion process may also differ from the shape of the object at the end of the expansion process. Preferably, the mounting unit comprises a material that maintains its shape upon contact with saliva.
[0039] In another preferred embodiment, the mounting unit is a longitudinally extended element, preferably like a thread, which is connected on one of its ends to a release unit (preferably the one facing the tongue) or which is connected on both of its ends to releasing units. Preferably, the mounting unit exhibits a certain degree of flexibility and elasticity so that it may be easily positioned into the interstice of two adjacent teeth, possibly by pushing, pressing, and/or pulling.
[0040] The dimensions of the mounting unit depend upon the location in the mouth of the patient where the pharmaceutical dosage form is to be positioned. When the pharmaceutical dosage form is to be mounted to the dental interstice between the two adjacent incisors, the length of the mounting unit is preferably within the range of not more than 0.5 cm. When the pharmaceutical dosage form is to be mounted to the dental interstice between the two adjacent molar tooth, the length of the mounting unit is preferably within the range of more than 0.5 cm, e.g. of about 1 cm.
[0041] In a preferred embodiment, the mounting unit is made from a flexible and elastic material and its length is shorter than the dental interstice between the two adjacent teeth where the pharmaceutical dosage form is to be mounted. Preferably, in the non-expanded state, the length of the elastic mounting unit is not more than about 95%, more preferably not more than about 90%, still more preferably not more than about 85%>, yet more preferably not more than about 80%> of the distance that is needed in order to mount the pharmaceutical dosage form to the dental interstice between the two adjacent teeth. According to this embodiment, when mounting the pharmaceutical dosage form at the desired position, the length of the mounting unit may transiently be extended by pulling, and once the pharmaceutical dosage form has been properly mounted, the restoring force of the elastic material provides additional fixation of the pharmaceutical dosage form to the denture.
[0042] The pharmaceutical dosage form according to the invention comprises a releasing unit comprising a pharmacologically active ingredient. The releasing unit is connected to the mounting unit and serves the purpose of releasing the pharmacologically active ingredient in a well-defined, controlled and safe manner. For that purpose, the releasing unit preferably has a predetermined surface that is exposed to saliva when the pharmaceutical dosage form is mounted to the denture. The release kinetics of the pharmacologically active ingredient into the saliva may then be controlled by adjustable factors, especially by the area of said surface and by the material from which the releasing unit is manufactured.
[0043] The releasing unit preferably provides comfort and a good mouth feeling. Preferably, the surface of the releasing unit is smooth, flexible and does not contain sharp edges, rims or flanges. Thus, the gingiva may not be damaged by the pharmaceutical dosage form and the releasing unit, respectively.
[0044] Preferably, the releasing unit comprises an erodible matrix material, preferably a material that is soluble in saliva, in which the pharmacologically active ingredient is embedded. [0045] For the purpose of the specification, soluble in saliva preferably means at least slightly soluble (10 to 1 g/L), more preferably at least sparingly soluble (33 to 10 g/L), still more preferably at least soluble (100 to 33 g/L), yet more preferably at least freely soluble (1000 to 100 g/L), even more preferably at least very soluble (greater or equal to 1000 g/L), in each case according to USP 23.
[0046] Suitable erodible matrix materials are known to the skilled person and besides the pharmacologically active ingredient may comprise a mixture of excipients such as fillers, binders, disintegrants, gelling agents, plasticizers, and the like. Preferably, the releasing unit is composed of a material that can be three-dimensionally printed, preferably by fused deposition modeling.
[0047] In a preferred embodiment, the release unit provides release of the pharmacologically active ingredient to the teeth. This may be achieved by shaping the pharmaceutical dosage form such that the surface of the release unit which provides release of the pharmacologically active ingredient comes into contact with the surface of the teeth.
[0048] In another preferred embodiment, the release unit provides release of the pharmacologically active ingredient to the gingiva. This may be achieved by shaping the pharmaceutical dosage form such that the surface of the release unit which provides release of the pharmacologically active ingredient comes into contact with the gingiva, the cheek pouch, and/or the palate.
[0049] In still another preferred embodiment, the release unit provides release of the pharmacologically active ingredient into the saliva which is then subsequently distributed in the oral cavity and finally swallowed by the patient. This may be achieved by shaping the pharmaceutical dosage form such that the surface of the release unit which provides release of the pharmacologically active ingredient comes into contact with saliva.
[0050] A skilled person recognizes that combinations of the above embodiments are also possible such that e.g. a first portion of the pharmacologically active ingredient is predominantly administered to the gingiva, whereas another portion of the pharmacologically active ingredient is predominantly released into the saliva.
[0051] According to a preferred embodiment, the release unit of the pharmaceutical dosage form has a predetermined surface that under physiological conditions comes into contact with the saliva and said predetermined surface preferably comprises two areas:
a drug releasing area that upon contact with saliva releases the pharmacologically active ingredient into the saliva; and
a passive area that comprises or is covered with a non-erodible material that is essentially insoluble in saliva.
[0052] The size of the drug releasing area can be adjusted to the desired release profile that is to be achieved by the pharmaceutical dosage form according to the invention. In general, the larger the drug releasing area the faster the release of the pharmacologically active ingredient. Providing the pharmaceutical dosage form according to the invention with a drug releasing area and with a passive area is advantageous with respect to a reproducible, adjustable and controlled drug release. Preferably, the drug releasing area comprises an erodible matrix material in which the pharmacologically active ingredient is embedded.
[0053] Preferably, the drug releasing area amounts to at most 99%, or at most 98%>, or at most 97%o, or at most 96%>, or at most 95%>; more preferably at most 94%>, or at most 93%>, or at most 92%>, or at most 91%, or at most 90%o; still more preferably at most 89%o, or at most 88%o, or at most 87%o, or at most 86%>, or at most 85%>; yet more preferably at most 84%>, or at most 83 %>, or at most 82%>, or at most 81%, or at most 80%o; even more preferably at most 89%o, or at most 88%o, or at most 87%o, or at most 86%>, or at most 85%>; most preferably at most 84%>, or at most 83%o, or at most 82%>, or at most 81%, or at most 80%o; and in particular at most 79%o, or at most 78%o, or at most 77%o, or at most 76%>, or at most 75%>; of the surface of the releasing unit, or of the total surface of the pharmaceutical dosage form according to the invention.
[0054] In a preferred embodiment of the pharmaceutical dosage form according to the invention, the mounting unit comprises a material which is insoluble or poorly soluble in saliva.
[0055] In a preferred embodiment of the pharmaceutical dosage form according to the invention, the mounting unit comprises a material which is erodible in saliva, preferably soluble in saliva.
[0056] Preferably, the mounting unit and the releasing unit are composed of different three-dimensionally printed materials. Preferably, the mounting unit is composed of a three-dimensionally printed material not containing the pharmacologically active ingredient and preferably the releasing unit is composed of a three- dimensionally printed material containing the pharmacologically active ingredient.
[0057] Preferably, the mounting unit and the releasing unit are composed of the same three-dimensionally printed material, with the only difference that the three-dimensionally printed material from which the mounting unit is made does not contain the pharmacologically active ingredient.
[0058] Preferably, the releasing unit is composed of a three-dimensionally printed material containing the pharmacologically active ingredient, which preferably is an analgesic.
[0059] In a preferred embodiment, the pharmaceutical dosage form according to the invention provides prolonged release of the pharmacologically active ingredient. In another preferred embodiment, the pharmaceutical dosage form according to the invention provides immediate release of the pharmacologically active ingredient. A skilled person recognizes that combinations of immediate and prolonged release are also possible, resulting e.g. in a bimodal release profile.
[0060] According to a preferred embodiment, the pharmaceutical dosage form according to the invention provides prolonged release of the pharmacologically active ingredient. Preferably, under physiological conditions, the pharmaceutical dosage form according to the invention exhibits a release profile according to any of embodiments A1 to A8 as compiled in the table here below:
A A A* A A5 A6 A As 30 min >5 % >5 % >5 % >5 % >5 % >5 % >5 % >5 %
60 min >10 % >10 % >10 % >10 % >10 % >10 % >10 % >10 %
2 h 15-70% 20-65% 25-60% 30-55% 15-60% 20-55% 25-50% 30-45%
4 h <75 <70 <65 <60 20-65% 25-50% 30-45% 35-40%
6 h <80% <80% <80% <80% 25-70% 30-65% 35-60% 40-55%
9 h >80% >80% >80% >80% <75 <70 <65 <60
12 h >95% >95% >95% >95% <80% <80% <80% <80%
18 h >95% >95% >95% >95% >80% >80% >80% >80%
24 h >95% >95% >95% >95% >95% >95% >95% >95%
[0061] According to another preferred embodiment, the pharmaceutical dosage form according to the invention provides immediate release of the pharmacologically active ingredient. The embodiment is particularly preferred when the pharmaceutical dosage form provides simultaneous drug release for systemic as well as local administration. Preferably, under physiological conditions, the pharmaceutical dosage form according to the invention exhibits a release profile according to any of embodiments B1 to B8 as compiled in the table here below:
Figure imgf000010_0001
[0062] The administration of the pharmacologically active ingredient from the pharmaceutical dosage form according to the invention may proceed locally and/or systemically, in the latter case orally (perorally) or buccally or sublingually.
[0063] Thus, according to a preferred embodiment, the pharmaceutical dosage form according to the invention is for local administration of the pharmacologically active ingredient. Administration may be topical.
[0064] According to another preferred embodiment, the pharmaceutical dosage form according to the invention is for systemic administration of the pharmacologically active ingredient; preferably for peroral or buccal or sublingual administration of the pharmacologically active ingredient.
[0065] The pharmacologically active ingredient that is contained in the pharmaceutical dosage form is not particularly limited. The pharmaceutical dosage form may contain a single pharmacologically active ingredient or a combination of two or more pharmacologically active ingredients or a combination of two or more derivatives of one and the same pharmacologically active ingredients such as different salts.
[0066] The pharmacologically active ingredient may be anyone for which buccal-systemic or local administration is desirable.
[0067] In a preferred embodiment, the pharmaceutical dosage form according to the invention provides local administration as well as systemic administration of one and the same pharmacologically active ingredient or of two different pharmacologically active ingredients. For example, the pharmaceutical dosage form may provide local administration of a local anesthetic (first pharmacologically active ingredient) and simultaneously - according to a corresponding or according to a different release kinetics - systemic administration of an analgesic.
[0068] When the pharmaceutical dosage form comprises a single releasing unit, the two different pharmacologically active ingredients are contained both in the releasing unit.
[0069] When the pharmaceutical dosage form comprises two releasing units, the two different pharmacologically active ingredients may be distributed over the releasing units in various manners, e.g.
- the entire amount of the first pharmacologically active ingredient may be contained in the first releasing unit, and the entire amount of the second pharmacologically active ingredient may be contained in the second releasing unit;
a portion of the first pharmacologically active ingredient may be contained in the first releasing unit, and the remainder of the first pharmacologically active ingredient as well as the entire amount of the second pharmacologically active ingredient may be contained in the second releasing unit;
- the entire amount of the first pharmacologically active ingredient as well as a portion of the second pharmacologically active ingredient may be contained in the first releasing unit, and the remainder of the second pharmacologically active ingredient may be contained in the second releasing unit;
a portion of the first pharmacologically active ingredient as well as a portion of the second pharmacologically active ingredient may be contained in the first releasing unit, and the remainder of the first pharmacologically active ingredient as well as the remainder of the second pharmacologically active ingredient may be contained in the second releasing unit.
[0070] Preferably, the pharmacologically active ingredient is selected from analgesics, stimulants, tranquilizers, narcotics and anesthetics. Thus, the invention also relates to the pharmaceutical dosage form according to the invention for use in the treatment of a disease or disorder, preferably of pain. The invention also relates to a method of treating a disease or disorder, preferably pain comprising the step of mounting a pharmaceutical dosage according to the invention into a dental interstice between two adjacent teeth of a patient in need of such treatment.
[0071] In a preferred embodiment, the pharmacologically active ingredient is for the treatment of diseases or disorders of the nervous system [ATC code N]; more preferably an analgesic [ATC code N02], or an antiepileptic [ATC code N03], or a psychoanaleptic [ATC code N06]; most preferably an opioid [ATC code N02A], an antiepileptic [ATC code N03A], or a psychostimulant [ATC code N06B].
[0072] Preferred pharmacologically active ingredients include but are not limited to asenapine, alfentanil, sufentanil, fentanyl, remifentanyl, bupreno hine, butorphanol, codeine, diphenoxylate, hydrocodone, hydromorphone, oxycodone, oxymorphone, levorphanol, levallorphan, loperamide, meperidine, morphine, naloxone, nalbuphine, nalmefene, Μΐο ηίηε, naltrexone, lidocaine, prochlorperazine, nitroglycerine, testosterone, nicotine, midazolam, and the like. [0073] The total weight of the pharmaceutical dosage form according to the invention is not particularly limited. Preferably, the pharmaceutical dosage form according to the invention has a total weight within the range of 100±50 mg, or 200±100 mg, or 300±150 mg, or 400±200 mg, or 500±250 mg, or 600±300 mg, or 700±350 mg, or 800±400 mg, or 900±450 mg, or 1000±500 mg, or 1200±600 mg, or 1400±700 mg, or 1600±800 mg, or 1800±900 mg, or 2000±1000 mg, or 2500±1250 mg, or 3000±1500 mg.
[0074] The shape of the pharmaceutical dosage form according to the invention is not particularly limited, as long as it may be mounted to the dental interstice between two adjacent teeth, or to more than one dental interstice between several adjacent teeth, by means of the mounting unit. The mounting is preferably accurate and flush fitted. This may principally be achieved by providing a variety of different shapes such that the patient may try which shape fits best at a given position in the denture. Preferably, however, the shape of the pharmaceutical dosage form is individually designed and adapted for an individual patient.
[0075] In a preferred embodiment, the pharmaceutical dosage form comprises a section having a shape that corresponds, preferably is individually adapted to correspond, to at least a section of the shape of the tooth or the two adjacent teeth. In another preferred embodiment, the mounting unit or the releasing unit comprises a section having a shape that corresponds, preferably is individually adapted to correspond, to at least a section of the shape of the tooth or the two adjacent teeth. For the purpose of specification, "a shape that corresponds" is to be understood in the sense that the shape of a section of the dosage form is the complement or counterpart of the shape of a section of the tooth or the two adjacent teeth. Thus, when the section of the tooth for example has a convex shape, the section of the dosage form, preferably of the mounting unit and/or of the releasing unit, preferably has a concave shape that matches with the convex shape of the section of the tooth.
[0076] Preferably, the pharmaceutical dosage form, preferably the mounting unit and/or the releasing unit, comprises a section having a surface that provides, preferably is individually adapted to provide, an intimate contact area with a surface of a section of at least one side of the tooth. According to this embodiment, the dosage form comprises a section that is individually formed and shaped such that its surface preferably provides a maximal contact interface with the surface of at least a section of the tooth or the two adjacent teeth. Thus, for example, when the surface of the section of the tooth has a convex shape, the surface of the section of the dosage form, preferably of the mounting unit and/or of the releasing unit, is preferably a concave complement or counterpart to fit in intimate contact therewith.
[0077] A tooth can be described by the five sides on the surface of the tooth which are:
- the inner (lingual, palatal) side, which is the side adjacent to the tongue;
- the mesial (anterior) side, which is the side closest to the middle line of the face (mandibular symphysis),
- the outer (buccal, labial, vestibular) side, which is the side adjacent to the cheek;
- the distal (posterior) side, which is the side furthest from to the middle line of the face (mandibular symphysis); and
- the crown, which is the side facing the upper jaw and lower jaw, respectively. [0078] Preferably, the surface of the section of the pharmaceutical dosage form, preferably of the mounting unit and/or of the releasing unit, provides, preferably is individually adapted to provide, an intimate contact area with a surface of a section of the inner (lingual, palatal) side, and/or the mesial (anterior) side, and/or the outer (buccal, labial, vestibular) side, and/or the distal (posterior) side of the tooth.
[0079] Preferably, the intimate contact area is at least 2.0 mm2, preferably at least 3.0 mm2, more preferably at least 4.0 mm2, still more preferably at least 5.0 mm2, yet more preferably at least 6.0 mm2, even more preferably at least 7.0 mm2, most preferably at least 8.0 mm2, and in particular at least 9.0 mm2.
[0080] Preferably, the pharmaceutical dosage form , preferably the mounting unit and/or the releasing unit, comprises
- a first section having a first surface that provides, preferably is individually adapted to provide, a first intimate contact area with a surface of a section of at least one side of the tooth; and
- a second section having a second surface that provides, preferably is individually adapted to provide, a second intimate contact area with a surface of a section of at least one side of the adjacent tooth.
[0081] Preferably,
- the first surface of the first section provides, preferably is individually adapted to provide, a first intimate contact area with the inner (lingual, palatal) side, and/or the mesial (anterior) side, and/or the outer (buccal, labial, vestibular) side, and/or the distal (posterior) side of the tooth; and
- the second surface of the second section provides, preferably is individually adapted to provide, a second intimate contact area with the inner (lingual, palatal) side, and/or the mesial (anterior) side, and/or the outer (buccal, labial, vestibular) side and/or the distal (posterior) side of the adjacent tooth.
[0082] Preferably, the first intimate contact area together with the second intimate contact area is at least 2.0 mm2, preferably at least 3.0 mm2, more preferably at least 4.0 mm2, still more preferably at least 5.0 mm2, yet more preferably at least 6.0 mm2, even more preferably at least 7.0 mm2, most preferably at least 8.0 mm2, and in particular at least 9.0 mm2.
[0083] By means of the mounting unit a custom-fit of the pharmaceutical dosage form according to the invention to the denture (teeth and/or jar), i.e. the tooth or the two adjacent teeth, of the patient can be achieved. Preferably, said custom-fit functions as a form-fit, positive fitting, positive locking, form-lock fixing, or the like.
[0084] Preferably, the mounting unit is mechanically mountable to the tooth or the two adjacent teeth. Preferably, the mounting unit is mechanically mountable to the tooth or the two adjacent teeth without the employment of adhesives, or wires, or brackets, or tapes, or elastic bands, which in each case would provide for fixation or adhesion on the tooth or the two adjacent teeth.
[0085] Preferably, the mounting unit is mountable to the tooth or the two adjacent teeth by a custom-fit. For the purpose of the specification, "custom-fit" means personalized with regard to shape and size. The custom-fit dosage form is modified with regard to some of its characteristics according to the patients' requirements, especially its geometric characteristics. Preferably, the custom-fit dosage form offers one-of-a-kind dosage forms that, due to their intrinsic characteristics and medical use, can be totally adapted to geometric characteristics in order to meet the patients' requirements. Preferably, "custom-fit" means that the shape of at least a portion of the pharmaceutical dosage form, particularly at least a portion of the shape of the mounting unit, is individually adapted to the shape of at least a portion of the tooth or the two adjacent teeth of a patient so that the pharmaceutical dosage form fits accurately at the determined tooth or two adjacent teeth. Preferably, a custom-fit of the pharmaceutical dosage form is achieved by a section of the dosage form having a shape that corresponds, preferably is individually adapted to correspond, to at least a section of the shape of the tooth or the two adjacent teeth.
[0086] In one preferred embodiment, the mounting unit is mountable to the tooth by clamping the mounting unit around the tooth, preferably by clamping the mounting unit around at least two sides of the tooth.
[0087] Preferably, the mounting unit is mountable to the tooth by clamping the mounting unit around the tooth, wherein the mounting unit is clamped around
- the inner side and the distal side; or the inner side and the mesial side; or
- the outer side and the distal side; or the outer side and the mesial side; or
- the outer side, the mesial side and the inner side; or
- the outer side, the distal side and the inner side; or
- the crown, the mesial side and the distal side; or
- the crown, the inner side and the outer side.
[0088] Preferably, the mounting unit is mountable to the tooth by clamping the mounting unit into a dental interstice between the two adjacent teeth. For the purpose of the specification, the term "dental interstice" is also referred to as "interproximal space" and describes the space between two adjacent teeth, i.e. the space between the distal side of one tooth and the mesial side of the adjacent other tooth or the mesial side of one tooth and the distal side of the adjacent other tooth, respectively.
[0089] Preferably, the mounting unit is mountable to the tooth by clamping the mounting unit into a dental interstice between the two adjacent teeth and at least one outer side or at least one inner side of one of the two adjacent teeth. Preferably, the mounting unit is clamped into a dental interstice between two adjacent teeth and the two outer sides or the two inner sides of the two adjacent teeth. Preferably, the mounting unit is clamped into a dental interstice between the two adjacent teeth and one outer side of one of the two adjacent teeth and one inner side of the other of the two adjacent teeth.
[0090] In a preferred embodiment, clamping of the mounting unit is achievable by pressing (pushing, pinching, shifting, slipping) the mounting unit in a vertical direction around the tooth or into the dental interstice between the two adjacent teeth. For the purpose of the specification, horizontal or vertical refers to directions of a patient sitting in an upright position. Thus, in a vertical directions means in a direction upwards to the upper jaw or downward to the lower jaw, respectively. In a horizontal direction means from the inside of the lips or cheek in the direction of the tongue or from the tongue in the direction of the lips or cheek, respectively.
[0091] Preferably, clamping of the mounting unit is achievable by pressing the mounting unit in a vertical direction when the mounting unit is clamped around
- the crown, the mesial side and the distal side; or
- the crown, the inner side and the outer side; or
- the inner side and the distal side; or the inner side and the mesial side; or
- the outer side and the distal side; or the outer side and the mesial side; or.
[0092] In another preferred embodiment, clamping of the mounting unit is achievable by pressing (pushing, pinching, shifting, slipping) the mounting unit in a horizontal direction around the tooth or into the dental interstice between the two adjacent teeth. Preferably, clamping of the mounting unit is achievable by pressing the mounting unit in a horizontal direction when the mounting unit is clamped around
- the inner side and the distal side; or the inner side and the mesial side; or
- the outer side and the distal side; or the outer side and the mesial side; or
- the outer side, the mesial side and the inner side; or
- the outer side, the distal side and the inner side.
[0093] Conventional dosage forms are mounted to a tooth by means of volume expansion, often upon contact with saliva, of the conventional dosage form or of a part of said dosage form such that the expanded volume provides for fixing of the dosage form on the tooth or in a dental interstice. Other mounting mechanisms for conventional dosage forms to a tooth involve the employment of adhering agents, or wires, or brackets, or tapes, or elastic bands, which provide for fixation or adhesion on a tooth. The details of such conventional mounting mechanisms for mounting a conventional dosage form to a tooth are known to a skilled person.
[0094] Preferably, the mounting unit is mountable to the tooth or the two adjacent teeth by a mounting mechanism which does not involve volume expansion of the pharmaceutical dosage form or of an element thereof. Preferably, the mounting mechanism does not involve volume expansion of the pharmaceutical dosage form or an element thereof such that the expanded volume provides for fixing the mounting unit in the dental interstice or provides for fixing the mounting around the tooth. Preferably, the mounting mechanism does not involve volume expansion of the pharmaceutical dosage form or of an element thereof upon contact with saliva.
[0095] Preferably, the pharmaceutical dosage form does not substantially swell upon contact with saliva in the oral cavity. For the purpose of the description, "not substantially swell" means that upon contact with saliva, the volume of the pharmaceutical dosage form does not increase by more than 1.0 vol.-%, or more than 1.2 vol.-%, or more than 1.4 vol.-%, or more than 1.6 vol.-%, or more than 1.8 vol.-%, or more than 2.0 vol.-%, or more than 2.2 vol.-%, or more than 2.4 vol.-%, or more than 2.6 vol.-%, or more than 2.6 vol.-%, in each case compared to its original volume prior to contact with saliva. Preferably, the pharmaceutical dosage form maintains its volume upon contact with saliva.
[0096] Preferably, the mounting unit is mountable to the tooth or the two adjacent teeth by a mounting mechanism which does not involve adhesion of the pharmaceutical dosage form to the tooth, to the two adjacent teeth, or to gingiva. Preferably, the mounting mechanism does not involve applying an adhesive to the tooth, to the two adjacent teeth or to the gingiva or to the dosage form prior to mounting of the mounting unit. Preferably, the mounting mechanism does not involve applying an adhesive prior to mounting of the mounting unit.
[0097] Preferably, the mounting unit is mountable to the tooth or the two adjacent teeth by a mounting mechanism which does not involve a material which has not been three-dimensionally printed. Preferably, said material which has not been three-dimensionally printed is selected form the group consisting of elastomers, rubber and metal.
[0098] In a preferred embodiment of the pharmaceutical dosage form according to the invention, the mounting unit comprises a distal element, a proximal element, and a base, wherein the base connects the distal element with the proximal element.
[0099] Preferably, the two adjacent teeth to which the mounting unit is mountable each have an inner (lingual, palatal) side, an mesial (anterior) side, an outer (buccal, labial, vestibular) side, and a distal (posterior) side, and the base preferably is mountable to the dental interstice between the two adjacent teeth in a manner such that the distal element is positioned at the outer side of the adjacent teeth, the proximal element is positioned at the inner side of the adjacent teeth, and the base is positioned at the dental interstice between the adjacent teeth.
[0100] In a preferred embodiment, the base of the mounting unit is mountable to the dental interstice between the two adjacent teeth in a manner such that the distal element is in intimate contact with the outer (buccal, labial, vestibular) side of the teeth. Preferably, the distal element comprises a section having a surface that provides an intimate contact area of the distal element with the surface of a section of the outer side of the two adjacent teeth. Preferably, said intimate contact area of the distal element is at least 2.0 mm2, preferably at least 3.0 mm2, more preferably at least 4.0 mm2, still more preferably at least 5.0 mm2, yet more preferably at least 6.0 mm2, even more preferably at least 7.0 mm2, most preferably at least 8.0 mm2, and in particular at least 9.0 mm2.
[0101] In another preferred embodiment, the base of the mounting unit is mountable to the dental interstice between the two adjacent teeth in a manner such that the proximal element is in intimate contact with the inner (lingual, palatal) side of the teeth. Preferably, the proximal element comprises a section having a surface that provides an intimate contact area of the proximal element with the surface of a section of the inner side of the two adjacent teeth. Preferably, said intimate contact area of the proximal element is at least 2.0 mm2, preferably at least 3.0 mm2, more preferably at least 4.0 mm2, still more preferably at least 5.0 mm2, yet more preferably at least 6.0 mm2, even more preferably at least 7.0 mm2, most preferably at least 8.0 mm2, and in particular at least 9.0 mm2. [0102] In still another preferred embodiment, the base of the mounting unit is mountable to the dental interstice between the two adjacent teeth in a manner such that the base intimately fills the dental interstice between the adjacent teeth. The dental interstice - also referred to as interproximal space - is the space between two adjacent teeth, which is usually bathed with saliva or any other liquid which is in the oral cavity. Preferably, the base of the mounting unit is not a hollow object and has a shape that corresponds to at least a section of the shape of at least one of the two sides of the adjacent teeth which flank the dental interstice, i.e. the mesial (anterior) side of the tooth and/or the distal (posterior) side of the adjacent other tooth or the distal (posterior) side of the tooth and/or the mesial (anterior) side of the adjacent other tooth.
[0103] Preferably, the base of the mounting unit comprises a section having a surface that provides an intimate contact area of the proximal element with the surface of a section of the mesial (anterior) side of the tooth and/or the distal (posterior) side of the adjacent tooth or with the surface of a section of the distal (posterior) side of the tooth and/or the mesial (anterior) side of the adjacent tooth. Preferably, said intimate contact area of the base is at least 2.0 mm2, preferably at least 3.0 mm2, more preferably at least 4.0 mm2, still more preferably at least 5.0 mm2, yet more preferably at least 6.0 mm2, even more preferably at least 7.0 mm2, most preferably at least 8.0 mm2, and in particular at least 9.0 mm2.
[0104] Preferably, the above embodiments are simultaneously realized.
[0105] Preferably, the distal element and/or the proximal element and/or the base has a shape that is adapted, preferably individually adapted to, at least a section of the shape of the two adjacent teeth and to at least a section of the shape of the dental interstice, respectively. A shape that is adapted in this context preferably is a shape which is the complement or counterpart of another shape. Thus, when the section of the two adjacent teeth for example have a convex shape, the section of the distal element and/or the proximal element and/or the base, preferably has/have a concave shape that matches with the convex shape of the section of the two adjacent teeth.
[0106] The distal element, the proximal element and the base may comprise the same material or different materials. In order to improve patient compliance and comfort, the distal element as well as the proximal element of the mounting unit may comprise a material that is softer than the material from which the base is formed.
[0107] In a preferred embodiment, the distal element, the proximal element and the base are composed of three-dimensionally printed materials. Preferably, the distal element and/or the proximal element are composed of a different three-dimensionally printed material than the base. In another preferred embodiment, the distal element, the proximal element and the base are composed of the same three-dimensionally printed materials.
[0108] In a preferred embodiment, the pharmaceutical dosage form according to the invention comprises a distal releasing unit connected to the distal element; and/or a proximal releasing unit connected to the proximal element. The distal releasing unit and the proximal releasing unit may comprise different pharmacologically active ingredients and/or may provide different release kinetics of the pharmacologically active ingredient. [0109] In a preferred embodiment, the distal releasing unit and/or the proximal releasing unit are composed of three-dimensionally printed materials. Preferably, the distal releasing unit and/or the proximal releasing unit are composed of a different three-dimensionally printed material than the distal element and/or the proximal element and/or the base. Preferably, the distal releasing unit and/or the proximal releasing unit are composed of a three- dimensionally printed material containing a pharmacologically active ingredient. Preferably, said pharmacologically active ingredient is an analgesic.
[0110] In another preferred embodiment, the distal releasing unit and/or the distal element and/or the proximal releasing unit and/or the proximal element are composed of the same three-dimensionally printed materials, with the only difference that the three-dimensionally printed material from which the distal element and/or the proximal element is/are made does not contain pharmacologically active ingredient.
[0111] Preferably, the pharmaceutical dosage form comprises no element selected from flexible films, flexible sheets, and discs. In contrast to the inventive dosage form, films or sheets have uniformly flat surfaces. Thus, the surfaces of said films or sheets do not correspond to or are not individually adapted to correspond, to the surface of a section of at least one side of a tooth and/or the surface of a section of at least one side of the adjacent tooth. The surface of discs may have a concave or convex shape, but the surface does also not individually correspond to the individual surface of at least one side of a tooth and/or the surface of at least one side of the adjacent tooth.
[0112] Preferably, the pharmaceutical dosage form does not assume the shape of a dental brace or dental bracket or a mouthgard (the latter term is synonymous to mouth protector, or mouth piece, or gumshield, or gumguard, or nightguard, or occlusal splint, or bite splint, or bite plane). A mouthgard preferably is made of a hard polymeric material and covers all teeth of the upper jaw or lower jaw, respectively. Dental braces or dental brackets are devices used in orthodontics that may help to position teeth. Preferably, the pharmaceutical dosage form does not assume the shape of a dental brace or dental bracket which is permanently attached to the teeth. Preferably, the pharmaceutical dosage form does not assume the shape of a dental brace or dental bracket which is not permanently attached to the teeth, preferably the shape of a dental brace or dental bracket which is made of metal hooks that surround the teeth and are enclosed by a plate, preferably made of a polymeric material, shaped to fit the patient's palate.
[0113] Preferably, the pharmaceutical dosage form according to the invention is for use in therapy, wherein the pharmaceutical dosage form is mounted to one or more dental interstices or adjacent teeth and thus positioned in the oral cavity for at least 3 hours, or for at least 3.5 hours, or for at least 4 hours, or for at least 4.5 hours, or for at least 5 hours, or for at least 5.5 hours, or for at least 6 hours, or for at least 6.5 hours, or for at least 7 hours, or for at least 7.5 hours, or for at least 8 hours, or for at least 8.5 hours, or for at least 9 hours, or for at least 9.5 hours, or for at least 10 hours, or for at least 10.5 hours, or for at least 11 hours, or for at least 11.5 hours, or for at least 12 hours, or for at least 14 hours, or for at least 16 hours, or for at least 18 hours, or for at least 20 hours, or for at least 22 hours, or for at least 24 hours.
[0114] Preferred embodiments of the pharmaceutical dosage form according to the invention are also illustrated by Figures 1 to 8 which are not to be construed as limiting the scope of the invention. [0115] Figure 1 schematically illustrates a comparatively simple embodiment of the pharmaceutical dosage form (1) according to the invention comprising mounting unit (2) and releasing unit (3).
[0116] Figure 2 schematically illustrates the part of a denture of a jaw comprising a tooth (4) and an adjacent tooth (5). Five sides of the tooth (4) are schematically illustrated in Figure 2, said five sides are:
- the inner side (4a), which is synonymous to the lingual side or palatal side, which is the side adjacent to the tongue;
- the mesial side (4b), which is synonymous to the anterior side, which is the side closest to the middle line of the face (mandibular symphysis),
- the outer side (4c), which is synonymous to the buccal side, or labial side, or vestibular side, which is the side adjacent to the cheek;
- the distal side (4d), which is synonymous to the posterior side, which is the side furthest from to the middle line of the face (mandibular symphysis); and
- the crown (4e), which is the side facing the upper jaw or lower jaw, respectively.
[0117] Further, Figure 2 schematically illustrates five sides of the adjacent tooth (5), said five sides are:
- the inner side (5a), which is synonymous to the lingual side or palatal side, which is the side adjacent to the tongue;
- the mesial side (5b), which is synonymous to the anterior side, which is the side closest to the middle line of the face (mandibular symphysis),
- the outer side (5c), which is synonymous to the buccal side, or labial side, or vestibular side, which is the side adjacent to the cheek;
- the distal side (5d), which is synonymous to the posterior side, which is the side furthest from to the middle line of the face (mandibular symphysis); and
- the crown (5e), which is the side facing the upper jaw or lower jaw, respectively.
[0118] Furthermore, Figure 2 schematically illustrates a dental interstice (6) between two adjacent teeth, said dental interstice (6) is flanked by the distal side (4d) of the tooth and the mesial side (5b) of the adjacent tooth.
[0119] Figure 3 schematically illustrates how the pharmaceutical dosage form (1) according to Figure 1 can be mounted to the dental interstice (6) between two adjacent teeth (4) and (5) by clamping the mounting unit (2) therein.
[0120] Figure 4 schematically illustrates other preferred embodiments of the pharmaceutical dosage form (1) according to the invention. Figure 4A shows a pharmaceutical dosage form (1), wherein the mounting unit (2) comprises a distal element (21), a proximal element (22), and a base (23), wherein the base (23) connects the distal element (21) with the proximal element (22). A distal releasing unit (31) is connected to the distal element (21) . Figure 4B shows an embodiment where a proximal releasing unit (32) is connected to the proximal element
(22) . Figure 4C shows an embodiment comprising two release units where a distal releasing unit (31) is connected to the distal element (21) and a proximal releasing unit (32) is connected to the proximal element (22).
[0121] Figure 5 schematically illustrates how the pharmaceutical dosage form (1) according to Figure 4 can be mounted to the dental interstice (6) between two adjacent teeth (4) and (5) by clamping the mounting unit (2) therein.
[0122] Figure 6 schematically illustrates an alternative shape of the pharmaceutical dosage form (1) where the mounting unit (2) comprises two opposite bases (23 a) and (23b) that are each clamped into the dental interstices (6) of two adjacent teeth (4) and (5).
[0123] Figure 7 illustrates an alternative shape of the pharmaceutical dosage form (1) where the denture of the patient is deficient, as one tooth is missing. The mounting unit (2) is nonetheless mounted into a dental interstice (6) between two adjacent teeth (4) and (5) thereby bridging the gap that is left by the missing tooth.
[0124] Figure 8 illustrates an alternative shape of the pharmaceutical dosage form (1) where the mounting unit (2) is not mounted into a dental interstice (6) between two adjacent teeth, but to a single tooth (4) at the end of the jar. The mounting unit (2) assumes a shape that resembles a horseshoe and can be clamped around the tooth (4). Mechanical mounting is achieved by a custom-fit (form-fit).
[0125] Figure 9 illustrates an alternative shape of the pharmaceutical dosage form comprising two mounting units (2a) and (2b) which are each mountable into a dental interstice (6) between two adjacent teeth (4) and (5). Mechanical mounting is achieved by a custom-fit (form-fit).
[0126] Another aspect of the invention relates to a process for the preparation of a pharmaceutical dosage form according to the invention as described above, said process comprising a three-dimensional printing step. It has been surprisingly found that pharmaceutical dosage forms according to the invention can be manufactured by three-dimensional printing technologies.
[0127] Preferably, the process comprises the step of
(a) scanning the dental interstice between two adjacent teeth of the patient where the pharmaceutical dosage form is later to be mounted in the oral cavity of the patient; and
(b) three-dimensionally printing the pharmaceutical dosage form with a shape that accurately fits into the dental interstice as scanned in step (a).
[0128] Scanning step (a) may involve the use of a laser. Suitable techniques are known to the skilled person and are commercially available. Preferably, the scanning step (a) involves employing cone beam computed tomography. The result of scanning step (a) is preferably used in order to calculate the appropriate shape of the pharmaceutical dosage form to be printed in step (b). Suitable computer software is also commercially available. [0129] Preferably, the scanning step (a) involves determining at least a section of the shape and/or the surface of a tooth or two adjacent teeth of a patient, to which the pharmaceutical dosage form is to be mounted. Preferably, the scanning step (a) involves determining at least a section of the shape and/or the surface of the distal side of a tooth and the mesial side of the other adjacent tooth or the mesial side of a tooth and the distal side of the other adjacent tooth, respectively.
[0130] Preferably, the pharmaceutical dosage form is designed and/or printed such that it comprises a section having a shape that corresponds to at least a section of the shape of the tooth or the two adjacent teeth determined in the scanning step (a).
[0131] Preferably, the three-dimensional printing step involves fused deposition modeling.
[0132] Machines for fused deposition modeling (FDM) are commercially available. The machines may dispense multiple materials to achieve different goals: For example, one material may be used to build up the pharmaceutical dosage form and another material may be used to build up a soluble support structure. The same applies to the materials of the mounting unit and the releasing unit as described above.
[0133] In FDM the pharmaceutical dosage form is produced by extruding small flattened strings of molten material to form layers as the material hardens immediately after extrusion from the nozzle. A thermoplastic filament is unwound from a coil and supplies material to an extrusion nozzle which can turn the flow on and off. A worm-drive may push the filament into the nozzle at a controlled rate. The nozzle is heated to melt the material. The thermoplastic material is heated above its glass transition temperature and is then deposited by an extrusion die. The nozzle can be moved in both horizontal and vertical directions by a numerically controlled mechanism. The nozzle follows a tool-path controlled by a computer-aided manufacturing (CAM) software package, and the pharmaceutical dosage form is built from the bottom up, one layer at a time. Stepper motors or servo motors are typically employed to move the extrusion die. The mechanism used is often an X-Y-Z rectilinear design, although other mechanical designs such as deltabot have been employed. Myriad materials are commercially available, such as polylactic acid (PLA), polyamide (PA), among many others (see Ursan et al., J Am Pharm Assoc (2003) 2013, 53(2), 136.44; Prasad et al., Drug Dev Ind Pharm 2015, 1-13).
[0134] Preferably, the three-dimensional printing step involves a powder-based three-dimensional printing technology. Typical powder-based three-dimensional printing technologies include, but are not limited to, Binder Jet Technique or Selective Laser Sintering. Selective Laser Sintering is a three-dimensional printing technique that involves sintering powdered forms of e.g. thermoplastic materials by a high-power laser beam layer-by- layer. In a first step of a three-dimensional printing step involving selective laser sintering a thin layer of powder is deposited on a build tray. The laser, which is levelled with a roller, heats the powder particles and fuses them to a solid layer. After the first layer has fused, the build tray moves downward and a new layer of powder is deposited and sintered. This procedure is repeated until the object to be printed is completed.
[0135] Preferably, the three-dimensional printing step involves Binder Jet Technique. The Binder Jet Technique employs a print head to disperse a continuous jet of a binder solution onto powder layers. The binder solution binds the powder particles as it touches them. In a first step of the three-dimensional printing process involving Binder Jet Technique a thin layer of powder is spread over a tray, which can be moved with a roller system. Then the print head selectively disperses a continuous jet of a binder solution onto the powder on the tray, which is moved so that the powder particles are bound according to the structure that is to be printed.
[0136] Preferably, the three-dimensional printing step involves a liquid-based three-dimensional printing technology. Typical liquid-based three-dimensional printing technologies include, but are not limited to stereolithography (SL or SLA) or PolyJet (Multijet) printing technology. Poly Jet printing technology is performed by jetting photopolymer materials in ultra-thin layers onto a build tray layer-by-layer, wherein each layer is cured by UV light immediately after it has been jetted.
[0137] Preferably, the three-dimensional printing step involves stereolithography printing technology. Stereolithography is a three-dimensional printing technique where liquid photopolymer in a vat is cured sequentially layer-by-layer by a low-power UV-laser. The laser is guided by a mirror to focus onto the surface of the liquid photopolymer in the vat.
[0138] When employing three-dimensional printing techniques it is possible to print three-dimensional microstructures in accordance with the resolution of the printing device. Preferably, the three-dimensional printing step involves printing the pharmaceutical dosage form, according to the resolution of the printing device, by depositing individual three-dimensional microstructures having an individual volume of at most 1.5 mm 3 , or of at most 1.4 mm 3 , or of at most 1.3 mm 3 , or of at most 1.2 mm 3 , or of at most 1.1 mm 3 , or of at most
1.0 mm 3 ,or of at most 0.9 mm 3 , or of at most 0.8 mm 3 , or of at most 0.7 mm 3 , or of at most 0.6 mm 3 , or of at most 0.5 mm 3 , or of at most 0.4 mm 3 , or of at most 0.3 mm 3 , or of at most 0.2 mm 3 , or of at most 0.1 mm 3.
[0041] Preferably, the three-dimensional printing step comprises printing at least two different three- dimensionally printable materials, which preferably are provided each in form of filaments useful for fused deposition modeling.
[0139] Pharmaceutical compositions, preferably three-dimensionally printable materials, that are suitable to be employed in the three-dimensional printing step according to the invention, preferably in fused deposition modeling, are preferably identical to or at least similar with pharmaceutical compositions that have been known to be suitable for processing by conventional hot melt extrusion technology. Fused deposition modeling has many similarities with conventional hot melt extrusion.
[0140] Preferably, the pharmaceutical dosage form is prepared by three-dimensionally printing at least two different pharmaceutical compositions, preferably two different three-dimensionally printable materials, that preferably are provided each in form of filaments useful for fused deposition modeling. Preferably, one pharmaceutical composition, preferably one three-dimensionally printable material, contains one or more pharmacologically active ingredients, whereas the other pharmaceutical composition, preferably the other three- dimensionally printable material, does not contain pharmacologically active ingredients. [0141] Both compositions, preferably both three-dimensionally printable materials, preferably contain pharmaceutical excipients that are conventionally employed in the manufacture of pharmaceutical dosage forms, preferably in the course of three-dimensional printing technology, especially fused deposition modeling. The following preferred embodiments apply to both pharmaceutical compositions, preferably both three- dimensionally printable materials, (in the following referred to as "pharmaceutical composition"), irrespective of whether they contain a pharmacologically active ingredient or not.
[0142] Preferably, the pharmaceutical composition, preferably the three-dimensionally printable material, comprises a plasticizer. Suitable plasticizers are known to the skilled person. Examples include but are not limited to polyethylene glycols, such as PEG 1500 or PEG 4000 or PEG 6000; citrates, phthalates, glycerin, sugar alcohols, various contents of copolymers (e.g. ethylene vinyl acetate (EVA) / vinyl acetate (VA)), and mixtures of any of the foregoing.
[0143] The content of plasticizer is preferably within the range of from 0.1 to 20 wt.-%, more preferably 5.0 to 17.5 wt.-%, still more preferably 7.5 to 15 wt.-%, relative to the total weight of the pharmaceutical composition, preferably the three-dimensionally printable material.
[0144] Preferably, the pharmaceutical composition, preferably the three-dimensionally printable material, comprises one or more matrix polymers. Suitable matrix polymers are known to the skilled person. Examples include but are not limited to polylactic acid (PLA); cellulose ethers such as methylcellulose (MC), ethyl- cellulose (EC), hydroxypropylcellulose (HPC) and hydroxypropylmethylcellulose (HPMC); vinyl polymers such as polyvinylpyrrolidone (e.g. Kollidon® PF 12) or blends thereof such as polyvinyl acetate/polyvinylpyrrolidone (e.g. Kollidon® SR). Other suitable polymers include ethylene vinyl acetate copolymers (EVA), polyvinyl chloride, polyethylene terephthalate (PET), polyurethanes (PU), polyamides (PA), polyacrylates and mixtures of any of the foregoing.
[0145] The pharmaceutical composition, preferably the three-dimensionally printable material, may consist of one or more matrix polymers. The total content of matrix polymers is preferably within the range of from 5.0 to 95 wt.-%, more preferably 10 to 90 wt.-%, still more preferably 25 to 85 wt.-%, relative to the total weight of the pharmaceutical composition, preferably the three-dimensionally printable material.
[0146] Representative pharmaceutical compositions, preferably three-dimensionally printable materials, that are useful for the purpose of the invention are compiled in the table here below:
Figure imgf000023_0001
[0147] For filament preparation, a matrix polymer or a mixture of various matrix polymers, e.g. hydroxypropylcellulose (HPC), may be stored 24 h in oven at 40 °C ; when required it may be mixed in a mortar with PEG 1500 or PEG 4000 (2 %, 5 %, 10 % by weight calculated with respect to the dry polymer). Hot-melt extrusion (HME) may be carried out in a twin-screw extruder (Haake MiniLab II, Thermo Scientific , USA) equipped with an aluminum rod - shaped die (ø 2.00 mm) . Extruded rods may be calibrated and rolled up on a spool.
[0148] Another aspect of the invention relates to a pharmaceutical dosage form that is obtainable by the process according to the invention as described above.
[0149] List of reference signs:
(1) - pharmaceutical dosage form
(2) - mounting unit
(3) - releasing unit
(4) - tooth
(4a) - inner side of the tooth
(4b) - mesial side of the tooth
(4c) - the outer side of the tooth
(4d) - distal side of the tooth
(4e) - crown of the tooth
(5) - adjacent tooth
(5a) - inner side of the adjacent tooth
(5b) - mesial side of the adjacent tooth
(5c) - the outer side of the adjacent tooth
(5d) - distal side of the adjacent tooth
(5e) - crown of the adjacent tooth
(6) - dental interstice
(21) - distal element
(22) - proximal element
(23) - base
(23 a) - opposite base mounted to the mesial side of a tooth
(23b) - opposite base mounted to the distal side of a tooth
(31) - distal releasing unit
(32) - proximal releasing unit

Claims

Patent claims:
1. A three-dim ensionally printed pharmaceutical dosage form (1) comprising
a mounting unit (2) which is mountable to a tooth (4) or two adjacent teeth (4) and (5); and a releasing unit (3) comprising a pharmacologically active ingredient.
2. The pharmaceutical dosage form (1) according to claim 1, wherein
- the mounting unit (2) comprises a material which is insoluble or poorly soluble in saliva; and/or
- the releasing unit (3) comprises a matrix material which is erodible in saliva.
3. The pharmaceutical dosage form (1) according to claim 1 or 2, wherein the mounting unit (2) and the releasing unit (3) are composed of different three-dimensionally printed materials.
4. The pharmaceutical dosage form (1) according to any of the preceding claims, wherein the mounting unit (2) does not comprise the pharmacologically active ingredient.
5. The pharmaceutical dosage form (1) according to any of the preceding claims, wherein the mounting unit (2) comprises a rigid material.
6. The pharmaceutical dosage form (1) according to any of the preceding claims, wherein the mounting unit (2) comprises a flexible material.
7. The pharmaceutical dosage form (1) according to any of the preceding claims, wherein the mounting unit (2) is mechanically mountable to the tooth (4) or the two adjacent teeth (4) and (5).
8. The pharmaceutical dosage form (1) according to any of the preceding claims, wherein the mounting unit (2) is mountable to the tooth (4) or to the two adjacent teeth (4) and (5) by a custom-fit.
9. The pharmaceutical dosage form (1) according to any of the preceding claims, wherein the mounting unit (2) is mountable to the tooth (4) by clamping the mounting unit (2) around the tooth (4).
10. The pharmaceutical dosage form (1) according to any of the preceding claims, wherein the mounting unit (2) is mountable to the two adjacent teeth (4) and (5) by clamping the mounting unit (2) into a dental interstice (6) between the two adjacent teeth (4) and (5).
11. The pharmaceutical dosage form (1) according to claims 9 or 10, wherein clamping is achievable by pressing the mounting unit (2) in a vertical direction around the tooth (4) or into the dental interstice (6) between the two adjacent teeth (4) and (5).
12. The pharmaceutical dosage form (1) according to claims 9 or 10, wherein clamping is achievable by pressing the mounting unit (2) in a horizontal direction around the tooth (4) or into the dental interstice (6) between the two adjacent teeth (4) and (5).
13. The pharmaceutical dosage form (1) according to any of the preceding claims, wherein the mounting unit (2) is mountable to the tooth (4) or the two adjacent teeth (4) and (5) by a mounting mechanism
- which does not involve volume expansion of the pharmaceutical dosage form (1) or of an element thereof; and/or
- which does not involve adhesion of the pharmaceutical dosage form (1) to the tooth (4), to the two adjacent teeth (4) and (5), or to gingiva; and/or
- which does not involve a material which has not been three-dimensionally printed.
14. The pharmaceutical dosage form (1) according to any of the preceding claims, wherein the pharmaceutical dosage form (1) does not substantially swell upon contact with saliva in the oral cavity.
15. The pharmaceutical dosage form (1) according to any of the preceding claims, wherein the pharmaceutical dosage form (1) comprises a section having a shape that corresponds to at least a section of the shape of the tooth (4) or the two adjacent teeth (4) and (5).
16. The pharmaceutical dosage form (1) according to any of the preceding claims, wherein the mounting unit
(2) comprises a section having a shape that corresponds to at least a section of the shape of the tooth (4) or the two adjacent teeth (4) and (5).
17. The pharmaceutical dosage form (1) according to any of the preceding claims, wherein the releasing unit
(3) comprises a section having a shape that corresponds to at least a section of the shape of the tooth (4) or the two adjacent teeth (4) and (5).
18. The pharmaceutical dosage form (1) according to any of the preceding claims, wherein the pharmaceutical dosage form (1), comprises a section having a surface that provides an intimate contact area with a surface of a section of at least one side of the tooth (4).
19. The pharmaceutical dosage form (1) according to claim 18, wherein the tooth (4) has an inner side (4a), a mesial side (4b), an outer side (4c), and a distal side (4d), and wherein the surface of the section of the pharmaceutical dosage form (1) provides an intimate contact area with a surface of a section of the inner side (4a), and/or the mesial side (4b), and/or the outer side (4c), and/or the distal side (4d) of the tooth (4).
20. The pharmaceutical dosage form (1) according to claim 18 or 19, wherein the intimate contact area is at least 2.0 mm2, preferably at least 3.0 mm2, more preferably at least 4.0 mm2, still more preferably at least 5.0 mm2, yet more preferably at least 6.0 mm2, even more preferably at least 7.0 mm2, most preferably at least 8.0 mm2, and in particular at least 9.0 mm2.
The pharmaceutical dosage form (1) according to any of the preceding claims, wherein the pharmaceutical dosage form (1) comprises
a first section having a first surface that provides a first intimate contact area with a surface of a section of at least one side of the tooth (4); and
a second section having a second surface that provides a second intimate contact area with a surface of a section of at least one side of the adjacent tooth (5).
The pharmaceutical dosage form (1) according to claim 21, wherein the tooth (4) and the adjacent tooth (5) each have an inner side (4a,5a), an mesial side (4b,5b), an outer side (4c,5c), and a distal side (4d,5d), wherein
- the first surface of the first section provides a first intimate contact area with the inner side (4a), and/or the mesial side (4b), and/or the outer side (4c), and/or the distal side (4d) of the tooth (4); and
- the second surface of the second section provides a second intimate contact area with the inner side (5a), and/or the mesial side (5b), and/or the outer side (5c) and/or the distal side (5d) of the adjacent tooth (5).
The pharmaceutical dosage form (1) according to claim 21 or 22, wherein the first intimate contact area together with the second intimate contact area is at least 2.0 mm2, preferably at least 3.0 mm2, more preferably at least 4.0 mm2, still more preferably at least 5.0 mm2, yet more preferably at least 6.0 mm2, even more preferably at least 7.0 mm2, most preferably at least 8.0 mm2, and in particular at least 9.0 mm2.
The pharmaceutical dosage form (1) according to any of the preceding claims, wherein the mounting unit (2) comprises a distal element (21), a proximal element (22), and a base (23), wherein the base (23) connects the distal element (21) with the proximal element (22).
The pharmaceutical dosage form (1) according to any of claims 24, wherein two adjacent teeth (4) and (5) to which the mounting unit (2) is mountable each have an inner (lingual, palatal) side (4a,5a), an outer (buccal, labial, vestibular) side (4c,5c), and wherein the base (23) is mountable to the dental interstice (6) between the two adjacent teeth (4) and (5) in a manner such that the distal element (21) is positioned at the outer side (4c,5c) of the adjacent teeth (4) and (5), the proximal element (22) is positioned at the inner side (4a,5a) of the adjacent teeth (4) and (5), and the base (23) is positioned at the dental interstice (6) between the adjacent teeth (4) and (5).
The pharmaceutical dosage form (1) according to claim 25, wherein the base (23) is mountable to the dental interstice (6) between the two adjacent teeth (4) and (5) in a manner such that
- the distal element (21) is in intimate contact with the outer side (4c,5c) of the adjacent teeth (4) and (5); and/or - the proximal element (22) is in intimate contact with the inner side (4a,5a) of the adjacent teeth (4) and (5); and/or
- the base (23) intimately fills the dental interstice (6) between the adjacent teeth (4) and (5).
27. The pharmaceutical dosage form (1) according to any of claims 24 to 26, wherein the distal element (21) and/or the proximal element (22) and/or the base (23) has a shape that is adapted to at least a section of the shape of the two adjacent teeth (4) and (5) and to at least a section of the shape of the dental interstice (6), respectively.
28. The pharmaceutical dosage form (1) according to any of claims 24 to 27, which comprises
a distal releasing unit (31) connected to the distal element (21); and/or
a proximal releasing unit (32) connected to the proximal element (22).
29. The pharmaceutical dosage form (1) according to claim 28, wherein the distal releasing unit (31) and the proximal releasing unit (32)
comprise different pharmacologically active ingredients; and/or
- provide different release kinetics of the pharmacologically active ingredient.
30. The pharmaceutical dosage form (1) according to any of the preceding claims, which comprises no element selected from flexible films, flexible sheets, and discs.
31. The pharmaceutical dosage form ( 1 ) according to any of the preceding claims, which does not assume the shape of a dental brace or a dental bracket or a mouthgard.
32. The pharmaceutical dosage form (1) according to any of the preceding claims, which provides prolonged release of the pharmacologically active ingredient.
33. The pharmaceutical dosage form (1) according to any of the preceding claims, which is for local administration of the pharmacologically active ingredient.
34. The pharmaceutical dosage form (1) according to any of claims 1 to 32, which is for systemic administration of the pharmacologically active ingredient.
35. The pharmaceutical dosage form (1) according to claim 34, which is for peroral administration of the pharmacologically active ingredient.
36. The pharmaceutical dosage form (1) according to claim 34, which is for buccal administration of the pharmacologically active ingredient.
37. The pharmaceutical dosage form (1) according to claim 34, which is for sublingual administration of the pharmacologically active ingredient.
38. The pharmaceutical dosage form (1) according to any of the preceding claims, wherein the pharmacologically active ingredient is selected from analgesics, stimulants, tranquilizers, narcotics, and anesthetics.
39. The pharmaceutical dosage form (1) according to any of the preceding claims for use in therapy, wherein the pharmaceutical dosage form (1) is mounted to one or more adjacent teeth (4) and (5) and thus positioned in the oral cavity for at least 6 hours.
40. The pharmaceutical dosage form (1) for use according to claim 39, wherein the pharmaceutical dosage form (1) is positioned in the oral cavity for at least 12 hours.
41. The pharmaceutical dosage form (1) for use according to claim 40, wherein the pharmaceutical dosage form (1) is positioned in the oral cavity for at least 24 hours.
42. A process for the preparation of a pharmaceutical dosage form (1) according to any of the preceding claims, wherein the process comprises a three-dimensional printing step.
43. The process according to claim 42, which comprises the step of
(a) scanning the dental interstice between two adjacent teeth of the patient where the pharmaceutical dosage form is later to be mounted in the oral cavity of the patient; and
(b) three-dimensionally printing the pharmaceutical dosage form with a shape that accurately fits into the dental interstice as scanned in step (a).
44. The process according to claim 43, wherein scanning step (a) involves the use of a laser.
45. The process according to claim 43 or 44, wherein the result of scanning step (a) is used in order to calculate the appropriate shape of the pharmaceutical dosage form to be printed in step (b).
46. The process according to any of claims 42 to 45, wherein the three-dimensional printing step involves fused deposition modeling.
47. The process according to any of claims 42 to 45, wherein the three-dimensional printing step involves a powder-based three-dimensional printing technology.
48. The process according to any of claims 42 to 45, wherein the three-dimensional printing step involves Binder Jet Technique.
49. The process according to any of claims 42 to 45, wherein the three-dimensional printing step involves a liquid-based three-dimensional printing technology.
50. The process according to any of claims 42 to 45, wherein the three-dimensional printing step involves Stereolithography printing technology.
51. The process according to any of claims 42 to 50, wherein the pharmaceutical dosage form is three- dimensionally printed by depositing individual three-dimensional microstructures having an individual volume of at most 1.5 mm3.
52. The process according to any of claims 42 to 51, wherein the three-dimensional printing step comprises three-dimensionally printing two different three-dimensionally printable materials.
53. A pharmaceutical dosage form obtainable by the process according to any of claims 42 to 52.
PCT/EP2017/059104 2016-04-20 2017-04-18 Pharmaceutical dosage form mountable to a tooth WO2017182425A1 (en)

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EP16166160.8 2016-04-20

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