CN1239425A - Pharmaceutical dosage form with multiple enteric polymer coatings for colonic delivery - Google Patents
Pharmaceutical dosage form with multiple enteric polymer coatings for colonic delivery Download PDFInfo
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- CN1239425A CN1239425A CN 96180548 CN96180548A CN1239425A CN 1239425 A CN1239425 A CN 1239425A CN 96180548 CN96180548 CN 96180548 CN 96180548 A CN96180548 A CN 96180548A CN 1239425 A CN1239425 A CN 1239425A
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Abstract
The present invention relates to a pharmaceutical composition in a unit dosage form for peroral administration in a human or lower animal, having a gastrointestinal tract comprising a small intestine and a colon with a lumen therethrough having an inlet to the colon from the small intestine, comprising: a safe and effective amount of a therapeutically active agent incorporated into or coated on the surface of a dosage form selected from the group consisting of a spherical substrate, an elliptical substrate, a hard capsule, or a compressed tablet, with a maximum diameter of about 3 mm to about 10 mm; and an enetric polymer coating material comprising at least one inner coating layer and one outer coating layer; wherein the dosage form has a smooth surface free from edges or sharp curves; the elliptical substrate and the hard capsule have a rtio of the long to short diameters of no greater than about 1.5; the therapeutically active agent is released at a point near the inlet to, or within the therapeutically active agent is released at a point near the inlet to, or within the colon; each of the inner coating layer is an enteric polymer that begins to dissolve in an aqueous media at a PH between about 5 to about 6.3; and the outer coating layer is an enteric polymer that beings to dissolve in an aqueous media at a pH between about 6.8 to about 7.2.
Description
Invention field
The present invention relates near the colon porch certain a bit or discharge the spherical dosage form of unit of the novelty of therapeutic agent in the colon.
Background of invention
Need in colon, discharge from the therapeutic activity agent of oral administered dosage form in some cases, described situation comprises: (1) topical therapeutic colonic diseases, as constipation, irritable bowel syndrome (IBS), Crohn disease, ulcerative colitis, cancer with do not need whole body to absorb the infection of therapeutic agent; (2) whole body absorb such as peptide and proteinic therapeutic agent, their can intracavity degraded in the harmonization of the stomach small intestinal; (3) whole body absorbs therapeutic agent, in oral back (promptly after the peak concentration that just needs to occur described therapeutic agent for a long time and pharmacologically active, oral before sleeping, the blood drug level peak value appearred to the preceding morning of getting up). colon discharges the therapeutic activity agent needs from oral administered dosage form: for Topically active or whole body absorption, can prevent to discharge described medicine, but allow in colon, to discharge at the harmonization of the stomach small intestinal.This preparation that requires successively to design has, with respect to other gastrointestinal tract part, the indication medicament arrives advantage (M.Ashford and the J.T.Fell of the gastrointestinal feature of colon, target administration magazine (J.Drug Targeting), 1994,2:241-258). variable feature comprises pH, ionic strength, superficial velocity and bacterial content and unit dose retention time (M.Ashford and the J.T.Fell therein of some region of anatomy chamber inclusions of gastrointestinal tract, the target administration magazine, 1994,2:241-258; S.S.Davis, controlled release magazine (J.Contr.Rel.) 1985,2:27-38).
Pharmaceutical unit dosage forms the retention time of stomach especially changeable (M.Ashford and J.T.Fell, target administration magazine (J.Drug Targeting), 1994,2:241-258).But unit dosage forms is constant relatively through the time of small intestinal, average about 3 hours (M.Ashford and J.T.Fell, target administration magazine (J.DrugTargeting), 1994,2:241-258).Residence time in the colon is usually than the length of gastrointestinal tract other parts, but the time in each section can change largely (M.Ashford and J.T.Fell, target administration magazine (J.Drug Targeting), 1994,2:241-258).
The pH characteristic of gastrointestinal tract chamber inclusions has also been characterized and has been found to be constant relatively (D.F.Evans, G.Pye, R.Bramley, A.G.Clark and T.J.Dyson, Gut, 1988,29:1035-1041). the pH of stomach can be changed by the meals state temporarily, but is usually less than about pH2.The pH of small intestinal is increased to about 7.2 of small intestinal tip part (ileum) gradually from about 5-5.5 in duodenal bulb.Obviously drop to approximately 6.3 at ileocecum junction pH value, be increased to about 7 gradually in the left side or the descending colon part of colon.
Colon is to have external antibacterial to exist with respect to the distinguishing characteristics of gastrointestinal tract other parts.Their energy enzyme catalysiss, and host animal can not carry out this reaction.
Usually have recognized that the medicament that design discharges for colon can show that preparation has arrived colon for the gastrointestinal tract other parts with one of following feature: the pH of (1) chamber inclusions up to the ileocecum junction total profile that raises; (2) unit dosage forms constant relatively retention time (the stomach retention time that compensation alters a great deal) in small intestinal; (3) exist in the colon external antibacterial (M.Ashford and J.T.Fell, target administration magazine (J.DrugTargeting), 1994,2:241-258).
The characteristic of the rising that the pH of employing gastrointestinal tract chamber inclusions is total typically adopts the film coating of enteric polymer as the dosage form of the design feature of indication arrival colon.These enteric polymers are in water and insoluble but began dissolved multi-anion copolymer at about 5 o'clock at pH at low pH.Commercially available enteric polymer begins dissolving when the about 5-7 of pH.
The example that utilizes this type ultimate principle to design at the colon delivery formulations comprises: USP5; 171; 580; December was authorized gondola Boehringer Ingelheim on the 15th in 1992; proposition is at large intestine; the preparation that particularly discharges in colon comprises the three layers of nuclear core that the protective layer coating of different solubilities is arranged of usefulness that contain active substance.Internal layer is Eudragit
S, thickness is about the 40-120 micron, middle coatings is the polymer of swellable, coating thickness is about 40-120 micron, and skin is cellulose ethanoate phthalic acid ester, hydroxypropylmethyl cellulose phthalate, polyvinyl acetate phthalic acid ester, hydroxyethyl-cellulose phthalic acid ester, cellulose ethanoate tetrahydrophthalic acid ester or Eudragit
L.In dosage form of the present invention, Eudragit
S is only as outer.
USP 4,910, and 021,1990,3,20 authorize Scherer Corp., proposed a kind of targeting drug release system, and wherein compositions comprises hard capsule or the soft capsule that contains active component such as insulin and absorption enhancer.Capsule is used in pH and is higher than 7 o'clock abundant dissolved film-forming composition coatings of energy, and the result can make described capsule by corrosion or stripping.Film-forming composition is Eudragit preferably
L, Eudragit
RS and Eudragit
The mixture of S, its consumption ratio are that deliquescent specific ratios can be provided more than pH7.
USP 4; 432; 966; 1984; 2; 21 authorize Roussel-UCLAF; proposed to have the compressed tablet of activating agent; applied by first coatings and second coatings; the film that first coatings comprises microcrystalline Cellulose and cellulosic low alkyl group ether mixture is formed with organic polymer; as ethyl cellulose, second coatings is selected from cellulose acetyl group phthalic acid ester; hydroxypropylmethyl cellulose phthalate; the benzo phenyl salicylic acid esters; cellulose acetyl group succinate; the copolymer of styrene and maleic acid; the gelatin of preparation; phenyl salicytate; keratin; stearic acid; myristic acid; glutelin; the copolymer of acrylic acid and methacrylic resin and maleic acid and phthalic acid derivatives.
Exist some difficulties with pH as the indicator that preparation arrives colon.Though the pH of chamber inclusions is increasing through small intestinal gradually from stomach, the pH of the chamber inclusions of proximal colonic is lower than small intestinal tip (ileum) and locates.This is because the existence that the effect of the about endophytic bacteria of colon has produced short-chain fatty acid.Therefore, given pH value can not distinguish the different piece of colon and small intestinal.Design makes therapeutic agent also can discharge therapeutic agent at small intestinal near ileum place (its pH is similar to proximal colonic) at the preparation that the pH of proximal colonic discharges.Therefore, people have proposed query M.Ashford, J.T.Fell, target administration magazine, 1994,2:241-258 to the effectiveness that uses enteric coating to reach colon release; M.Ashford, J.T.Fell, D.Attwood, and P.J.woodhead, Inpharm magazine, 1993,91:241-245; M.Ashford, J.T.Fell, D.Attwood, H.L.Sharma and P.J.woodhead, the Inpharm magazine, 1993,95:193-199).
Though only the pH of chamber inclusions can not make other different piece of colon and small intestinal make a distinction, but pH value can distinguish stomach and small intestinal and colon really. use enteric polymer coatings that stomach and small intestinal are distinguished in the prior art widely, and prevent that preparation from discharging therapeutic agent before the stomach emptying.This application causes being studying for a long period of time that the safety that confirms these polymer is carried out, and lot of documents has disclosed these polymer are applied to the appropriate method on the preparation and the commercial source of many enteric polymers as the coating thing.
Now have recognized that, the dosage form (its time delay is corresponding to the time of staying of harmonization of the stomach small intestinal) that therapeutic agent postpone to be discharged will provide colon discharge (S.S.Davis, J.Contr.Rel., 1985,2:27-38).This supposes that mainly based on the constant rational residence time in small intestinal other use enteric polymer coatings can prevent based on postponing the stomach residence time that the machine-processed time activates compensate for variable before making preparation arrive small intestinal.The time delay mechanism that proposes comprise based on slow stripping (A.Gazzaniga, P.Lamartino, the G.Maffione and the M.E.Sangalli of the irrelevant coating of pH, Proceed.6th Int.Conf.on Pharm.Techn. (Paris) 305-313,1992), controlled and pH are irrelevant, the infiltration that water is coated is so that activate disintegrate (F.Theeuwes, the P.L.Wong of dosage form by osmotic pressure, T.L.Burkoth and D.A.Fox, absorb and metabolism at colonic drug, P.R.Bieck edits, Marcel Dekker, Inc., New York, Basel, Hong Kong, 137-158 (1993)) or by physics swelling (R.Ishino, H.Yoshino, Y.Kirakawa and K.Noda, Chem.Pharm, Bull., 1992,40:3036-3041) reach the hydration that has nothing to do with pH and come swelling and ejection stopper (I.R.Wilding, S.S.Davis, M.Bakhshaee, H.N.E.Stevens, R.A.Sparrow and J.Brennan, Pharm.Res., 1992,9:654-657).Such means are in the preparation size, the repeatability of release time, and complexity and expense aspect can not be entirely satisfactory.
Though enteric polymer has very long commerce to use history and they stomach residence times of compensate for variable inherently, produce therapeutic agent based on the time with their and postpone to discharge (based on the dissolving of enteric polymer coatings) and do not obtain promotion.The chances are for this because the changeableness of enteric polymer stripping is the function with small intestinal and colonic lumen inclusions pH and rapid change.But the dosage form that discharges with the colon that reaches the preparation polymer coating dissolution time that discharges based on the intestinal colon with enteric polymer has various advantages with regard to certified safety of these polymer and industrial applicibility method.
An object of the present invention is to provide by using unique, a plurality of enteric polymer coatings layers, the colon that makes therapeutic agent just postpone the unit dosage forms that discharges up to proximal colonic discharges therapeutic agent.
Summary of the invention
The present invention relates to for gastrointestinal people or lower animal being arranged with the oral pharmaceutical composition of unit dosage forms, described gastrointestinal tract comprises small intestinal and colon, and there is tube chamber the centre, from small intestinal one colon that enters the mouth is arranged, and described compositions comprises:
A. mix or wrap in the therapeutic activity agent of the safe and effective amount on dosage form surface, described dosage form is selected from sphere matrix, ellipticalness substrate, hard capsule or compressed tablets, and its maximum gauge is about 3 millimeters to 10 millimeters; With
B. the enteric polymer coatings material that comprises coatings and one deck outer coatings layer in one deck at least;
Dosage form smooth surface wherein, non-flanged or sharp keen curve; The ratio in the long and short footpath of ellipticalness substrate and hard capsule is not more than about 1.5; The therapeutic activity agent near the porch of colon certain a bit or in colon, discharge; Coatings is to begin dissolved enteric polymer in pH for the aqueous medium between about 5-6.3 in each; The outer coatings layer is to begin dissolved enteric polymer in pH for the aqueous medium between about 6.8-7.2.
Detailed Description Of The Invention
Use enteric polymer to come the later treatment agent to discharge from pharmaceutical unit dosage forms, arrive colon until described dosage form, this is not success fully as yet so far.Unsuccessful reason comprises:
A. with respect to distal small intestine (ileum), the pH of proximal colonic chamber inclusions reduces, the recognition factor that this has hindered foregoing use pH to discharge as colon;
B. be difficult to design the enteric polymer coatings on a kind of unit dosage forms, when this dosage form remains in the small intestinal, because the small intestinal and the pH of colonic lumen inclusions and the variation coating of speed can dissolve fully; With
C. in conventional unit formulation, the weak part of the enteric polymer coatings of formation edge and sharp keen curve breaks enteric polymer coatings too early and discharges therapeutic agent.
What the dosage form of enteric polymer coatings of the present invention was designed to therapeutic agent delays release time roughly corresponding to the time of staying in small intestinal, rather than with given pH value as the recognition factor that arrives colon.This has eliminated proximal colonic with respect to the ileum pH caused problem that descends.
The present inventor has found that, solubility behavior that can be by 1. selected enteric polymers is as dosage form size and the pH of aqueous medium and the knowledge of function of speed, 2. by estimating that the pH of the segmental chamber of dissection inclusions and superficial velocity decide the consumption and the type of the needed enteric polymer of the time of staying that makes therapeutic agent delay to discharge roughly to be equivalent in small intestinal continuously for small intestinal and colon.Because need be in colon final stripping enteric coating, must select the enteric polymer of component unit dosage form coatings and be applied on the dosage form, the result was proximal colonic or at maximum pH about 6.3 o'clock, and coating can dissolve.If use single enteric polymer, reaching therapeutic agent, to delay to discharge required enteric polymer consumption quite big, substantially exceeds consumption that prior art discloses (referring to P﹠amp; The patent application of awaiting the reply jointly of G, file number: 5673, Kelm and Manring, 1995,5,17 submit to).But,, can reduce and reach the total amount that slow release is put the enteric polymer coatings agent that needs if use unique, a plurality of enteric polymer coatings layers.Outermost layer is made of enteric polymer, and described enteric polymer begins dissolving when the about 6.8-7.2 of pH, and its consumption is such, makes this coatings in the consoluet amount in distal small intestine part (ileum) lining.Interior coatings is made of the dissolved enteric polymer of beginning under the about 5.0-6.3 of pH, and its consumption is can dissolve fully substantially in proximal colonic.Like this, the function of outer coatings layer is to discharge when dosage form prevents therapeutic agent during through the gastrointestinal tract tip.The function of interior coatings is the release of further later treatment agent, arrives the colon proximal end until dosage form.
Dosage form of the present invention enteric polymer coatings dissolving fully basically before discharging therapeutic agent ideally is so that the predetermined dissolution time of enteric polymer coatings of guaranteeing specified rate is corresponding to release time that delays of therapeutic agent.This requires the enteric polymer film coating thickness on the dosage form even.Weak part in the enteric polymer coatings can betide the edge and the sharp keen curve place of conventional formulation, causes enteric polymer coatings to break too early and the release of therapeutic agent.Therefore, dosage form of the present invention is spheric or oval-shaped, and size is almost even, has slick surface, does not have edge or sharp keen curve basically, so that each unit dosage forms has the enteric polymer coatings of uniform thickness.
The present invention relates to for gastrointestinal people or lower animal being arranged with the oral pharmaceutical composition of unit dosage forms, described gastrointestinal tract comprises small intestinal and colon, and there is tube chamber the centre, from small intestinal one colon that enters the mouth is arranged, and described compositions comprises:
A. mix or wrap in the therapeutic activity agent of the safe and effective amount on dosage form surface, described dosage form is selected from sphere matrix, ellipticalness substrate, hard capsule or compressed tablets, and its maximum gauge is about 3 millimeters to about 10 millimeters; With
B. the enteric polymer coatings material that contains at least one an interior coatings and an outer coatings layer;
Dosage form smooth surface wherein, non-flanged or sharp keen curve; The ratio in the long and short footpath of ellipticalness substrate and hard capsule is not more than about 1.5; The therapeutic activity agent near the porch of colon certain a bit or in colon, discharge; Coatings is the dissolved enteric polymer of beginning in the aqueous medium between the about 5-6.3 of pH in each; The outer coatings layer is the dissolved enteric polymer of beginning in the aqueous medium between the about 6.8-7.2 of pH.
The routine that dosage form of the present invention is different from the period that prolongs slow release therapeutic agent and has a prolongation discharges the compositions that the control (delaying) of the continued treatment effect that can reach is released.Dosage form of the present invention prevents the release of active therapeutic agent before dosage form arrives colon.Therapeutic agent rate of release subsequently requires to decide according to the pharmacokinetics of particular therapeutic agent, can be from rapidly to slowly.
Preferably, the enteric polymer coatings material has an interior coatings and an outer coatings layer.
The therapeutic activity agent
Method and composition of the present invention comprises the therapeutic activity agent of safe and effective amount." safe and effective amount " used herein is illustrated in the rational medical judgment scope, and the consumption of therapeutic activity agent is high enough to provide significantly actively improvement to the disease that quilt is treated, but low to avoiding serious adverse (having rational benefit/danger ratio).The therapeutic activity agent of safe and effective amount is decided on the order of severity of the specified disease of being treated, the age of being treated patient and health, disease, the persistent period of treatment, the character of common therapy, chosen factors such as therapeutic agent.
The therapeutic agent that is fit to mix the present composition is that those colonic discharge or the useful therapeutic agent of treatment when delaying to discharge.These therapeutic agents comprise and are used for the topical therapeutic colonic diseases, as constipation, diarrhoea, irritable bowel syndrome (IBS), Crohn disease, ulcerative colitis, cancer with do not need whole body to absorb the therapeutic agent of the infection of therapeutic agent.These therapeutic agents comprise the cathartic such as pyrrole benzene oxygen sulphur salt (picosulfate) and sennoside, anti-diarrhea agents such as the chlorine loperamide, nonsteroidal anti-inflammatory such as 5-aminosalicylic acid, glucocorticoids and antimicrobial such as dexamethasone, particularly such as the effective medicine of anti-anaerobe of methotrexate, such as the chemotherapeutics of the immunosuppressant and the treatment cancer of ciclosporin A.
The therapeutic agent of some, particularly peptide and protein can be degraded in the generation cavity in stomach and small intestinal.Colon is the preferred place that absorbs this compounds, because enzymatic activity lower (M.Mackay and E.Tomlinson in the colonic lumen, colonic drug absorbs and metabolism (Colonic Drug Absorption and Metabolism), P.R.Bieck edits, Marcel Dekker, Inc., the USA New York, Basel, Hong Kong, 137-158 (1993)).The peptide and the protein that have the general bioavailability advantage of improvement in colon when discharging comprise calcitonin, insulin and human growth hormone.Under specific situation, peptide or protein can be prepared with a kind of system increases this macromolecular absorption (Colonic Drug Absorption and Metabolism), and P.R.Bieck edits, MarcelDekker, Inc., USA New York, Basel, Hong Kong, 137-158 (1993)).
The whole body absorption therapeutic agent that need delay to occur (promptly oral before sleep, as the morning getting up before to occur the peak value of blood drug level) significantly for the whole body peak concentration of oral drugs and pharmacologically active also needs the release of colon.This is for such as asthma, arthritis, inflammation, coronary artery infraction and the disease advantageous particularly (B.Lemmer of the rhythm and pace of moving things between anginal daytime, Pulsatile Drug Delivery, R.Gumy, H.E.Junginger and N.A.Pepas edit, Wissenschaftliche Verlagsgesellschaft mbH, Stuttgart, 11-24 (1993)).The medicine that changes its effect in clinical research the every day of having reported comprises cardiovascular drugs such as beta-Blocking agent (acebutolol, Propranolol), calcium channel blocker (verapamil) and ACE inhibitor (enalapril), anticarcinogen such as cisplatin and amycin, antasthmatic such as theophylline, the Psychotropic drug diazepam, H
1-antihistaminic such as terfenadine, NSAID (non-steroidal anti-inflammatory drug) such as flurbiprofen, naproxen and sieve former times health and H
2-blocker such as cimetidine and ranitidine.
The known method that meets physical and chemical properties of drugs and pharmacodynamic properties thereof of the available present technique of therapeutic activity agent field personnel is mixed the surperficial or middle of one of several substrate described herein.Recognize that now the rate of release of therapeutic activity agent in colon depends on the method for mixing of therapeutic activity agent and the consumption and the character of any excipient.Rate of release should be to make the therapeutic activity of medicament reach maximum.
" excipient " used herein expression mixes with the therapeutic activity agent or common doped matrix surface or intermediary any component.Excipient can make on the easy doped matrix of therapeutic activity agent or in the substrate, improves the release of therapeutic activity agent in the substrate, stablize the absorption of therapeutic activity agent or the agent of increase therapeutic activity.Excipient should be safe under the level of preparation being used for, and with the therapeutic activity agent be compatible.The prescription of therapeutic activity agent and excipient can be selected for the standard that reaches required rate of release, stability, absorbs and be convenient to prepare dosage form according to present technique field personnel are known.
Dosage form
The therapeutic activity agent of safe and effective amount is impregnated in or wraps in the dosage form surface that is selected from sphere matrix, ellipticalness substrate, hard capsule or compressed tablets, the about 3-10 millimeter of the maximum gauge of these dosage forms; Wherein dosage form has the smooth surface of non-flanged or sharp keen curve; The ratio of the line of apsides of oval substrate and hard capsule is not more than about 1.5.
Dosage form of the present invention preferably be selected from gelatin soft capsule, can fusion or molded ball or the oval ball made of any pharmaceutically acceptable excipient of mold pressing, on the nucleus that pharmaceutically acceptable any inert excipient is made, carry out coating and the ball made, have smooth unskirted hard capsule, and the compressed tablets of sealing, wherein dosage form has the smooth surface of non-flanged or sharp keen curve, and the ratio in the long and short footpath of ellipticalness substrate and hard capsule is not more than 1.5.
A kind of axiolitic solid configuration of " ellipticalness substrate " used herein expression, wherein all surfaces are almost the planar solid of ellipse or circumference, by equation x
2/ a
2+ y
2/ b
2+ z
2/ c
2Expression, b=c wherein, a/b≤1.5, " a " is between 3 and 10 millimeters.
" smooth surface that does not have edge or sharp keen curve " used herein is illustrated in and do not have the edge on the dosage form, and these edges are enough to form the weak part with respect to average coating thickness on enteric coating.Particularly preferred dosage form is the sphere that diameter is about the 3-8 millimeter; More preferably about 4-7 millimeter.Preferably all dosage forms all have uniform size before with polymer coating material coating.With all spheric diameters basically average diameter 5% in be good, preferably in about 2%.Smooth surface and evenly size make coating thickness even, therefore stripping polymer coating material equably.
Dosage form preferably is made up of sphere matrix (as sugared ball NF) coated and/or the non-activity that the coating processing is made.These substrate through the screening and/or (promptly separating with weight checker) the go-on-go size of weighing, obtain needed homogeneous diameter before coating.Preferably basically all spheric diameters all average diameter about 5% in, be more preferred from about 2%.Then it is used therapeutic activity agent coating.The therapeutic activity agent is fixed on the sugared ball with the water solublity inert polymer and is advisable, and is preferably low-viscosity hydroxypropylcelluloand or hydroxypropyl emthylcellulose.The ratio of adhesive polymer and therapeutic activity agent is about 1: 10 to 10: 1; Be preferably about 1: 5 to 5: 1; Be more preferred from about 1: 4 to 1: 1.
The coating of therapeutic activity agent on sugared ball can at random be about the 10-50 micron with inertia water-soluble polymer bag coat to thickness, is preferably about 20-40 micron.This coat is called the barrier coating herein.The barrier coating preferably is made up of low-viscosity hydroxypropylmethylc,llulose.When substrate is sugared ball, and interior enteric polymer coatings material is when being Cellacefate, and dosage form preferably also comprises one deck barrier coating between therapeutic activity agent and Cellacefate.Activating agent coating and barrier coating can adopt any the whole bag of tricks well known by persons skilled in the art to put on the commercially available inertia sphere matrix, these methods include but not limited to bore a hole pan coating and fluidized bed coating.
Dosage form also can comprise inertia molding spherical or ellipticalness substrate." mold pressing " used herein refers to fusion or semisolid pharmaceutically acceptable inert material injection nib are made its solidified method.Therefore, the diameter of nib has determined the diameter of substrate.Suitable material includes, but is not limited to edible pharmaceutically acceptable wax, as Cera Flava, paraffin, Brazil wax, the about triglyceride more than 50 ℃ of fusing point, and as tristearin, and the about high molecular weight polyethylene glycol more than 50 ℃ of fusing point.The therapeutic activity agent can be in mold process doped matrix or on the substrate after the mold pressing coating, and randomly use water solublity inert polymer bag coat as mentioned above.
Further preferred unit dosage forms is the elasticity gelatin soft capsule of sphere or ellipticalness.This elasticity gelatin soft capsule filling is suspended in the therapeutic activity agent in the appropriate excipients compatible with gelatin soft capsule.
The ratio that further preferred unit dosage forms is long and short footpath is not more than the non-flanged hard capsule (being starch or snap fit capsule) of 1.5 smooth sealing.An example is that (length of this capsule major axis is not more than about 1.5 times of capsule minor axis diameter less than about 10 millimeters for Greenwood, the no marginal surface starch capsule of the Capill by name of commodity SC) available from Capsulgel.The solid therapeutic activity agent of filling or be dissolved in or be suspended in therapeutic activity agent in the appropriate excipients compatible as mentioned above of this starch capsule with capsule wall.
Preferred in addition unit dosage forms is that maximum gauge is about the non-flanged of 3-10 millimeter and the spherical or oval compressed tablets of sharp keen curve.Tablet comprises the therapeutic activity agent of solid form, forms with conventional equipment and method compacting.
The enteric polymer coatings material
In the present composition, the polymer coating material near colon and small intestinal junction or before arriving colon, can prevent dosage form through upper gastro-intestinal tract in dosage form, discharges the therapeutic activity agent when comprising oral cavity, esophagus, stomach and small intestinal.This can get rid of the therapeutic activity agent upper gastro-intestinal tract carry out that whole body absorbs and/or the therapeutic activity agent that discharges diluted in upper gastro-intestinal tract.Therefore, the polymer coating material provides the method that the therapeutic activity agent is discharged into colon with conc forms with the cooperation spherical or oval-shaped substrate with smooth surface.
" enteric polymer coatings material " used herein refers to center on and wrap up fully the material of the therapeutic activity agent in the unit dosage forms before oral.Polymer coating material of the present invention does not contain any reactive compound of the present invention, i.e. therapeutic activity agent.In addition, the present invention does not comprise the enteric coating crystallite spheroid of reactive compound or the enteric coating granule of granule or reactive compound.Preferably, the fundamental quantity of enteric polymer coatings material or all amount is all dissolved before the therapeutic activity agent discharges in the dosage form, therapeutic activity agent is as a result delayed the ground stripping.
The selective polymer coating material is so that dosage form approximately arrives the porch between small intestinal and the colon or discharges therapeutic activity agent agent after this in colon the time.Selection is based on the pH curve of small intestinal and colon.The pH of small intestinal rises to about 7.2 of small intestine distal end part (ileum) gradually from the about 5-5.5 in pyloric cap.Obviously drop to approximately 6.3 at ileocecum junction pH value, be increased to about 7 gradually in the left side or the descending colon part of colon.For about 3 hours of corresponding elapsed time at small intestinal being provided and making the porch of medicine between small intestinal and colon or the expected dissolution time that in colon, discharges subsequently, coating should begin dissolving in the pH of small intestinal scope, and continues stripping under the pH of colon near-end.This represent the single coatings of single enteric polymer coatings material in the about 5-6.3 scope of pH, begin the dissolving, this require the coating minimum thickness be 250 microns (referring to P﹠amp; The G patent application file number 5673 that awaits the reply jointly, Kelm and Manring, 1995,5,17 submit to).The single coats of enteric polymer coatings material is in higher pH level, and 7 begin dissolving according to appointment, and the coating thickness of the dosage form of inlet or arrival colon is thin slightly between this requirement arrival small intestinal and the colon.But when dosage form reached colon, any residual coating was insoluble to the near-end that pH is lower than 7 colon, like this medicine was delayed pH that dosage form arrives the chamber and just discharged greater than 7 colon part.
In order in proximal colonic, to discharge, make enteric polymer coatings thickness minimum simultaneously, enteric polymer coatings material of the present invention is by successive a plurality of, and preferably two, the multiple coatings of different materials constitutes.Outside coatings is by being that the enteric polymer coatings material that begins stripping between about 6.8-7.2 constitutes at pH, and its consumption is when dosage form consoluet amount of this layer during at small intestine distal end.Internal layer is by at the about 5-6.3 of pH, and preferably between the about 5-6 of pH, optimum is the dissolved enteric polymer coatings material of beginning between the about 5-5.5 of pH.The consumption of internal layer is such, makes medicine delay dosage form and arrives just release in porch between small intestinal and the colon or the colon.Like this, to be prophylactic agent discharge to the small intestine distal end place at stomach the outer coatings layer function of enteric polymer coatings material, the function of interior coatings be prophylactic agent the small intestine distal end place between small intestinal and the colon inlet or colon in discharge (outermost coatings is molten at this moment goes).
The enteric polymer coatings material of preferred outer coatings layer comprises the material of pH-sensitivity, and it is complete in the low pH environment of stomach and small intestinal, but begins dissolving in the aqueous solution between the about 6.8-7.2 of pH.Coating thickness depends on the size of unit dosage forms, and its scope is about 20-50 micron.The preferred material of the outer coatings layer of enteric polymer coatings material is poly-(methacrylic acid, methyl methacrylate) 1: 2 (Eudragit
S), poly-(methacrylic acid, methyl methacrylate) 1: 1 (Eudragit
L) with poly-(methacrylic acid, methyl methacrylate) 1: 2 (Eudragit
S) mixture, its ratio are about 1: 10 to 1: 2, preferably about 1: 5 to about 1: 3.Particularly preferably be Eudragit
S.
Eudragit
L is the anionic copolymer derived from methacrylic acid and methyl methacrylate, about 1: 1 of the ratio of free carboxy and ester group, and mean molecule quantity is about 135,000, and Rohm Tech produces; Eudragit
S is the anionic copolymer derived from methacrylic acid and methyl methacrylate, about 1: 2 of the ratio of its free carboxy and ester group, and its mean molecule quantity is about 135,000, and Rohm Tech produces.
The preferred coating material of inner coating layer comprises the material of pH-sensitivity, and it is complete in the low pH environment of stomach and small intestinal, but at small intestine distal end, particularly beginning disintegrate or dissolving under the pH of colon near-end.Interior coatings polymer has low apparent pKa scope, so that return-and the pH drop minimum of caecum valve.Interior coatings enteric polymer begins dissolving in the aqueous solution between the about 5-6.3 of pH.Particularly importantly enteric polymer is soluble at the near-end of colon, and wherein the pH of intracavity typically is lower than the distal portions of small intestinal owing to there has been the short-chain fatty acid of the metabolic activity generation that remains in the antibacterial in the colon.
The enteric polymer coatings material of internal layer is selected from the cellulose ethanoate phthalic acid ester; Cellulose ethanoate benzenetricarboxylic acid ester (trimelliate); Hydroxypropylmethyl cellulose phthalate; The hydroxypropyl methyl cellulose acetate succinate; The polyvinylacetate phthalic acid ester; Poly-(methacrylic acid, methyl methacrylate) 1: 1; Poly-(methacrylic acid, ethyl acrylate) 1: 1; With the mixture compatible with it, preferably gathered (methacrylic acid, methyl methacrylate) 1: 1 and poly-(methacrylic acid, ethyl acrylate) 1: 1, with and compatible mixture, more preferably poly-(methacrylic acid, ethyl acrylate) 1: 1.
The object lesson of these polymer coating materials comprises: Eudragit
L, a kind of anionic copolymer derived from methacrylic acid and methyl methacrylate, the ratio of free carboxy and ester group is about 1: 1, and mean molecule quantity is about 135,000;
Eudragit
L 30 D, a kind of aqueous dispersions of acrylic resin, derived from the anionic copolymer of methacrylic acid and ethyl acrylate, the ratio of free carboxy and ester group is about 1: 1, and mean molecule quantity is about 250,000; (providing) with the aqueous dispersions that contains 30%w/w dryness lacquer material;
Eudragit
L 100-55, derived from the anionic copolymer of methacrylic acid and ethyl acrylate, the ratio of free carboxy and ester group is about 1: 1, and mean molecule quantity is about 100,000;
Cellacefate or CAP
, Eastman Chemical sells; Acetic acid benzenetricarboxylic acid cellulose, the CAT that Eastman Chemical sells
Hydroxypropyl Methylcellulose Phathalate (the USP/NF type 220824) HPMCP 50 that Shin Etsu Chemical sells
(USP/NF type 200731) HPMCP55
Acetic acid phthalic acid polyvinyl ester, PVAP
, Colorcon sells; HPMC-AS, HPMCAS
, Shin Etsu Chemical sells.
Preferred polymer coating material is poly-(methacrylic acid, ethyl acrylate) 1: 1 (Eudragit
L100-55), for for about 4-7 millimeter, preferable coating thickness is about the 120-350 micron respectively and is about the 100-300 micron for diameter.
Another kind of preferred polymer is poly-(methacrylic acid, methyl methacrylate) 1: 1 (Eudragit
L), it is to the about 4-7 millimeter of diameter, and preferred coating thickness is about 110-300 micron and about 90-250 micron respectively.
On the preparation total amount of enteric polymer coatings must be enough to make preparation in arriving gastrointestinal tract near colon opening part or colon position before coating do not occur dissolving fully, thereby discharge the therapeutic activity agent at colonic.This need seek a kind of dosage form that can not produce the marginal surface or the sharp keen curve of weak part on coating.Coating on the weak part will dissolve before dosage form reaches colon, causes the therapeutic activity agent to discharge prematurely.
In the document to carried out through the gastrointestinal pharmaceutical dosage form feature description (that is, and M.Ashford and J.T.Fell, target administration magazine (J.Drug Targeting), 1994,2:241-258).The stomach emptying meeting of pharmaceutical dosage form is very different, but constant relatively through the time of small intestinal, on average is about 3 hours.The pH-dissolubility behavior of enteric polymer of the present invention is such, when dosage form enteric polymer coatings before the stomach emptying tangible dissolving can not take place, reach the factor that colon discharges the required coating consumption of therapeutic activity agent as decision thereby eliminated stomach emptying parameter.Therefore the consumption of enteric polymer coatings should be dissolved substantially consumption in about 3 hours small bowel transit time.
The dissolving of enteric polymer of the present invention is influenced by the speed of dosage form size, pH, ionic strength and ambient water medium.Three factors of the latter can change with the length of small intestinal and colon.In addition, these factors change with every kind of enteric polymer the influence of dissolution velocity.But the consumption of the single coatings of enteric polymer is in essence, and wherein enteric polymer is dissolved at the near-end of colon, as P﹠amp; The G patent application file number 5673 that awaits the reply jointly is described, Kelm and Manring, and 1995,5,17 submit to.An importance of the present invention is to use a plurality of coatings of enteric polymer, and wherein outermost layer is lower than constituting of about 6.8 times insoluble enteric polymers or enteric polymer by pH.Internal layer begins dissolved enteric polymer by pH and constitutes under about 5-6.3, so that dissolve at the near-end of colon.Use the multilamellar of methods described herein,, reduced the total amount of enteric polymer coatings layer with respect to single coatings of using at the dissolved enteric polymer of colon near-end.
The prior parameter that decision delays dosage form enteric polymer consumption of release medicine before arriving colon comprises the pH dissolubility property of the enteric polymer that is used for outer coatings layer and interior coatings and the size of dosage form.Following table 1 has shown that the roughly minimum amount of enteric polymer and polymer begin dissolved pH value and dosage form size thereof.Also exemplified the example of enteric polymer.
Table 1
| Diameter (mm) | Layer | ??pH | Minimum thickness (μ m) | Enteric polymer for example |
| ????3 | Internal layer | ??5.0 | ????150 | ????HPMCP?50 |
| ????3 | Outer | ??7.0 | ????40 | ??Eudragit S |
| ????5 | Internal layer | ??5.0 | ????130 | ????HPMCP?50 |
| ????5 | Outer | ??7.0 | ????30 | ??Eudragit S |
| ????10 | Internal layer | ??5.0 | ????100 | ????HPMCP?50 |
| ????10 | Outer | ??7.0 | ????20 | ??Eudragit S |
| ????3 | Internal layer | ??5.5 | ????140 | ?Eudragit L100-55 |
| ????3 | Outer | ??7.0 | ????40 | ??Eudragit S |
| ????5 | Internal layer | ??5.5 | ????120 | ?Eudragit L100-55 |
| ????5 | Outer | ??7.0 | ????30 | ??Eudragit S |
| ????10 | Internal layer | ??5.5 | ????90 | ?Eudragit L100-55 |
| ????10 | Outer | ??7.0 | ????20 | ??Eudragit S |
| ????3 | Internal layer | ??6.0 | ????130 | ??Eudragit L |
| ????3 | Outer | ??7.0 | ????40 | ??Eudragit S |
| ????5 | Internal layer | ??6.0 | ????110 | ??Eudragit L |
| ????5 | Outer | ??7.0 | ????30 | ??Eudragit S |
| ????10 | Internal layer | ??6.0 | ????80 | ??Eudragit L |
| ????10 | Outer | ??7.0 | ????20 | ??Eudragit S |
With any technology well-known in the art, include, but is not limited to the coating pan coating in tool hole and the method for fluidized bed coating, can be applied on sphere or the oval substrate with the enteric polymer coatings material with the solution in pharmaceutically acceptable solvent (as at ethanol, acetone, isopropyl alcohol, ethyl acetate or its mixture), with the buffered aqueous solution of ammonium hydroxide or in the form of the finely divided liquid of water.
In order to increase the elasticity of coating material, the preferred coating material of the present invention also comprises plasticizer.Suitable manufacturing methods comprises Polyethylene Glycol, propylene glycol, dibutyl phthalate, diethyl phthalate, tributyl citrate, tributyorin, glycolic acid butyl phthalyl butyl ester (Santicizer
B-16, Monsanto sells), glyceryl triacetate, Oleum Ricini and citrate; Preferred plasticizer is dibutyl phthalate or triethyl citrate.The amount of these plasticizers is to make art for coating be easy to carry out and obtain the amount of the enhanced even coating membrane of physical stability.In general, coating material contains the 0-50% that accounts for enteric polymer weight, preferably about 0-25%, the more preferably plasticizer of about 10-20%.
In addition, in order to be easy to carry out art for coating, enteric-coating material also can contain the inert solid microgranule.Preferred inert solid microgranule comprises Pulvis Talci and titanium dioxide.
The selection of the selection of optional plasticizer, optional inert solid microgranule and consumption level thereof, coated formula type (solvent, ammonium salt aqueous solution or aqueous dispersions) and coating method are decided according to standard well-known in the art according to concrete enteric polymer that uses and used dosage form type.
Preparation method
Enteric polymer is applied on sphere or the oval substrate as the solution in organic solvent usually.Usually the solvent that uses as excipient is dichloromethane, ethanol, methanol, isopropyl alcohol, acetone, ethyl acetate and their mixture.Mainly come selective solvent according to the dissolubility of polymer, the easiness of evaporation and the viscosity of solution.
Some polymer also obtain with the aqueous systems form.At present, the U.S. sells the enteric polymer coatings of three kinds of aqueouss.They are Eudragit
L30D (West Germany sells for EUDRAGIT L100-55, Rohm-Haas GmBH); Aquateric
(product that contains Cellacefate, FMC Corp. sells, pennsylvania, USA, Philadelphia); And Coateric
(a kind of product of polyethylene acetic acid O-phthalic vinyl acetate, by Colorcon, Inc. sells, pennsylvania, USA, Western-style pastry).Do not resemble organic solution, do not have high viscosity but these water based systems high concentrations prepare.These water systems are the problem relevant with organic system not also, as the toxicity of residual solvent in flammable, the dosage form etc.
Use method well-known in the art, as carrying out coating by continuous or short spray method or by drenching with fluid unit, tool hole coating pan, conventional dose coating pan, pressed coated etc.
Following non-restrictive example provides present composition typical formulation.
Embodiment 1
Be prepared as follows the dosage form of following prescription:
| Substrate | The barrier coating | ||
| Composition | ????Wt(mg) | Composition | ????Wt(mg) |
| The sugar ball, USP | ????212 | ??HPMC，USP1 | ????5 |
| Dexamethasone | ????3 | ||
| ??HPMC，USP 1 | ????1 | ||
| Interior enteric coating | Outer enteric coating | ||
| Composition | ????Wt(mg) | Composition | ??Wt(mg) |
| Eudragit L100-55 2 | ????18 | ??Eudragit S 3 | ????5 |
| Dibutyl phthalate | ????4 | Dibutyl phthalate | ????1 |
| Pulvis Talci, USP 1 | ????8 | Red iron oxide | ????1 |
| Pulvis Talci, USP | ????2 | ||
1Hydroxypropyl emthylcellulose, USP, Methocel
E15LV, Dow Chemical.
2Poly-(methacrylic acid, ethyl acrylate) 1: 1, Eudragit
L100-55, Rohm Tech produces.
3Poly-(methacrylic acid, methyl methacrylate) 1: 2, Eudragit
S, Rohm Tech produces.
Substrate
The level of dexamethasone with 2.7 weight % is dispersed in the water, is binder polymer with 0.9 weight %HPMC, working off one's feeling vent one's spleen/bed tempertaure keeps in the about 40 ℃ tool hole coating pan it being sprayed on the sugared ball (diameter 6.53-6.63mm).
The barrier coating
With the water-soluble 4 weight % solution that obtain of HMPC, in keeping about 40 ℃ tool hole coating pan, exit gas/bed tempertaure above-mentioned substrate is carried out coating with it.
Interior enteric coating
With Eudragit
L100-55 and dibutyl phthalate are dissolved in the solution of isopropyl alcohol, acetone and water (37: 9: 1) separately with 8.0% and 1.6% (overall weight percent).Then Pulvis Talci is suspended in this solution with 3.3% (weight) level.Substrate after exit gas/bed tempertaure keeps in the about 30 ℃ tool hole coating pan mixture with gained to above-mentioned barrier coating is carried out coating.
Outer enteric coating
With Eudragit
S and dibutyl phthalate are dissolved in the solution of isopropyl alcohol, acetone and water (37: 9: 1) separately with 8.0% and 1.6% (overall weight percent).Then the ferrum oxide Pulvis Talci is suspended in this solution with 1.2% (weight) and 2.1% (weight) level respectively.Substrate after exit gas/bed tempertaure keeps in the about 30 ℃ tool hole coating pan mixture with gained to above-mentioned barrier coating is carried out coating.Embodiment 2 is prepared as follows the dosage form of following prescription:
| Substrate | |
| Composition | ????Wt.(mg) |
| Medium chain triglyceride 1 | ????63 |
| CREMOPHORE EL, NF | ????2 |
| Poloxamer 182 | ????20 |
| Propranolol alkali | ????15 |
| The spherical elasticity gelatin soft capsule of #3 | ????N/A |
| Interior enteric coating | Outer enteric coating | ||
| Composition | ????Wt(mg) | Composition | ??Wt(mg) |
| Eudragit L100-55 2 | ????18 | ??Eudragit S 3 | ????5 |
| Dibutyl phthalate | ????4 | Dibutyl phthalate | ????1 |
| Pulvis Talci, USP 1 | ????8 | Red iron oxide | ????1 |
| Pulvis Talci, USP | ????2 | ||
1Captex
300，ABITEC?Corp.
2Poly-(methacrylic acid, ethyl acrylate) 1: 1, Eudragit
L100-55, Rohm Tech produces.
3Poly-(methacrylic acid, methyl methacrylate) 1: 2, Eudragit
S, Rohm Tech produces.
Substrate
Medium chain triglyceride, CREMOPHORE EL and poloxamer 182 are mixed the solution that forms gala fat.Then Propranolol alkali is dissolved in this gala fat excipient, with the 100mg amount it is inserted #3 elasticity snap fit capsule with conventional equipment then.
Interior enteric coating
With Eudragit
L100-55 and dibutyl phthalate are dissolved in the solution of isopropyl alcohol, acetone and water (37: 9: 1) separately with 8.0% and 1.6% (overall weight percent).Then Pulvis Talci is suspended in this solution with 3.3% (weight) level.Substrate after exit gas/bed tempertaure keeps in the about 30 ℃ tool hole coating pan mixture with gained to above-mentioned barrier coating is carried out coating.
Outer enteric coating
With Eudragit
S and dibutyl phthalate are dissolved in the solution of isopropyl alcohol, acetone and water (37: 9: 1) separately with 8.0% and 1.6% (overall weight percent).Then the ferrum oxide Pulvis Talci is suspended in this solution with 1.2% (weight) and 2.1% (weight) level.Substrate after exit gas/bed tempertaure keeps in the about 30 ℃ tool hole coating pan mixture with gained to above-mentioned barrier coating is carried out coating.
Embodiment 3
Be prepared as follows the dosage form of following prescription:
| Substrate | |
| Composition | ????Wt.(mg) |
| The sugar ball, USP | ????50 |
| Aminosalicylic acid (Mesalamine) | ????200 |
| ???????HPMC，USP 1 | ????50 |
| Interior enteric coating | Outer enteric coating | ||
| Composition | ??Wt(mg) | Composition | Wt(mg) |
| ??Eudragit L 2 | ????8 | ????Eudragit S 3 | ????3 |
| Dibutyl phthalate | ????1.6 | Dibutyl phthalate | ????0.6 |
| Pulvis Talci, USP 1 | ????3 | Red iron oxide | ????0.5 |
| Pulvis Talci, USP | ????1 | ||
1Hydroxypropyl emthylcellulose, USP, Methocel
E15LV, Dow Chemical.
2Poly-(methacrylic acid, methyl olefin(e) acid methyl ester) 1: 1, Eudragit
L100-55, Rohm Tech produces.
3Poly-(methacrylic acid, methyl methacrylate) 1: 2, Eudragit
S, Rohm Tech produces.
Substrate
In CF granulation machine (Vector corp.), aminosalicylic acid (Mesalamine) is gone up coating at sugared ball (diameter 2.9-3.1 millimeter) with the bonding aqueous solution of 10 weight %HPMC.
Interior enteric coating
With Eudragit
L and dibutyl phthalate are dissolved in the solution of isopropyl alcohol, acetone and water (37: 9: 1) separately with 8.0% and 1.6% (overall weight percent).Then Pulvis Talci is suspended in this solution with 3.3% (weight) level.Substrate after exit gas/bed tempertaure keeps in the about 30 ℃ tool hole coating pan mixture with gained to above-mentioned barrier coating is carried out coating.
Outer enteric coating
With Eudragit
S and dibutyl phthalate are dissolved in the solution of isopropyl alcohol, acetone and water (37: 9: 1) separately with 8.0% and 1.6% (overall weight percent).Then the ferrum oxide Pulvis Talci is suspended in this solution with 1.2% (weight) and 2.1% (weight) level.Substrate after exit gas/bed tempertaure keeps in the about 30 ℃ tool hole coating pan mixture with gained to above-mentioned barrier coating is carried out coating.
Embodiment 4
Be prepared as follows the dosage form of following prescription:
| Substrate | |
| Composition | ????Wt.(mg) |
| Oleic acid | ????30 |
| Polyoxyethylene 60 castor oil hydrogenated, NF | ????69.5 |
| Salmon calcitonin | ????0.5 |
| The spherical elasticity gelatin soft capsule of #3 | ????N/A |
| Interior enteric coating | Outer enteric coating | ||
| Composition | ????Wt(mg) | Composition | ??Wt(mg) |
| Eudragit L100-55 1 | ????18 | ??Eudragit S 2 | ????5 |
| Dibutyl phthalate | ????4 | Dibutyl phthalate | ????1 |
| Pulvis Talci, USP 1 | ????8 | Red iron oxide | ????1 |
| Pulvis Talci, USP | ????2 | ||
1Poly-(methacrylic acid, ethyl acrylate) 1: 1, Eudragit
L100-55, Rohm Tech produces.
2Poly-(methacrylic acid, methyl methacrylate) 1: 2, Eudragit
S, Rohm Tech produces.
Substrate
Oleic acid and polyoxyethylene 60 castor oil hydrogenated are mixed formation solution.Then salmon calcitonin is dispersed in this gala fat excipient, with the 100mg amount it is inserted #3 elasticity snap fit capsule with conventional equipment then.
Interior enteric coating
With Eudragit
L100-55 and dibutyl phthalate are dissolved in the solution of isopropyl alcohol, acetone and water (37: 9: 1) separately with 8.0% and 1.6% (overall weight percent).Then Pulvis Talci is suspended in this solution with 3.3% (weight) level.Substrate after exit gas/bed tempertaure keeps in the about 30 ℃ tool hole coating pan mixture with gained to above-mentioned barrier coating is carried out coating.
Outer enteric coating
With Eudragit
S and dibutyl phthalate are dissolved in the solution of isopropyl alcohol, acetone and water (37: 9: 1) separately with 8.0% and 1.6% (overall weight percent).Then the ferrum oxide Pulvis Talci is suspended in this solution with 1.2% (weight) and 2.1% (weight) level.Substrate after exit gas/bed tempertaure keeps in the about 30 ℃ tool hole coating pan mixture with gained to above-mentioned barrier coating is carried out coating.
Though the present invention has disclosed specific technical scheme, it is apparent that present technique field personnel can make various changes and modification to the present invention and do not deviate from the spirit and scope of the present invention.Appending claims has covered all this classes in the scope of the invention to be changed.
Claims (10)
1. a confession has gastrointestinal people or lower animal with the oral pharmaceutical composition of unit dosage forms, and described gastrointestinal tract comprises small intestinal and colon, and there is tube chamber the centre, from small intestinal one colon that enters the mouth is arranged, and described compositions comprises:
A. mix or wrap in the therapeutic activity agent of the safe and effective amount on dosage form surface, described dosage form is selected from sphere matrix, ellipticalness substrate, hard capsule or compressed tablets, and its maximum gauge is about the 3-10 millimeter; With
B. the enteric polymer coatings material that contains at least one an interior coatings and an outer coatings layer;
Dosage form smooth surface wherein, non-flanged or sharp keen curve; The ratio in the long and short footpath of ellipticalness substrate and hard capsule is not more than 1.5; The therapeutic activity agent near the porch of colon certain a bit or in colon, discharge; Coatings is the dissolved enteric polymer of beginning in the aqueous medium between the pH5-6.3 in each; The outer coatings layer is the dissolved enteric polymer of beginning in the aqueous medium between the pH6.8-7.2.
2. compositions as claimed in claim 1, wherein dosage form is selected from the elasticity gelatin soft capsule, can be melted or molding spherical substrate or oval substrate that any pharmaceutically acceptable excipient of mold pressing is made, carries out coating or coating and sphere matrix or the oval substrate made on the nucleus that pharmaceutically acceptable any inert excipient is made, preferably bright soft capsule of elasticity or sugared ball.
3. compositions as claimed in claim 1, wherein the enteric polymer coatings material comprises interior coatings, and coatings is selected from the cellulose ethanoate phthalic acid ester in this; Cellulose ethanoate benzenetricarboxylic acid ester; Hydroxypropylmethyl cellulose phthalate; The hydroxypropyl methyl cellulose acetate succinate; The polyvinylacetate phthalic acid ester; Poly-(methacrylic acid, methyl methacrylate) 1: 1; Poly-(methacrylic acid, ethyl acrylate) 1: 1; With the mixture compatible with it.
4. compositions according to claim 1, wherein outside coatings is selected from poly-(methacrylic acid, methyl methacrylate) 1: 2, poly-(methacrylic acid, methyl methacrylate) 1: 1 and poly-(methacrylic acid, methyl methacrylate) 1: 2 mixture, its ratio are 1: 10 to 1: 2; Preferably wherein the outer coatings layer is that coating thickness is poly-(methacrylic acid, the methyl methacrylate) 1: 2 of 20-50 micron.
5. a confession has gastrointestinal people or lower animal with the oral pharmaceutical composition of unit dosage forms, and described gastrointestinal tract comprises small intestinal and colon, and there is tube chamber the centre, from small intestinal one colon that enters the mouth is arranged, and described compositions comprises:
A. mix the therapeutic activity agent of the safe and effective amount in the elasticity gelatin soft capsule that maximum gauge is about the 3-10 millimeter; With
B. the enteric polymer coatings material comprises poly-(methacrylic acid, ethyl acrylate) 1: 1 or poly-(methacrylic acid, methyl methacrylate) interior coatings of 1: 1 and poly-(methacrylic acid, methyl methacrylate) outer coatings layer of 1: 2;
Elasticity gelatin soft capsule smooth surface wherein, non-flanged or sharp keen curve; The therapeutic activity agent near the porch of colon certain a bit or in colon, discharge.
6. a confession has gastrointestinal people or lower animal with the oral pharmaceutical composition of unit dosage forms, and described gastrointestinal tract comprises small intestinal and colon, and there is tube chamber the centre, from small intestinal one colon that enters the mouth is arranged, and described compositions comprises:
A. wrap in the therapeutic activity agent of the safe and effective amount on sugared bulb matrix surface, the maximum gauge of described sugared bulb matrix is the 3-10 millimeter, and the diameter that is preferably wherein all sugared bulb matrixs basically is in 5% scope of average diameter;
B. the enteric polymer coatings material comprises poly-(methacrylic acid, ethyl acrylate) 1: 1 or poly-(methacrylic acid, methyl methacrylate) interior coatings of 1: 1 and poly-(methacrylic acid, methyl methacrylate) outer coatings layer of 1: 2;
C. optional is, the barrier coating, and hydroxypropyl emthylcellulose preferably, it is wrapping on the sugared bulb matrix behind therapeutic activity agent coating,
Wherein sugared bulb matrix smooth surface, non-flanged or sharp keen curve; The therapeutic activity agent near the porch of colon certain a bit or in colon, discharge.
7. as claim 1,5 or 6 described compositionss, wherein the therapeutic activity agent is selected from pyrrole benzene oxygen sulphur salt (picosulfate), Senna fruit glycoside, diarrhea, non-steroidal anti-inflammatory agent, glucocorticoid, antimicrobial, immunosuppressant, chemotherapeutant, peptide class, protein-based, beta blocker, calcium channel blocker, ACE inhibitor, H
2Blocker, antiasthmatics and antihistaminic.
8. according to claim 3,5 or 6 described compositionss, wherein interior coatings is poly-(methacrylic acid, ethyl acrylate) 1: 1, and when diameter was 4 millimeters, coating thickness was the 120-350 micron, and when diameter was 7 millimeters, coating thickness was the 100-300 micron.
9. according to claim 3,5 or 6 described compositionss, wherein interior coatings is poly-(methacrylic acid, methyl methacrylate) 1: 1, and when diameter was 4 millimeters, coating thickness was the 110-300 micron, and when diameter was 7 millimeters, coating thickness was the 90-250 micron.
10. the colon to human body or rudimentary animal provides the method that the therapeutic activity agent discharges, and comprises claim 1, the 5 or 6 described compositionss of the safe and effective amount of orally give.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 96180548 CN1239425A (en) | 1996-11-15 | 1996-11-15 | Pharmaceutical dosage form with multiple enteric polymer coatings for colonic delivery |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 96180548 CN1239425A (en) | 1996-11-15 | 1996-11-15 | Pharmaceutical dosage form with multiple enteric polymer coatings for colonic delivery |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN1239425A true CN1239425A (en) | 1999-12-22 |
Family
ID=5127980
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN 96180548 Pending CN1239425A (en) | 1996-11-15 | 1996-11-15 | Pharmaceutical dosage form with multiple enteric polymer coatings for colonic delivery |
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Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2004084867A1 (en) * | 2003-03-26 | 2004-10-07 | Beijing Orientking Pharmaceutical Science & Technology Co., Ltd. | The colon-targeted pharmaceutical compositions of gastrointestinal motility drugs and their use |
| CN1314390C (en) * | 2001-11-23 | 2007-05-09 | 宝洁公司 | Pharmaceutical dosage form with multiple coatings |
| CN102526743A (en) * | 2011-12-29 | 2012-07-04 | 郑州瑞龙制药股份有限公司 | Coating material for complex tablets and preparation method thereof |
| US8580302B2 (en) | 2000-11-20 | 2013-11-12 | Warner Chilcott Company, Llc | Pharmaceutical dosage form with multiple coatings for reduced impact of coating fractures |
| CN110200949A (en) * | 2012-04-30 | 2019-09-06 | 狄洛特医药有限公司 | The pharmaceutical preparation of sustained release |
| CN110251522A (en) * | 2019-07-12 | 2019-09-20 | 新疆畜牧科学院兽医研究所（新疆畜牧科学院动物临床医学研究中心） | PH Dependent Gradient discharges VK3Medical composition and its use |
| CN113226292A (en) * | 2018-12-07 | 2021-08-06 | 狄洛特医药有限公司 | Delayed release pharmaceutical formulation comprising an outer layer with an enzymatically degradable polymer, composition thereof and method for the manufacture thereof |
-
1996
- 1996-11-15 CN CN 96180548 patent/CN1239425A/en active Pending
Cited By (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US8580302B2 (en) | 2000-11-20 | 2013-11-12 | Warner Chilcott Company, Llc | Pharmaceutical dosage form with multiple coatings for reduced impact of coating fractures |
| US9089492B2 (en) | 2000-11-20 | 2015-07-28 | Warner Chilcott Company, Llc | Pharmaceutical dosage form with multiple coatings for reduced impact of coating fractures |
| CN1314390C (en) * | 2001-11-23 | 2007-05-09 | 宝洁公司 | Pharmaceutical dosage form with multiple coatings |
| WO2004084867A1 (en) * | 2003-03-26 | 2004-10-07 | Beijing Orientking Pharmaceutical Science & Technology Co., Ltd. | The colon-targeted pharmaceutical compositions of gastrointestinal motility drugs and their use |
| CN102526743A (en) * | 2011-12-29 | 2012-07-04 | 郑州瑞龙制药股份有限公司 | Coating material for complex tablets and preparation method thereof |
| CN110200949A (en) * | 2012-04-30 | 2019-09-06 | 狄洛特医药有限公司 | The pharmaceutical preparation of sustained release |
| CN110200949B (en) * | 2012-04-30 | 2021-11-16 | 狄洛特医药有限公司 | Delayed release pharmaceutical formulations |
| CN113226292A (en) * | 2018-12-07 | 2021-08-06 | 狄洛特医药有限公司 | Delayed release pharmaceutical formulation comprising an outer layer with an enzymatically degradable polymer, composition thereof and method for the manufacture thereof |
| CN110251522A (en) * | 2019-07-12 | 2019-09-20 | 新疆畜牧科学院兽医研究所（新疆畜牧科学院动物临床医学研究中心） | PH Dependent Gradient discharges VK3Medical composition and its use |
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