EP1653932A1 - Modified release compositions for minocycline - Google Patents
Modified release compositions for minocyclineInfo
- Publication number
- EP1653932A1 EP1653932A1 EP04744025A EP04744025A EP1653932A1 EP 1653932 A1 EP1653932 A1 EP 1653932A1 EP 04744025 A EP04744025 A EP 04744025A EP 04744025 A EP04744025 A EP 04744025A EP 1653932 A1 EP1653932 A1 EP 1653932A1
- Authority
- EP
- European Patent Office
- Prior art keywords
- granules
- cellulose
- coating
- minocycline
- pharmaceutical composition
- Prior art date
- Legal status (The legal status 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 status listed.)
- Withdrawn
Links
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
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
- A61K9/1605—Excipients; Inactive ingredients
- A61K9/1629—Organic macromolecular compounds
- A61K9/1652—Polysaccharides, e.g. alginate, cellulose derivatives; Cyclodextrin
-
- 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
- A61K31/65—Tetracyclines
-
- 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
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
- A61K9/1605—Excipients; Inactive ingredients
- A61K9/1617—Organic compounds, e.g. phospholipids, fats
- A61K9/1623—Sugars or sugar alcohols, e.g. lactose; Derivatives thereof; Homeopathic globules
-
- 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
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
- A61K9/5005—Wall or coating material
- A61K9/5021—Organic macromolecular compounds
- A61K9/5036—Polysaccharides, e.g. gums, alginate; Cyclodextrin
- A61K9/5042—Cellulose; Cellulose derivatives, e.g. phthalate or acetate succinate esters of hydroxypropyl methylcellulose
Definitions
- the technical field of the present invention relates to nonspheronized multiparticulate modified release compositions for 7-dimethylamino-6-deoxy-6- demethyltetracycline (minocycline) or non-toxic acid addition salts thereof.
- the present invention relates to a modified release compositions that deliver minocycline in a pulsatile manner over a prolonged period and processes for their preparation.
- Minocycline and its non-toxic acid addition salts are widely used in therapy primarily for their antimicrobial effects.
- the preparation of minocycline is disclosed in U.S. Patent Nos. 3,148,212 and 3,226,436.
- Minocycline hydrochloride a pharmaceutically acceptable salt of the drug, has been available in the United States in the form of immediate release oral capsules containing lOOmg of the drug. It is typically administered in humans in doses of about 200mg initially followed by 1 OOmg every twelve hours; or 200mg initially followed by 50mg every six hours. Oral dosage units typically comprise from about 50mg to about lOOmg of minocycline hydrochloride.
- Minocycline is absorbed at different rates in different portions of the gastrointestinal tract.
- Conventional dosage form and delayed release forms containing minocycline require frequent ingestion of multiple doses per day, resulting in wide variations in serum concentration throughout the course of treatment, and in poor patient compliance.
- U.S. Patent No. 5,283,065 discloses a controlled release pharmaceutical composition in oral tablet dosage form comprising two types of granules, active granules and compressible granules.
- the active granules comprise the active ingredient blended with a diluent and the compressible granules comprise a mono- or disaccharide in a diffusible matrix.
- the compressible granules distort and fill voids to provide a cushion to prevent the active granules from breaking during the tabletting process. This is described as guarding against any loss of the controlled release properties.
- U.S. Patent Nos. 5,262,173; 5,300,304; 5,348,748 and 5,413,777 generally disclose pharmaceutical delivery systems of minocycline that include mixtures or separate units of pH sensitive polymer coated spherical granules adapted to release minocycline in a medium having a pH in the range of from about 4.0 to about 7.5 and coated or uncoated quick release granules adapted to release minocycline in a medium having a pH of less than about 3.9, pH adapted multi-coated compositions and oral dosage unit forms such as liquids, capsules and tablets containing the units.
- These delivery systems release minocycline in a pulsatile manner and maintain therapeutic blood level concentrations of minocycline in a patient for twenty-four hours.
- a general process disclosed by the above mentioned patents includes the following step: (a) forming a blend of minocycline and pharmaceutically acceptable excipients; (b) granulating the blend in presence of a granulating liquid; (c) extruding the resultant granulate; (d) spheronizing the resulting extrudates; and (e) drying the spherical granules.
- Spheronization is a process which results in the formation of spherical particles from wet granulations. It requires additional equipment such as the marumerizer.
- a wet granulation containing the active, diluent and binder is first passed through an extruding machine to form rod-shaped cylindrical segments. After extrusion the segments are placed into the marumerizer where they are shaped into spheres by centrifugal and frictional forces on a rotating plate.
- modified release minocycline composition can be prepared without carrying out the additional process of spheronization.
- a non-spheronized, multiparticulate modified release pharmaceutical composition includes a core, a pH sensitive coating, and optionally, one or more pharmaceutically acceptable excipients.
- the core includes an effective antibacterial amount of minocycline or non-toxic acid addition salt thereof and at least one pharmaceutically acceptable excipient.
- Embodiments of the pharmaceutical composition may include one or more of the following features.
- the non-toxic acid addition salt of minocycline may be hydrochloride salt.
- the non-toxic acid addition salt of minocycline may be present in an amount ranging from about 25 to 400 mg by weight based on the total weight of the composition.
- the pH sensitive coating may be rapidly and completely erodible in a medium having a pH in the range of from about 4.0 to about 7.5.
- the pH sensitive coating may include polymers selected from amongst one or more of hydroxypropyl methylcellulose phthalate, cellulose acetate phthalate, hydroxypropyl methyl cellulose succinate, copolymers of (meth) acrylic acid and acrylic acid, polyvinyl acetate phthalate, cellulose acetate trimellitate and mixtures thereof.
- composition may be incorporated into a dosage form comprising one or more of hard gelatin capsules, soft gelatin capsules, sachets, and tablets.
- the pharmaceutically acceptable excipients may be one or more of diluents, binders, lubricants, disintegrants, flavoring agents and colorants.
- a multiple delivery, non-spheronized, multiparticulate modified release pharmaceutical composition includes one or more initial loading quick release granules and one or more secondary loading polymer-coated granules.
- the one or more initial loading quick release granules include an effective antibacterial amount of minocycline or a non-toxic acid addition salt and at least one pharmaceutically acceptable excipient and an optional polymer coating on the initial loading granules.
- the polymer coating is rapidly and completely erodible in a medium having a pH in the range of from about 0.1 to about 7.5.
- the one or more secondary loading polymer-coated granules include an effective antibacterial amount of minocycline or a non-toxic acid addition salt and at least one pharmaceutically acceptable excipient and a polymer coating on the secondary loading granules.
- the polymer coating is rapidly and completely erodible in a medium having a pH in the range of from about 4.0 to about 7.5.
- Embodiments of the modified release pharmaceutical composition may include one or more of the following features.
- the non-toxic acid addition salt of minocycline may be hydrochloride salt.
- the non-toxic acid addition salt of minocycline may be present in an amount ranging from about 25 to 400 mg by weight based on the total weight of the composition.
- a ratio of the initial loading quick release granules to the secondary loading granules may range from about 30:70 to about 70:30.
- the quick release granules may be uncoated.
- the pharmaceutically acceptable excipients may be selected from amongst diluents and binders.
- the diluents may be selected from amongst one or more of microcrystalline cellulose, powdered cellulose, lactose, starch, mannitol, calcium hydrogen phosphate and dextrose.
- the binders may be selected from amongst one or more of carboxymethyl cellulose, hydroxypropyl cellulose, hydroxyl ethyl cellulose, polyvinylpyrrolidone, hydroxypropyl methyl cellulose, cellulose acetate, methyl cellulose, ethyl cellulose, gelatin, tragacanth and gum arabic.
- the coating for the quick release granules may constitute about 1 to 10% w/w of the total composition.
- the polymers for the coating quick of the release granules may be selected from amongst one or more of hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose and mixtures thereof.
- the coating for the secondary loading granules may constitute about 1 to about 20% w/w of the total composition.
- the polymers for the coating of the secondary granules may be selected from amongst one or more of hydroxypropyl methylcellulose phthalate, cellulose acetate phthalate, hydroxypropyl methyl cellulose succinate, copolymers of (meth) acrylic acid and acrylic acid commercially available as Eudragits, polyvinyl acetate phthalate, cellulose acetate trimellitate and mixtures thereof.
- the coating composition may further include one or more of plasticizers, lubricants, pigments and colorants.
- the non-spheronized, multiparticulate modified release composition may be incorporated into a dosage form, such as one or more of hard gelatin capsules, soft gelatin capsules, sachets, and tablets.
- a process for the preparation of multiple delivery non-spheronized, multiparticulate modified release systems includes the steps of forming one or more initial loading quick release granules and forming one or more secondary loading polymer-coated granules.
- the one or more initial loading quick release granules are formed by (i) blending an effective antibacterial amount of minocycline or non-toxic acid addition salt thereof and at least one pharmaceutically acceptable excipient to form a blend, (ii) granulating the blend to form a wet mass, (iii) extruding the wet mass to form granules, (iv) drying the granules, (v) optionally coating the granules with a pH-independent coating which is adapted to release minocycline rapidly and completely in a medium having a pH in the range of 0.1 to 7.5, and (vi) drying the coated granules.
- the one or more secondary loading polymer-coated granules are formed by (i) blending an effective antibacterial amount of minocycline or non-toxic acid addition salt thereof and at least one pharmaceutically acceptable excipient to form a blend, (ii) granulating the blend to form wet mass, (iii) extruding the wet mass to form granules, (iv) drying the granules, (v) coating the dried granules with a pH-dependent coating which is adapted to release minocycline in a medium having a pH in the range of from about 4.0 to about 7.5, and (vi) drying the granules.
- Embodiments of the process may include one or more of the following features.
- the non-toxic acid addition salt of minocycline may be hydrochloride salt.
- the non-toxic acid addition salt of minocycline may be present in an amount ranging from about 25 to 400 mg by weight based on the total weight of the composition.
- a ratio of initial loading quick release granules to the secondary loading granules may range from about 30:70 to about 70:30.
- the pharmaceutically acceptable excipients may be selected from amongst diluents and binders.
- the diluents may be selected from amongst microcrystalline cellulose, powdered cellulose, lactose, starch, mannitol, calcium hydrogen phosphate and dextrose.
- the binders may be selected from amongst carboxymethyl cellulose, hydroxypropyl cellulose, hydroxyl ethyl cellulose, polyvinylpyrrolidone, hydroxypropyl methylcellulose, cellulose acetate, methyl cellulose, ethyl cellulose, gelatin, tragacanth and gum arabic.
- the granulation may be carried out using aqueous solvents or non-aqueous solvents.
- the non-aqueous solvent may be one or more of alcohols, ethyl alcohol, isopropyl alcohol, ketones, acetone, ethyl methyl ketone, chlorinated hydrocarbons, dichloroethane, and trichloroethane.
- the coating for the quick release granules may constitutes about 1 to 10% w/w of the total composition.
- the coating of the quick release granules may be one or more of hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose and mixtures thereof.
- the coating for the secondary loading granules may constitute about 1 to about 20% w/w of the total composition.
- the coating of the secondary granules may be one or more of hydroxypropyl methylcellulose phthalate, cellulose acetate phthalate, hydroxypropyl methyl cellulose succinate, copolymers of (meth) acrylic acid and acrylic acid, polyvinyl acetate phthalate, cellulose acetate trimellitate and mixtures thereof.
- the coating compositions may further include one or more of plasticizers, lubricants, pigments and colorants.
- a method of treating bacterial infections in mammals in need of treatment comprising administering to the mammal a multiple delivery, non-spheronized, multiparticulate modified release pharmaceutical composition of minocycline or its non-toxic acid addition salts.
- the composition includes one or more initial loading quick release granules and one or more secondary loading polymer-coated granules.
- the one or more initial loading quick release granules include an effective antibacterial amount of minocycline or a non-toxic acid addition salt and at least one pharmaceutically acceptable excipient and an optional polymer coating on the initial loading granules.
- the polymer coating is rapidly and completely erodible in a medium having a pH in the range of from about 0.1 to about 7.5.
- the one or more secondary loading polymer-coated granules include an effective antibacterial amount of minocycline or a non-toxic acid addition salt and at least one pharmaceutically acceptable excipient and a polymer coating on the secondary loading granules.
- the polymer coating is rapidly and completely erodible in a medium having a pH in the range of from about 4.0 to about 7.5.
- Minocycline may be used as base per se or as non-toxic acid addition salts of organic or inorganic acids, e.g., sulfonic, trichloroacetic or hydrochloric acid. Particularly, minocycline is used as the hydrochloride salt.
- the non-spheronized, multiparticulate modified release composition and oral dosage unit forms may contain from about 25 mg to about 400 mg of minocycline or non- toxic acid additive salt.
- the ratio of initial loading quick release granules to the secondary loading polymer coated granules ranges from 30:70 to about 70:30. Particularly, the ratio ranges from about 40:60 to about 60:40.
- the rapid and complete release of the initial loading component releases greater than about 70 percent, in particular greater than about 80 percent of minocycline in less than about 90 minutes, and in particular less than about 60 minutes in a medium having a pH in between 0.1 to 7.5. Therefore, any polymer coating of the initial loading component must be specifically rapidly erodible or dissolvable to permit the initial loading component to meet these conditions.
- the rapid and complete release of the secondary loading component or single coated core is such that the secondary loading component or single coated core releases greater than about 50 percent and particularly greater than about 70 percent of minocycline in less than about 90 minutes in a medium having a pH in the range of from about 4.0 to about 7.5.
- compositions used in the dosage form may be selected from amongst diluents and binders.
- Suitable diluents may be selected from amongst, but not limited to, one or more of microcrystalline cellulose, powdered cellulose, lactose, starch, mannitol, calcium hydrogen phosphate, dextrose and mixtures thereof.
- Suitable binders may be selected from amongst, but not limited to, one or more of carboxymethyl cellulose, hydroxypropyl cellulose, hydroxyl ethyl cellulose, polyvinylpyrrolidone, hydroxypropyl methyl cellulose, cellulose acetate, methyl cellulose, ethyl cellulose, gelatin, tragacanth, gum arabic and mixtures thereof.
- the blend of minocycline and one or more excipients is granulated with a suitable solvent to an extrudable consistency.
- suitable solvents for granulation may be selected from amongst water, alcohols like ethyl alcohol or isopropyl alcohol; ketones like acetone or ethylmethyl ketone; and chlorinated hydrocarbons like dichloroethane and trichloroethane.
- the wet granulated mass is extruded at a high speed through a plate in an extruder to form cylindrical extrudes.
- the wet granules are dried under conditions effective for drying, e.g., in an oven or fluidized bed dryer.
- the quick release granules are uncoated or optionally coated with a polymer coating which is rapidly and substantially completely erodible in a medium having a pH in between 0.1 to 7.5.
- Suitable film-forming polymers which are used for coating quick release granules may be selected from amongst, but not limited to, one or more of hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose and mixtures thereof.
- the coatings may include conventional additives such as plasticizers, pigments, colorants etc.
- the coating may be applied as a solution in an organic solvent or as aqueous dispersion.
- the solvent may be selected from water, alcohols, ketones, esters, chlorinated hydrocarbons or mixtures thereof.
- the optional coating layer for quick release granules comprise about 1 to about 10% w/w of the total composition. Particularly, the coating comprises about 2 to 6% w/w of the total composition.
- Secondary loading coated granules are prepared by coating the uncoated quick release granules with a polymer which is rapidly and completely erodible in a medium having a pH in the range of from about 4.0 to about 7.5. This erodibility range ensures release in the upper small intestine and particularly in the duodenum, thereby inhibiting erosion in a pH below the range specified.
- Polymers for coating the secondary loading granules may be selected from, but not limited to, one or more of hydroxypropyl methylcellulose phthalate, cellulose acetate phthalate, hydroxypropyl methyl cellulose succinate, copolymers of (meth)acrylic acid and acrylic acid commercially available as Eudragits, polyvinyl acetate phthalate, cellulose acetate trimellitate, and mixtures thereof.
- the coating composition may also comprise additional components described above, such as plasticizers, pigments, colorants and lubricants.
- plasticizers may be selected from one or more of castor oil, mineral oil, propylene glycol, triethylene mono-oleate, triethyl citrate, triacetin, glyceryl monostearate and diethyl phthalate.
- Suitable lubricants may be selected from one or more of talc, anhydrous colloidal silica, magnesium stearate, glyceryl monostearate and beeswax.
- the coating layer for the secondary loading coated granulates comprises about 5.0 to about 10% w/w of the total composition.
- the coating can be applied using a conventional coating pan or a spray coater, or a rotating perforated pan or an automated system, such as CF granulator, a fluidized bed process or any other suitably automated coating equipment.
- the non-spheronized, multiparticulate modified release compositions may be incorporated into various dosage forms such as hard gelatin capsules, soft-gelatin capsules or compressed tablets.
- the dosage forms may comprise a combination of quick-release and secondary loading coated granules.
- the dosage forms may comprise only one type of granule which is coated with a polymer coating adapted to be erodible rapidly and completely in a medium having a pH in the range of from 4.0 to 7.5.
- the non-spheronized, multiparticulate modified release compositions are incorporated into different dosage forms either alone or with the addition of pharmaceutically acceptable excipients such as lubricants, disintegrants, flavouring agents and colorants.
- Example 1 illustrate various aspects of the present inventions. These examples are for illustration only and should not be construed to limit the scope of the inventions.
- Example 1 illustrate various aspects of the present inventions. These examples are for illustration only and should not be construed to limit the scope of the inventions.
- Minocycline hydrochloride was mixed with microcrystalline cellulose and lactose.
- step 3 The extrudes of step 3 were dried in fluid bed dryer to get dried extrudes with a moisture content that was less than 5%w/w.
- the dried extrudes were coated in a fluid bed processor with the following coating composition to obtain a weight gain of about 2-3%w/w:
- coated granules equivalent to 100 mg minocycline were filled into hard gelatin capsules.
- Table 1 shows the dissolution data of minocycline hydrochloride 100 mg capsules prepared as per the composition of Example 1.
- the dissolution was carried out in 900 ml buffer pH 4.5 using USP Apparatus Type I (basket) at a speed of 100 rpm.
- the dried extrudes were divided into two parts: Part A for immediate release (IR) coating and Part B for modified release (MR) coating.
- IR coating The extrudes were coated in a fluid bed processor with the following coating composition to achieve a weight gain of about 2-4%w/w:
- MR Coating The granules were coated in fluid bed processor with following the coating composition to obtain a weight gain of about 7-8%w/w:
- Table 2 shows the dissolution data of minocycline hydrochloride 100 mg capsules prepared as per the composition of Example 2.
- the dissolution was carried out in 900 ml buffer pH 1.2 and pH 4.5 using USP Apparatus Type I (basket) at a speed of 100 rpm.
- Example 1 Pharmacokinetic evaluation Capsules made according to Example 1 (A) and Example 2 (B) were subjected to pharmacokinetic investigation along with the innovator's capsules, 100 mg (R), currently marketed by American Cyanamid under the brand name Minocin MR ® .
- the extent of absorption for the test products (A and B) was comparable to that for reference product as indicated by the ratio of test to reference (A R and B/R ratio).
- the 90% confidence intervals were found to be within the bioequivalence acceptance range of 80-120% for the untransformed data (as per DCGI draft guidelines). The results are shown in Table 3. Table 3. 90% Confidence intervals for untransformed data
- Eudragit materials can be used as a pH sensitive coating polymers. Accordingly, it is not intended that the invention be limited, except as by the appended claims.
Abstract
The technical field of the present invention relates to nonspheronized multiparticulate modified release compositions of 7-dimethylamino-6-deoxy-6-demethyltetracycline (minocycline) or non-toxic acid addition salts thereof. In particular, the present invention relates to a modified release compositions that deliver minocycline in a pulsatile manner over a prolonged period and processes for their preparation.
Description
MODIFIED RELEASE COMPOSITIONS FOR MINOCYCLINE
Technical Field of Invention
The technical field of the present invention relates to nonspheronized multiparticulate modified release compositions for 7-dimethylamino-6-deoxy-6- demethyltetracycline (minocycline) or non-toxic acid addition salts thereof. In particular, the present invention relates to a modified release compositions that deliver minocycline in a pulsatile manner over a prolonged period and processes for their preparation.
Background of the Invention
Minocycline and its non-toxic acid addition salts are widely used in therapy primarily for their antimicrobial effects. The preparation of minocycline is disclosed in U.S. Patent Nos. 3,148,212 and 3,226,436.
Minocycline hydrochloride, a pharmaceutically acceptable salt of the drug, has been available in the United States in the form of immediate release oral capsules containing lOOmg of the drug. It is typically administered in humans in doses of about 200mg initially followed by 1 OOmg every twelve hours; or 200mg initially followed by 50mg every six hours. Oral dosage units typically comprise from about 50mg to about lOOmg of minocycline hydrochloride.
Minocycline is absorbed at different rates in different portions of the gastrointestinal tract. Conventional dosage form and delayed release forms containing minocycline require frequent ingestion of multiple doses per day, resulting in wide variations in serum concentration throughout the course of treatment, and in poor patient compliance. There have been many attempts to prepare controlled release formulations of minocycline, with varying degrees of success.
U.S. Patent No. 5,283,065 discloses a controlled release pharmaceutical composition in oral tablet dosage form comprising two types of granules, active granules and compressible granules. The active granules comprise the active ingredient blended with a diluent and the compressible granules comprise a mono- or disaccharide in a diffusible matrix. The compressible granules distort and fill voids to provide a cushion to
prevent the active granules from breaking during the tabletting process. This is described as guarding against any loss of the controlled release properties.
U.S. Patent Nos. 5,262,173; 5,300,304; 5,348,748 and 5,413,777 generally disclose pharmaceutical delivery systems of minocycline that include mixtures or separate units of pH sensitive polymer coated spherical granules adapted to release minocycline in a medium having a pH in the range of from about 4.0 to about 7.5 and coated or uncoated quick release granules adapted to release minocycline in a medium having a pH of less than about 3.9, pH adapted multi-coated compositions and oral dosage unit forms such as liquids, capsules and tablets containing the units. These delivery systems release minocycline in a pulsatile manner and maintain therapeutic blood level concentrations of minocycline in a patient for twenty-four hours.
All of the above mentioned patents relate to modified release capsules of minocycline. However, in each these patents, the inventors have an emphasis on the spheronization process and the production of spherical granules. The inventors also state that the composition produced by the spheronization process provide the desired release rate without the coatings. A general process disclosed by the above mentioned patents includes the following step: (a) forming a blend of minocycline and pharmaceutically acceptable excipients; (b) granulating the blend in presence of a granulating liquid; (c) extruding the resultant granulate; (d) spheronizing the resulting extrudates; and (e) drying the spherical granules.
Spheronization is a process which results in the formation of spherical particles from wet granulations. It requires additional equipment such as the marumerizer.
According to this process, a wet granulation containing the active, diluent and binder, is first passed through an extruding machine to form rod-shaped cylindrical segments. After extrusion the segments are placed into the marumerizer where they are shaped into spheres by centrifugal and frictional forces on a rotating plate. Surprisingly, the inventors have discovered that modified release minocycline composition can be prepared without carrying out the additional process of spheronization.
Summary of the Invention
In one general aspect there is provided a non-spheronized, multiparticulate modified release pharmaceutical composition. The composition includes a core, a pH sensitive coating, and optionally, one or more pharmaceutically acceptable excipients. The core includes an effective antibacterial amount of minocycline or non-toxic acid addition salt thereof and at least one pharmaceutically acceptable excipient.
Embodiments of the pharmaceutical composition may include one or more of the following features. For example, the non-toxic acid addition salt of minocycline may be hydrochloride salt. The non-toxic acid addition salt of minocycline may be present in an amount ranging from about 25 to 400 mg by weight based on the total weight of the composition.
The pH sensitive coating may be rapidly and completely erodible in a medium having a pH in the range of from about 4.0 to about 7.5. The pH sensitive coating may include polymers selected from amongst one or more of hydroxypropyl methylcellulose phthalate, cellulose acetate phthalate, hydroxypropyl methyl cellulose succinate, copolymers of (meth) acrylic acid and acrylic acid, polyvinyl acetate phthalate, cellulose acetate trimellitate and mixtures thereof.
The composition may be incorporated into a dosage form comprising one or more of hard gelatin capsules, soft gelatin capsules, sachets, and tablets. The pharmaceutically acceptable excipients may be one or more of diluents, binders, lubricants, disintegrants, flavoring agents and colorants.
In another general aspect there is provided a multiple delivery, non-spheronized, multiparticulate modified release pharmaceutical composition. The composition includes one or more initial loading quick release granules and one or more secondary loading polymer-coated granules. The one or more initial loading quick release granules include an effective antibacterial amount of minocycline or a non-toxic acid addition salt and at least one pharmaceutically acceptable excipient and an optional polymer coating on the initial loading granules. The polymer coating is rapidly and completely erodible in a medium having a pH in the range of from about 0.1 to about 7.5. The one or more secondary loading polymer-coated granules include an effective antibacterial amount of minocycline or a non-toxic acid addition salt and at least one pharmaceutically acceptable
excipient and a polymer coating on the secondary loading granules. The polymer coating is rapidly and completely erodible in a medium having a pH in the range of from about 4.0 to about 7.5.
Embodiments of the modified release pharmaceutical composition may include one or more of the following features. For example, the non-toxic acid addition salt of minocycline may be hydrochloride salt. The non-toxic acid addition salt of minocycline may be present in an amount ranging from about 25 to 400 mg by weight based on the total weight of the composition. A ratio of the initial loading quick release granules to the secondary loading granules may range from about 30:70 to about 70:30. The quick release granules may be uncoated.
The pharmaceutically acceptable excipients may be selected from amongst diluents and binders. The diluents may be selected from amongst one or more of microcrystalline cellulose, powdered cellulose, lactose, starch, mannitol, calcium hydrogen phosphate and dextrose. The binders may be selected from amongst one or more of carboxymethyl cellulose, hydroxypropyl cellulose, hydroxyl ethyl cellulose, polyvinylpyrrolidone, hydroxypropyl methyl cellulose, cellulose acetate, methyl cellulose, ethyl cellulose, gelatin, tragacanth and gum arabic.
The coating for the quick release granules may constitute about 1 to 10% w/w of the total composition. The polymers for the coating quick of the release granules may be selected from amongst one or more of hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose and mixtures thereof.
The coating for the secondary loading granules may constitute about 1 to about 20% w/w of the total composition. The polymers for the coating of the secondary granules may be selected from amongst one or more of hydroxypropyl methylcellulose phthalate, cellulose acetate phthalate, hydroxypropyl methyl cellulose succinate, copolymers of (meth) acrylic acid and acrylic acid commercially available as Eudragits, polyvinyl acetate phthalate, cellulose acetate trimellitate and mixtures thereof. The coating composition may further include one or more of plasticizers, lubricants, pigments and colorants.
The non-spheronized, multiparticulate modified release composition may be incorporated into a dosage form, such as one or more of hard gelatin capsules, soft gelatin capsules, sachets, and tablets.
In another general aspect there is provided a process for the preparation of multiple delivery non-spheronized, multiparticulate modified release systems. The process includes the steps of forming one or more initial loading quick release granules and forming one or more secondary loading polymer-coated granules. The one or more initial loading quick release granules are formed by (i) blending an effective antibacterial amount of minocycline or non-toxic acid addition salt thereof and at least one pharmaceutically acceptable excipient to form a blend, (ii) granulating the blend to form a wet mass, (iii) extruding the wet mass to form granules, (iv) drying the granules, (v) optionally coating the granules with a pH-independent coating which is adapted to release minocycline rapidly and completely in a medium having a pH in the range of 0.1 to 7.5, and (vi) drying the coated granules. The one or more secondary loading polymer-coated granules are formed by (i) blending an effective antibacterial amount of minocycline or non-toxic acid addition salt thereof and at least one pharmaceutically acceptable excipient to form a blend, (ii) granulating the blend to form wet mass, (iii) extruding the wet mass to form granules, (iv) drying the granules, (v) coating the dried granules with a pH-dependent coating which is adapted to release minocycline in a medium having a pH in the range of from about 4.0 to about 7.5, and (vi) drying the granules.
Embodiments of the process may include one or more of the following features. For example,^ the non-toxic acid addition salt of minocycline may be hydrochloride salt. The non-toxic acid addition salt of minocycline may be present in an amount ranging from about 25 to 400 mg by weight based on the total weight of the composition. A ratio of initial loading quick release granules to the secondary loading granules may range from about 30:70 to about 70:30.
The pharmaceutically acceptable excipients may be selected from amongst diluents and binders. The diluents may be selected from amongst microcrystalline cellulose, powdered cellulose, lactose, starch, mannitol, calcium hydrogen phosphate and dextrose. The binders may be selected from amongst carboxymethyl cellulose, hydroxypropyl cellulose, hydroxyl ethyl cellulose, polyvinylpyrrolidone, hydroxypropyl methylcellulose, cellulose acetate, methyl cellulose, ethyl cellulose, gelatin, tragacanth and gum arabic.
The granulation may be carried out using aqueous solvents or non-aqueous solvents. The non-aqueous solvent may be one or more of alcohols, ethyl alcohol, isopropyl alcohol, ketones, acetone, ethyl methyl ketone, chlorinated hydrocarbons, dichloroethane, and trichloroethane. The coating for the quick release granules may constitutes about 1 to 10% w/w of the total composition. The coating of the quick release granules may be one or more of hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose and mixtures thereof.
The coating for the secondary loading granules may constitute about 1 to about 20% w/w of the total composition. The coating of the secondary granules may be one or more of hydroxypropyl methylcellulose phthalate, cellulose acetate phthalate, hydroxypropyl methyl cellulose succinate, copolymers of (meth) acrylic acid and acrylic acid, polyvinyl acetate phthalate, cellulose acetate trimellitate and mixtures thereof.
The coating compositions may further include one or more of plasticizers, lubricants, pigments and colorants.
In another general aspect there is provided a method of treating bacterial infections in mammals in need of treatment, the method comprising administering to the mammal a multiple delivery, non-spheronized, multiparticulate modified release pharmaceutical composition of minocycline or its non-toxic acid addition salts. The composition includes one or more initial loading quick release granules and one or more secondary loading polymer-coated granules. The one or more initial loading quick release granules include an effective antibacterial amount of minocycline or a non-toxic acid addition salt and at least one pharmaceutically acceptable excipient and an optional polymer coating on the initial loading granules. The polymer coating is rapidly and completely erodible in a medium having a pH in the range of from about 0.1 to about 7.5. The one or more secondary loading polymer-coated granules include an effective antibacterial amount of minocycline or a non-toxic acid addition salt and at least one pharmaceutically acceptable excipient and a polymer coating on the secondary loading granules. The polymer coating is rapidly and completely erodible in a medium having a pH in the range of from about 4.0 to about 7.5.
The details of one or more embodiments of the inventions are set forth in the description below. Other features, objects and advantages of the inventions will be apparent from the description and claims. For example, the inventors have provided a simple, easy, economical and time saving process for preparing modified release minocycline compositions.
Detailed Description of the Invention
The present invention is not limited to particular process steps and materials disclosed herein, but are extended to equivalents thereof as would be recognized by those ordinarily skilled in the relevant arts. It should also be understood that terminology employed herein is used for the purpose of describing particular embodiments only and is not intended to be limiting.
Minocycline may be used as base per se or as non-toxic acid addition salts of organic or inorganic acids, e.g., sulfonic, trichloroacetic or hydrochloric acid. Particularly, minocycline is used as the hydrochloride salt. The non-spheronized, multiparticulate modified release composition and oral dosage unit forms may contain from about 25 mg to about 400 mg of minocycline or non- toxic acid additive salt.
The ratio of initial loading quick release granules to the secondary loading polymer coated granules ranges from 30:70 to about 70:30. Particularly, the ratio ranges from about 40:60 to about 60:40.
The rapid and complete release of the initial loading component releases greater than about 70 percent, in particular greater than about 80 percent of minocycline in less than about 90 minutes, and in particular less than about 60 minutes in a medium having a pH in between 0.1 to 7.5. Therefore, any polymer coating of the initial loading component must be specifically rapidly erodible or dissolvable to permit the initial loading component to meet these conditions.
The rapid and complete release of the secondary loading component or single coated core is such that the secondary loading component or single coated core releases greater than about 50 percent and particularly greater than about 70 percent of minocycline
in less than about 90 minutes in a medium having a pH in the range of from about 4.0 to about 7.5.
Pharmaceutically acceptable excipients used in the dosage form may be selected from amongst diluents and binders. Suitable diluents may be selected from amongst, but not limited to, one or more of microcrystalline cellulose, powdered cellulose, lactose, starch, mannitol, calcium hydrogen phosphate, dextrose and mixtures thereof. Suitable binders may be selected from amongst, but not limited to, one or more of carboxymethyl cellulose, hydroxypropyl cellulose, hydroxyl ethyl cellulose, polyvinylpyrrolidone, hydroxypropyl methyl cellulose, cellulose acetate, methyl cellulose, ethyl cellulose, gelatin, tragacanth, gum arabic and mixtures thereof.
The blend of minocycline and one or more excipients is granulated with a suitable solvent to an extrudable consistency. Suitable solvents for granulation may be selected from amongst water, alcohols like ethyl alcohol or isopropyl alcohol; ketones like acetone or ethylmethyl ketone; and chlorinated hydrocarbons like dichloroethane and trichloroethane.
The wet granulated mass is extruded at a high speed through a plate in an extruder to form cylindrical extrudes. The wet granules are dried under conditions effective for drying, e.g., in an oven or fluidized bed dryer.
The quick release granules are uncoated or optionally coated with a polymer coating which is rapidly and substantially completely erodible in a medium having a pH in between 0.1 to 7.5. Suitable film-forming polymers which are used for coating quick release granules may be selected from amongst, but not limited to, one or more of hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose and mixtures thereof. The coatings may include conventional additives such as plasticizers, pigments, colorants etc. The coating may be applied as a solution in an organic solvent or as aqueous dispersion. The solvent may be selected from water, alcohols, ketones, esters, chlorinated hydrocarbons or mixtures thereof.
The optional coating layer for quick release granules comprise about 1 to about 10% w/w of the total composition. Particularly, the coating comprises about 2 to 6% w/w of the total composition.
Secondary loading coated granules are prepared by coating the uncoated quick release granules with a polymer which is rapidly and completely erodible in a medium having a pH in the range of from about 4.0 to about 7.5. This erodibility range ensures release in the upper small intestine and particularly in the duodenum, thereby inhibiting erosion in a pH below the range specified.
Polymers for coating the secondary loading granules may be selected from, but not limited to, one or more of hydroxypropyl methylcellulose phthalate, cellulose acetate phthalate, hydroxypropyl methyl cellulose succinate, copolymers of (meth)acrylic acid and acrylic acid commercially available as Eudragits, polyvinyl acetate phthalate, cellulose acetate trimellitate, and mixtures thereof.
The coating composition may also comprise additional components described above, such as plasticizers, pigments, colorants and lubricants. Suitable plasticizers may be selected from one or more of castor oil, mineral oil, propylene glycol, triethylene mono-oleate, triethyl citrate, triacetin, glyceryl monostearate and diethyl phthalate. Suitable lubricants may be selected from one or more of talc, anhydrous colloidal silica, magnesium stearate, glyceryl monostearate and beeswax. The coating layer for the secondary loading coated granulates comprises about 5.0 to about 10% w/w of the total composition.
The coating can be applied using a conventional coating pan or a spray coater, or a rotating perforated pan or an automated system, such as CF granulator, a fluidized bed process or any other suitably automated coating equipment. The non-spheronized, multiparticulate modified release compositions may be incorporated into various dosage forms such as hard gelatin capsules, soft-gelatin capsules or compressed tablets. The dosage forms may comprise a combination of quick-release and secondary loading coated granules. Alternatively, the dosage forms may comprise only one type of granule which is coated with a polymer coating adapted to be erodible rapidly and completely in a medium having a pH in the range of from 4.0 to 7.5.
The non-spheronized, multiparticulate modified release compositions are incorporated into different dosage forms either alone or with the addition of pharmaceutically acceptable excipients such as lubricants, disintegrants, flavouring agents and colorants.
The following examples illustrate various aspects of the present inventions. These examples are for illustration only and should not be construed to limit the scope of the inventions. Example 1
# removed during processing Process:
1. Minocycline hydrochloride was mixed with microcrystalline cellulose and lactose.
2. Water was added gradually with mixing to the dry mix (of step 1) to prepare a wet mass with a moisture content of about 25-35%w/w.
3. The wet mass was extruded to obtain non-spherical granules, or extrudes.
4. The extrudes of step 3 were dried in fluid bed dryer to get dried extrudes with a moisture content that was less than 5%w/w.
. The dried extrudes were coated in a fluid bed processor with the following coating composition to obtain a weight gain of about 2-3%w/w:
# Removed during processing
The coated granules equivalent to 100 mg minocycline were filled into hard gelatin capsules.
Table 1 shows the dissolution data of minocycline hydrochloride 100 mg capsules prepared as per the composition of Example 1. The dissolution was carried out in 900 ml buffer pH 4.5 using USP Apparatus Type I (basket) at a speed of 100 rpm.
Table 1. In vitro release of minocycline modified release capsules of Example 1 at pH 4.5
Example 2
# removed during processing
Process: Similar to Example 1
The dried extrudes were divided into two parts: Part A for immediate release (IR) coating and Part B for modified release (MR) coating.
IR coating: The extrudes were coated in a fluid bed processor with the following coating composition to achieve a weight gain of about 2-4%w/w:
MR Coating: The granules were coated in fluid bed processor with following the coating composition to obtain a weight gain of about 7-8%w/w:
# Removed during processing
The IR coated granules equivalent to 55 mg minocycline were mixed with the MR coated granules equivalent to 45 mg and the resulting mixed granules equivalent to 100 mg minocycline were filled into hard gelatin capsules.
Table 2 shows the dissolution data of minocycline hydrochloride 100 mg capsules prepared as per the composition of Example 2. The dissolution was carried out in 900 ml buffer pH 1.2 and pH 4.5 using USP Apparatus Type I (basket) at a speed of 100 rpm.
Table 2. In vitro release of minocycline modified release capsules of Example 2 at pH 1.2 and pH 4.5
Pharmacokinetic evaluation Capsules made according to Example 1 (A) and Example 2 (B) were subjected to pharmacokinetic investigation along with the innovator's capsules, 100 mg (R), currently marketed by American Cyanamid under the brand name Minocin MR®. The extent of absorption for the test products (A and B) was comparable to that for reference product as indicated by the ratio of test to reference (A R and B/R ratio). The 90% confidence intervals were found to be within the bioequivalence acceptance range of 80-120% for the untransformed data (as per DCGI draft guidelines). The results are shown in Table 3.
Table 3. 90% Confidence intervals for untransformed data
While several particular forms of the invention have been illustrated and described, it will be apparent that various modifications and combinations of the invention detailed in the text can be made without departing from the spirit and scope of the invention. For example, Eudragit materials can be used as a pH sensitive coating polymers. Accordingly, it is not intended that the invention be limited, except as by the appended claims.
Claims
We Claim: 1. A non-spheronized, multiparticulate modified release pharmaceutical composition comprising: a core comprising: a) an effective antibacterial amount of minocycline or non-toxic acid addition salt thereof, b) at least one pharmaceutically acceptable excipient, a pH sensitive coating; and optionally, one or more pharmaceutically acceptable excipients.
2. The pharmaceutical composition according to claim 1, wherein the non- toxic acid addition salt of minocycline comprises hydrochloride salt.
3. The pharmaceutical composition according to claim 1, wherein the non- toxic acid addition salt of minocycline is present in an amount ranging from about 25 to 400 mg by weight based on the total weight of the composition.
4. The pharmaceutical composition according to claim 1, wherein the pH sensitive coating is rapidly and completely erodible in a medium having a pH in the range of from about 4.0 to about 7.5.
5. The pharmaceutical composition according to claim 1, wherein the composition is incorporated into a dosage form comprising one or more of hard gelatin capsules, soft gelatin capsules, sachets, and tablets.
6. The pharmaceutical composition according to claim 1, wherein the pharmaceutically acceptable excipients comprise one or more of diluents, binders, lubricants, disintegrants, flavoring agents and colorants.
7. The pharmaceutical composition according to claim 1, wherein the pH sensitive coating comprises polymers selected from amongst one or more of hydroxypropyl methylcellulose phthalate, cellulose acetate phthalate, hydroxypropyl methyl cellulose succinate, copolymers of (meth) acrylic acid and acrylic acid, polyvinyl acetate phthalate, cellulose acetate trimellitate and mixtures thereof.
8. A multiple delivery, non-spheronized, multiparticulate modified release pharmaceutical composition comprising: a) one or more initial loading quick release granules comprising: i. an effective antibacterial amount of minocycline or a non-toxic acid addition salt and at least one pharmaceutically acceptable excipient, and, ii. an optional polymer coating on the initial loading granules, the polymer coating being rapidly and completely erodible in a medium having a pH in the range of from about 0.1 to about 7.5; and b) one or more secondary loading polymer-coated granules comprising: i. an effective antibacterial amount of minocycline or a non-toxic acid addition salt and at least one pharmaceutically acceptable excipient; and ii. a polymer coating on the secondary loading granules, the polymer coating being rapidly and completely erodible in a medium having a pH in the range of from about 4.0 to about 7.5.
9. The modified release pharmaceutical composition according to claim 8, wherein the non-toxic acid addition salt of minocycline comprises hydrochloride salt.
10. The modified release pharmaceutical composition according to claim 8, wherein the non-toxic acid addition salt of minocycline is present in an amount ranging from about 25 to 400 mg by weight based on the total weight of the composition.
11. The modified release pharmaceutical composition according to claim 8, wherein a ratio of the initial loading quick release granules to the secondary loading granules ranges from about 30:70 to about 70:30.
12. The modified release pharmaceutical composition according to claim 8, wherein the pharmaceutically acceptable excipients are selected from amongst diluents and binders.
13. The modified release pharmaceutical composition according to claim 12, wherein the diluents are selected from amongst one or more of microcrystalline cellulose, powdered cellulose, lactose, starch, mannitol, calcium hydrogen phosphate and dextrose.
14. The modified release pharmaceutical composition according to claim 12, wherein the binders are selected from amongst one or more of carboxymethyl cellulose, hydroxypropyl cellulose, hydroxyl ethyl cellulose, polyvinylpyrrolidone, hydroxypropyl methyl cellulose, cellulose acetate, methyl cellulose, ethyl cellulose, gelatin, tragacanth and gum arabic.
15. The modified release pharmaceutical composition according to claim 8, wherein the quick release granules are uncoated.
16. The modified release pharmaceutical composition according to claim 8, wherein the coating for quick release granules constitutes about 1 to 10% w/w of the total composition.
17. The modified release pharmaceutical composition according to claim 8, wherein the polymers for coating quick release granules are selected from amongst one or more of hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose and mixtures thereof.
18. The modified release pharmaceutical composition according to claim 8, wherein the coating on the secondary loading granules constitutes about 1 to about 20% w/w of the total composition.
19. The modified release pharmaceutical composition according to claim 8, wherein the polymers for coating the secondary granules are selected from amongst one or more of hydroxypropyl methylcellulose phthalate, cellulose acetate phthalate, hydroxypropyl methyl cellulose succinate, copolymers of (meth) acrylic acid and acrylic acid commercially available as Eudragits, polyvinyl acetate phthalate, cellulose acetate trimellitate and mixtures thereof.
20. The modified release pharmaceutical composition according to claim 8, wherein the coating composition further comprises one or more of plasticizers, lubricants, pigments and colorants.
21. The modified release pharmaceutical composition according to claim 8, wherein the non-spheronized, multiparticulate modified release composition is incorporated into a dosage foim, the dosage form comprising one or more of hard gelatin capsules, soft gelatin capsules, sachets, and tablets.
22. A process for the preparation of multiple delivery non-spheronized, multiparticulate modified release systems, the process comprising the steps of: a) forming one or more initial loading quick release granules by: blending an effective antibacterial amount of minocycline or non-toxic acid addition salt thereof and at least one pharmaceutically acceptable excipient to form a blend, granulating the blend to form a wet mass, extruding the wet mass to form granules, drying the granules, optionally coating the granules with a pH-independent coating which is adapted to release minocycline rapidly and completely in a medium having a pH in the range of 0.1 to 7.5, and drying the coated granules; and b) forming one or more secondary loading polymer-coated granules by: blending an effective antibacterial amount of minocycline or non-toxic acid addition salt thereof and at least one pharmaceutically acceptable excipient to form a blend, granulating the blend to form wet mass, extruding the wet mass to form granules, drying the granules, coating the dried granules with a pH-dependent coating which is adapted to release minocycline in a medium having a pH in the range of from about 4.0 to about 7.5, and drying the granules.
23. The process according to claim 22, wherein the non-toxic acid addition salt of minocycline comprises hydrochloride salt.
24. The process according to claim 22, wherein the non-toxic acid addition salt of minocycline is present in an amount ranging from about 25 to 400 mg by weight based on the total weight pf the composition.
25. The process according to claim 22, wherein the ratio of initial loading quick release granules to the secondary loading granules ranges from 30:70 to about 70:30.
26. The process according to claim 22, wherein the pharmaceutically acceptable excipients are selected from amongst diluents and binders.
27. The process according to claim 26, wherein the diluents are selected from amongst microcrystalline cellulose, powdered cellulose, lactose, starch, mannitol, calcium hydrogen phosphate and dextrose.
28. The process according to claim 26, wherein the binders are selected from amongst carboxymethyl cellulose, hydroxypropyl cellulose, hydroxyl ethyl cellulose, polyvinylpyrrolidone, hydroxypropyl methylcellulose, cellulose acetate, methyl cellulose, ethyl cellulose, gelatin, tragacanth and gum arabic.
29. The process according to claim 22, wherein the granulation is carried out using aqueous solvents or non-aqueous solvents.
30. The process according to claim 29, wherein the non-aqueous solvent comprises one or more of alcohols, ethyl alcohol, isopropyl alcohol, ketones, acetone, ethyl methyl ketone, chlorinated hydrocarbons, dichloroethane, and trichloroethane.
31. The process according to claim 22, wherein the coating for the quick release granules constitutes about 1 to 10% w/w of the total composition.
32. The process according to claim 22, wherein the coating of the quick release granules comprises one or more of hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose and mixtures thereof.
33. The process according to claim 22, wherein the coating for the secondary loading granules constitutes about 1 to about 20% w/w of the total composition.
34. The process according to claim 22, wherein the coating of the secondary granules comprises one or more of hydroxypropyl methylcellulose phthalate, cellulose acetate phthalate, hydroxypropyl methyl cellulose succinate, copolymers of (meth) acrylic acid and acrylic acid, polyvinyl acetate phthalate, cellulose acetate trimellitate and mixtures thereof.
35. The process according to claim 22, wherein coating compositions further comprises one or more of plasticizers, lubricants, pigments and colorants.
36. A method of treating bacterial infections in mammals in need of treatment, the method comprising administering to the mammal the composition of claim 1.
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
IN924DE2003 | 2003-07-24 | ||
PCT/IB2004/002366 WO2005009416A1 (en) | 2003-07-24 | 2004-07-23 | Modified release compositions for minocycline |
Publications (1)
Publication Number | Publication Date |
---|---|
EP1653932A1 true EP1653932A1 (en) | 2006-05-10 |
Family
ID=34090478
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
EP04744025A Withdrawn EP1653932A1 (en) | 2003-07-24 | 2004-07-23 | Modified release compositions for minocycline |
Country Status (2)
Country | Link |
---|---|
EP (1) | EP1653932A1 (en) |
WO (1) | WO2005009416A1 (en) |
Cited By (16)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US9439857B2 (en) | 2007-11-30 | 2016-09-13 | Foamix Pharmaceuticals Ltd. | Foam containing benzoyl peroxide |
US9492412B2 (en) | 2002-10-25 | 2016-11-15 | Foamix Pharmaceuticals Ltd. | Penetrating pharmaceutical foam |
US9539208B2 (en) | 2002-10-25 | 2017-01-10 | Foamix Pharmaceuticals Ltd. | Foam prepared from nanoemulsions and uses |
US9549898B2 (en) | 2007-12-07 | 2017-01-24 | Foamix Pharmaceuticals Ltd. | Oil and liquid silicone foamable carriers and formulations |
US9572775B2 (en) | 2009-07-29 | 2017-02-21 | Foamix Pharmaceuticals Ltd. | Non surfactant hydro-alcoholic foamable compositions, breakable foams and their uses |
US9622947B2 (en) | 2002-10-25 | 2017-04-18 | Foamix Pharmaceuticals Ltd. | Foamable composition combining a polar solvent and a hydrophobic carrier |
US9662298B2 (en) | 2007-08-07 | 2017-05-30 | Foamix Pharmaceuticals Ltd. | Wax foamable vehicle and pharmaceutical compositions thereof |
US9668972B2 (en) | 2002-10-25 | 2017-06-06 | Foamix Pharmaceuticals Ltd. | Nonsteroidal immunomodulating kit and composition and uses thereof |
US9675700B2 (en) | 2009-10-02 | 2017-06-13 | Foamix Pharmaceuticals Ltd. | Topical tetracycline compositions |
US9682021B2 (en) | 2006-11-14 | 2017-06-20 | Foamix Pharmaceuticals Ltd. | Substantially non-aqueous foamable petrolatum based pharmaceutical and cosmetic compositions and their uses |
US9713643B2 (en) | 2002-10-25 | 2017-07-25 | Foamix Pharmaceuticals Ltd. | Foamable carriers |
US9849142B2 (en) | 2009-10-02 | 2017-12-26 | Foamix Pharmaceuticals Ltd. | Methods for accelerated return of skin integrity and for the treatment of impetigo |
US10322085B2 (en) | 2002-10-25 | 2019-06-18 | Foamix Pharmaceuticals Ltd. | Dicarboxylic acid foamable vehicle and pharmaceutical compositions thereof |
US10350166B2 (en) | 2009-07-29 | 2019-07-16 | Foamix Pharmaceuticals Ltd. | Non surface active agent non polymeric agent hydro-alcoholic foamable compositions, breakable foams and their uses |
US10398641B2 (en) | 2016-09-08 | 2019-09-03 | Foamix Pharmaceuticals Ltd. | Compositions and methods for treating rosacea and acne |
US10821077B2 (en) | 2002-10-25 | 2020-11-03 | Foamix Pharmaceuticals Ltd. | Dicarboxylic acid foamable vehicle and pharmaceutical compositions thereof |
Families Citing this family (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US7704518B2 (en) | 2003-08-04 | 2010-04-27 | Foamix, Ltd. | Foamable vehicle and pharmaceutical compositions thereof |
WO2010125470A2 (en) | 2009-04-28 | 2010-11-04 | Foamix Ltd. | Foamable vehicle and pharmaceutical compositions comprising aprotic polar solvents and uses thereof |
HUE033161T2 (en) | 2010-05-12 | 2017-11-28 | Rempex Pharmaceuticals Inc | Tetracycline compositions |
Family Cites Families (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
DK0418565T3 (en) * | 1989-09-21 | 1995-01-23 | American Cyanamid Co | Pulsed minocycline delivery system once daily |
-
2004
- 2004-07-23 EP EP04744025A patent/EP1653932A1/en not_active Withdrawn
- 2004-07-23 WO PCT/IB2004/002366 patent/WO2005009416A1/en active Application Filing
Non-Patent Citations (1)
Title |
---|
See references of WO2005009416A1 * |
Cited By (40)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US9713643B2 (en) | 2002-10-25 | 2017-07-25 | Foamix Pharmaceuticals Ltd. | Foamable carriers |
US9539208B2 (en) | 2002-10-25 | 2017-01-10 | Foamix Pharmaceuticals Ltd. | Foam prepared from nanoemulsions and uses |
US10322085B2 (en) | 2002-10-25 | 2019-06-18 | Foamix Pharmaceuticals Ltd. | Dicarboxylic acid foamable vehicle and pharmaceutical compositions thereof |
US10821077B2 (en) | 2002-10-25 | 2020-11-03 | Foamix Pharmaceuticals Ltd. | Dicarboxylic acid foamable vehicle and pharmaceutical compositions thereof |
US10117812B2 (en) | 2002-10-25 | 2018-11-06 | Foamix Pharmaceuticals Ltd. | Foamable composition combining a polar solvent and a hydrophobic carrier |
US9622947B2 (en) | 2002-10-25 | 2017-04-18 | Foamix Pharmaceuticals Ltd. | Foamable composition combining a polar solvent and a hydrophobic carrier |
US9492412B2 (en) | 2002-10-25 | 2016-11-15 | Foamix Pharmaceuticals Ltd. | Penetrating pharmaceutical foam |
US9668972B2 (en) | 2002-10-25 | 2017-06-06 | Foamix Pharmaceuticals Ltd. | Nonsteroidal immunomodulating kit and composition and uses thereof |
US11033491B2 (en) | 2002-10-25 | 2021-06-15 | Vyne Therapeutics Inc. | Dicarboxylic acid foamable vehicle and pharmaceutical compositions thereof |
US9682021B2 (en) | 2006-11-14 | 2017-06-20 | Foamix Pharmaceuticals Ltd. | Substantially non-aqueous foamable petrolatum based pharmaceutical and cosmetic compositions and their uses |
US9662298B2 (en) | 2007-08-07 | 2017-05-30 | Foamix Pharmaceuticals Ltd. | Wax foamable vehicle and pharmaceutical compositions thereof |
US11103454B2 (en) | 2007-08-07 | 2021-08-31 | Vyne Therapeutics Inc. | Wax foamable vehicle and pharmaceutical compositions thereof |
US10369102B2 (en) | 2007-08-07 | 2019-08-06 | Foamix Pharmaceuticals Ltd. | Wax foamable vehicle and pharmaceutical compositions thereof |
US9439857B2 (en) | 2007-11-30 | 2016-09-13 | Foamix Pharmaceuticals Ltd. | Foam containing benzoyl peroxide |
US9549898B2 (en) | 2007-12-07 | 2017-01-24 | Foamix Pharmaceuticals Ltd. | Oil and liquid silicone foamable carriers and formulations |
US11433025B2 (en) | 2007-12-07 | 2022-09-06 | Vyne Therapeutics Inc. | Oil foamable carriers and formulations |
US9795564B2 (en) | 2007-12-07 | 2017-10-24 | Foamix Pharmaceuticals Ltd. | Oil-based foamable carriers and formulations |
US9572775B2 (en) | 2009-07-29 | 2017-02-21 | Foamix Pharmaceuticals Ltd. | Non surfactant hydro-alcoholic foamable compositions, breakable foams and their uses |
US10092588B2 (en) | 2009-07-29 | 2018-10-09 | Foamix Pharmaceuticals Ltd. | Foamable compositions, breakable foams and their uses |
US11219631B2 (en) | 2009-07-29 | 2022-01-11 | Vyne Pharmaceuticals Inc. | Foamable compositions, breakable foams and their uses |
US10350166B2 (en) | 2009-07-29 | 2019-07-16 | Foamix Pharmaceuticals Ltd. | Non surface active agent non polymeric agent hydro-alcoholic foamable compositions, breakable foams and their uses |
US10265404B2 (en) | 2009-10-02 | 2019-04-23 | Foamix Pharmaceuticals Ltd. | Compositions, gels and foams with rheology modulators and uses thereof |
US10821187B2 (en) | 2009-10-02 | 2020-11-03 | Foamix Pharmaceuticals Ltd. | Compositions, gels and foams with rheology modulators and uses thereof |
US10238746B2 (en) | 2009-10-02 | 2019-03-26 | Foamix Pharmaceuticals Ltd | Surfactant-free water-free foamable compositions, breakable foams and gels and their uses |
US10213512B2 (en) | 2009-10-02 | 2019-02-26 | Foamix Pharmaceuticals Ltd. | Topical tetracycline compositions |
US9675700B2 (en) | 2009-10-02 | 2017-06-13 | Foamix Pharmaceuticals Ltd. | Topical tetracycline compositions |
US10463742B2 (en) | 2009-10-02 | 2019-11-05 | Foamix Pharmaceuticals Ltd. | Topical tetracycline compositions |
US10517882B2 (en) | 2009-10-02 | 2019-12-31 | Foamix Pharmaceuticals Ltd. | Method for healing of an infected acne lesion without scarring |
US10610599B2 (en) | 2009-10-02 | 2020-04-07 | Foamix Pharmaceuticals Ltd. | Topical tetracycline compositions |
US10137200B2 (en) | 2009-10-02 | 2018-11-27 | Foamix Pharmaceuticals Ltd. | Surfactant-free water-free foamable compositions, breakable foams and gels and their uses |
US10322186B2 (en) | 2009-10-02 | 2019-06-18 | Foamix Pharmaceuticals Ltd. | Topical tetracycline compositions |
US10835613B2 (en) | 2009-10-02 | 2020-11-17 | Foamix Pharmaceuticals Ltd. | Compositions, gels and foams with rheology modulators and uses thereof |
US9849142B2 (en) | 2009-10-02 | 2017-12-26 | Foamix Pharmaceuticals Ltd. | Methods for accelerated return of skin integrity and for the treatment of impetigo |
US10946101B2 (en) | 2009-10-02 | 2021-03-16 | Vyne Therapeutics Inc. | Surfactant-free water-free foamable compositions, breakable foams and gels and their uses |
US10967063B2 (en) | 2009-10-02 | 2021-04-06 | Vyne Therapeutics Inc. | Surfactant-free, water-free formable composition and breakable foams and their uses |
US10086080B2 (en) | 2009-10-02 | 2018-10-02 | Foamix Pharmaceuticals Ltd. | Topical tetracycline compositions |
US10029013B2 (en) | 2009-10-02 | 2018-07-24 | Foamix Pharmaceuticals Ltd. | Surfactant-free, water-free formable composition and breakable foams and their uses |
US10849847B2 (en) | 2016-09-08 | 2020-12-01 | Foamix Pharamaceuticals Ltd. | Compositions and methods for treating rosacea and acne |
US11324691B2 (en) | 2016-09-08 | 2022-05-10 | Journey Medical Corporation | Compositions and methods for treating rosacea and acne |
US10398641B2 (en) | 2016-09-08 | 2019-09-03 | Foamix Pharmaceuticals Ltd. | Compositions and methods for treating rosacea and acne |
Also Published As
Publication number | Publication date |
---|---|
WO2005009416A1 (en) | 2005-02-03 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
US5601845A (en) | Pharmaceutical spheroid formulation | |
US6426091B1 (en) | Sustained-release theophylline tablet | |
EP1653932A1 (en) | Modified release compositions for minocycline | |
JP3140764B2 (en) | Pulsatile once-daily release system of minocycline | |
JP4879351B2 (en) | Pharmaceutical solid formulation | |
EP1318792B1 (en) | Sustained release composition containing clarithromycin | |
AU6699100A (en) | Oral pharmaceutical forms of administration with a delayed action | |
CA2199345A1 (en) | Controlled-release composition | |
JP2003508430A (en) | Sustained release dosage form containing tramadol saccharinate | |
US20030157169A1 (en) | Controlled release dosage form of [R-(Z)]-alpha-(methoxyimino)-alpha-(1-azabicyclo[2.2.2]oct-3-yl)acetonitrile monohydrochloride | |
HU204201B (en) | Coating materialdetermining delivery of active components from pharmaceutical compositions, and process for producing phrmaceutical compositions containing this coating material | |
JP2004521910A (en) | Tramadol | |
US20080199527A1 (en) | Enteric Coated Azithromycin Multiparticulates | |
AU2003288604A1 (en) | Controlled release pharmaceutical compositions of tamsulosin | |
MXPA06008854A (en) | Extended release coated microtablets of venlafaxine hydrochloride. | |
WO2009069089A9 (en) | Levetiracetam controlled release composition | |
EP0929301A2 (en) | Controlled release dosage form of r-(z)]-alpha-(methoxyimino)-alpha-(1-azabicyclo 2.2.2]oct-3-yl)acetonitrile monohydrochloride | |
RU2275191C2 (en) | Pharmaceutical compositions consisting of multiple particles with sustained-release of serotonin reuptake selective inhibitor | |
US20120027822A1 (en) | Process for Producing Rapidly Disintegrating Spheroids (Pellets), Granules and/or Mixtures Thereof | |
US20080113030A1 (en) | Sustained release tamsulosin formulations | |
KR20100103629A (en) | Coated extended release pharmaceutical compositions of levetiracetam | |
US20080193537A1 (en) | Morphine Sulfate Formulations | |
WO2004050064A1 (en) | Method of manufacturing controlled release formulation using pelletizer | |
US20190000784A1 (en) | Pulsatile release pharmaceutical composition comprising naftazone or one of its salts | |
WO2008062426A2 (en) | Formulation of benzazepine derivatives |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
PUAI | Public reference made under article 153(3) epc to a published international application that has entered the european phase |
Free format text: ORIGINAL CODE: 0009012 |
|
17P | Request for examination filed |
Effective date: 20060224 |
|
AK | Designated contracting states |
Kind code of ref document: A1 Designated state(s): AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HU IE IT LI LU MC NL PL PT RO SE SI SK TR |
|
AX | Request for extension of the european patent |
Extension state: AL HR LT LV MK |
|
17Q | First examination report despatched |
Effective date: 20080116 |
|
STAA | Information on the status of an ep patent application or granted ep patent |
Free format text: STATUS: THE APPLICATION IS DEEMED TO BE WITHDRAWN |
|
18D | Application deemed to be withdrawn |
Effective date: 20080529 |