WO2004091587A1 - Liberation multiple de medicaments anti-diabete et procede de production associe - Google Patents

Liberation multiple de medicaments anti-diabete et procede de production associe Download PDF

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Publication number
WO2004091587A1
WO2004091587A1 PCT/IN2003/000311 IN0300311W WO2004091587A1 WO 2004091587 A1 WO2004091587 A1 WO 2004091587A1 IN 0300311 W IN0300311 W IN 0300311W WO 2004091587 A1 WO2004091587 A1 WO 2004091587A1
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Prior art keywords
pharmaceutical composition
composition according
active agent
pharmaceutically active
matrix material
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PCT/IN2003/000311
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English (en)
Inventor
Ramachandran Thembalath
Yatish Kumar Bansal
Vaishali Manish Tawde
Vinod Kumar TIWARI
Vivek Kamlakar Jadhav
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Ipca Laboratories Limited
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Application filed by Ipca Laboratories Limited filed Critical Ipca Laboratories Limited
Priority to AU2003282374A priority Critical patent/AU2003282374A1/en
Publication of WO2004091587A1 publication Critical patent/WO2004091587A1/fr

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    • 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
    • A61K31/13—Amines
    • A61K31/155—Amidines (), e.g. guanidine (H2N—C(=NH)—NH2), isourea (N=C(OH)—NH2), isothiourea (—N=C(SH)—NH2)
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • 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
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2072—Pills, tablets, discs, rods characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms
    • A61K9/2086—Layered tablets, e.g. bilayer tablets; Tablets of the type inert core-active coat
    • A61K9/209—Layered tablets, e.g. bilayer tablets; Tablets of the type inert core-active coat containing drug in at least two layers or in the core and in at least one outer layer
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics

Definitions

  • the invention relates to the field of medicine and pharmacology. More specifically, the invention relates to a pharmaceutical composition comprising at least two different pharmaceutically active ingredients, the release profile of a first active ingredient being different from the release profile of a second active ingredient.
  • the pharmaceutical composition ofthe invention is particularly indicated in the treatment of diabetes.
  • Diabetes mellitus is a group of disorders of carbohydrate metabolism in which the action of insulin is diminished or absent through altered secretion, decreased insulin activity or a combination of both factors.
  • IDDM insulin-dependent diabetes mellitus
  • NIDDM non- insulin-dependent diabetes mellitus
  • Type II diabetes mellitus is a common disease increasingly affecting people worldwide. While type II diabetes affects less than 10% ofthe population in developed countries, the prevalence ofthe disease is growing faster among the Asian population, especially Asian immigrants. Antidiabetic drugs have therefore become an area of immense interest and attention for the research community throughout the world.
  • First line therapy in both type I and type II diabetes involves dietary control and, especially in the case of type II diabetes, increased exercise routine. If patients with type II diabetes have not achieved suitable control within about three months after dietary modification and increased physical activity, then oral hypoglycemic drugs may be indicated.
  • the two major classes of such drugs are sulfonylureas and biguanides. Sulfonylureas act mainly by increasing endogenous insulin secretion. Biguanides act chiefly by decreasing hepatic gluconeogeneis and increasing peripheral utilization of glucose.
  • Metformin (N, N - dimethyl imidocarbonimidic diamide) is a typical biguanide and is an active ingredient used in oral hypoglycemic drugs for the treatment of type II diabetes mellitus in humans and other mammals. It is typically administered in the form of a pharmaceutically acceptable salt, usually a hydrochloride salt. Metformin is not chemically or pharmacologically related to any other class of hypoglycemic agents. Unless otherwise indicated, this specification will use "metformin” to mean metformin and pharmaceutically acceptable salts thereof. Metformin is often indicated for patients who are not effectively treated with a sulfonylurea drug independently.
  • Metformin hydrochloride is a white to off-white crystalline compound having the molecular formula C- t H ⁇ Ns.HCl (molecular wt. 165.63) and is freely soluble in water and practically insoluble in acetone, ether and chloroform. Oral doses of metformin are generally recommended in the range of 500 to 2500 mg a day and a single dose may vary from 500 to 850 mg. Metformin can exert its hypoglycemic effect even in the absence of insulin, particularly in patients who are not effectively treated with sulfonylureas.
  • Metformin is not chemically related to sulfonylurea, but it is routinely used in combination with a sulfonylurea and shows synergistic properties in some cases.
  • Other biguanides such as phenformin and buformin can also be used in combination with metformin.
  • Glimepiride is an oral blood glucose lowering drug of the sulfonylurea class. Chemically, glimepiride is identified as l-[[p-[2-(3-ethyl-4-methyl-2-oxo-3-pyrroline-l- carboxamido)ethyl]phenyl]sulfonyl]-3-(trans-4-methylcyclohexyl)urea. Glimepiride is a white to yellowish-white crystalline odorless powder having the molecular formula C 24 H 34 N ⁇ 5 S (molecular wt 490.62) and is practically insoluble in water.
  • US Patent 6031004 describes a method for the treatment of diabetes employing metformin hydrochloride and other salts by themselves or in combination with another anti-diabetic agent (e.g. a hypoglycemic agent such as glyburide, glipizide, glimepiride, acarbose, miglitol, troglitazone or insulin).
  • a hypoglycemic agent such as glyburide, glipizide, glimepiride, acarbose, miglitol, troglitazone or insulin.
  • the dosage is disclosed as an oral tablet form.
  • Metformin salts of dibasic acids that are equivalent to metformin hydrochloride are also described.
  • US Patent 6475521 discloses a biphasic controlled release system for high solubility pharmaceuticals.
  • a metformin hydrochloride salt or a salt of metformin with a dibasic acid is used in combination with another hypoglycemic agent, for example a sulfonylurea such as glyburide, glimepiride, glipizide, gliclazide or chlorpropamide, for the treatment of diabetes.
  • a suitable excipient a hydrophilic and/or hydrophobic polymer
  • US Patent 6524618 describes an extended-release matrix formulation capable of being directly compressed into tablets comprising metformin hydrochloride blended with specific excipients in the form of a free flowing powder.
  • Metformin hydrochloride is also used in combination with another anti-diabetic agents selected from the group consisting of sulfonylureas (eg. glimepiride, glipyride, glipizide, glyburide, and gliciazide), ⁇ - glucosidaze inhibitors and glitazones as well as combinations of two or more of the foregoing anti-diabetic agents.
  • WO-A-02094285 describes orally administered galenic preparations (such as tablets, capsules, powders and the like), which consist of biguanide, preferably metformin and at least one other hypoglycemic active agent (glibenclamide, pioglitazone hydrochloride, rosiglitazone maleate, nateglinide, glipizide, glimepiride).
  • This capsule-shaped tablet consists of a core based on metformin further coated with a film that enables prolonged release in vivo of metformin.
  • the capsule may be coated with the said at least one other hypoglycemic active agent and may allow for the prolonged release of the agent.
  • a pharmaceutical composition comprising a matrix material having first pharmaceutically active agent dispersed therein, the dispersion of the first agent within the matrix material being effective to delay the release profile on administration of the pharmaceutical composition with respect to the release profile of a second pharmaceutically active agent provided in the composition outside ofthe matrix material.
  • the first pharmaceutically active agent and the second pharmaceutically active agent may, in one preferred composition according to the invention, be independently indicated in the treatment of diabetes.
  • the first pharmaceutically active agent and the second pharmaceutically active agent are selected from respectively different classes of chemical compound.
  • the first and second active agents in the composition may be selected to exhibit a synergistic effect for treatment of a disease or a condition, such as diabetes.
  • the first pharmaceutically active agent is a biguanide compound, preferably metformin.
  • the second pharmaceutically active agent is a sulfonylurea compound, preferably glimepiride.
  • the matrix material is preferably a polymeric material or mixture of polymeric materials and is preferably insoluble or only sparingly soluble in water.
  • the matrix material has the capacity to absorb water from its surrounding environment and to swell on such absorption.
  • Preferred polymeric materials include carbomers, such as carbomer 971, cellulosic polymers and alkyl cellulosic polymers such as methyl cellulose, ethyl cellulose, hydroxyethyl cellulose, hydroxy propyl cellulose, hydroxypropyl methyl cellulose, hydroxypropyl methyl cellulose phthalate and mixtures of two or more thereof. Hydroxypropyl methyl cellulose is especially preferred, preferably with a viscosity in the range of 15000 - 100000 cps. Combinations of carbomers with cellulosic polymers are also particularly suitable as the matrix material.
  • the matrix material is biodegradable.
  • the polymer ofthe matrix material may account for 15-25% or 15-20% of the total mass ofthe pharmaceutical composition
  • the first pharmaceutically active agent is dispersed substantially homogenously throughout the matrix material.
  • the release profile ofthe second pharmaceutically active agent be such that release ofthe second agent begins only a short time, for example in less than about 30 minutes, preferably less than about 15 minutes and most preferably less than about 5 minutes after administration. Release of the second agent may begin substantially immediately after administration. Release of the first pharmaceutically active agent is delayed relative to the second agent, and may also be extended to take place over a longer timescale with respect to the second agent.
  • the second active agent sulfonylurea for example, may conveniently be provided in combination with a solubilising agent to provide a predetermined substantially immediate release on administration of the composition.
  • a solubilising agent to provide a predetermined substantially immediate release on administration of the composition.
  • Sodium lauryl sulphate is one preferred solubilising agent, which may suitably be present in an amount of from 0.2-2% ofthe total mass ofthe composition.
  • the second active agent may be therefore provided in combination with an effective amount of one or more immediate release excipients selected, for example, from one or more of: sodium starch glycolate, sodium lauryl sulphate, croscarmellose sodium and betacyclodextrin.
  • one or more immediate release excipients selected, for example, from one or more of: sodium starch glycolate, sodium lauryl sulphate, croscarmellose sodium and betacyclodextrin.
  • the pharmaceutical composition ofthe invention is suitably provided in a tablet form for oral administration and is preferably provided as a layered tablet, with a first layer comprising the matrix material and the first pharmaceutically active agent (optionally in combination with other exipients, colourants, binders, diluents, disintegrants, fillers, lubricants, glidants, taste-masking agents and the like) and a second layer comprising the second pharmaceutically active agent (optionally in combination with other exipients, colourants, diluents, disintegrants, binders, fillers, lubricants, glidants, taste-masking agents and the like).
  • the first active agent may suitably be present in the first layer in an amount ranging from 500 mg to 850 mg.
  • the second active agent may suitably be present in the second layer in an amount ranging from 1 mg to 5 mg.
  • binding agent when a binding agent is present in the composition, preferred binding agents (for combination with the first active agent) include polyvinylpyrrolidone, starch or mixtures thereof.
  • polyvinylpyrrolidone When present, polyvinylpyrrolidone preferably has a grade varying from 10 - 120. The percentage of binding agent, when present, is preferably from 1-10% of the total mass ofthe composition.
  • preferred diluents include micro crystalline cellulose, starch and lactose. Such diluents, when used, may suitably be present in an amount of from 5-10% of the total mass of the composition.
  • preferred diluents include microcrystalline cellulose, dicalcium phosphate or mixtures thereof. Such diluents may suitably be present in an amount of from 10 - 20 % ofthe total mass ofthe composition.
  • disintegrants when a disintegrant is present in the composition, preferrred disintegrants (provided in combination with the second active agent) include sodium starch glycolate and croscarmellose sodium. Such disintegrants may suitably be present in an amount of from 0.2-2% ofthe total mass ofthe composition.
  • a preferred lubricant is magnesium stearate.
  • Such lubricants may suitably be present in an amount of from 0.01-0.02% ofthe total mass ofthe preparation.
  • a preferred glidant is colloidal silicon dioxide.
  • Such glidants may suitably be present in an amount of from 1-2% ofthe total mass ofthe composition.
  • the invention provides a pharmaceutical preparation in tablet form comprising two or more active ingredients with pre-determined release profiles, at least one active ingredient having a release profile that differs substantially from the release profile of another ofthe other active ingredient.
  • Preferred pharmaceutical compositions ofthe invention will: provide immediate release of sulfonylurea by using a solubilizing agent in an effective manner in a first layer; use a combination of two specific hydroxypropyl methyl cellulose and/or carbomer polymers in a second layer to aid effective release of the drug over a specific period of time independent of pH affects; provide a two drug combination therapy having a synergistic effect over control of blood glucose in diabetic patients; allow reduced frequency of drug dosing and hence improve patient compliance; maintain a steady drug concentration in the blood circulation with the help of a sustained release layer; and minimize incidence and severity of adverse side effects.
  • the present invention therefore relates to a pharmaceutical composition adapted for dual release at different rates of combined pharmaceutical active agents, for example agents having anti-diabetic activity, in which at least one ofthe active ingredients is, preferably homogenously, dispersed throughout a rate controlling polymer matrix, release of the at least one active ingredient being controlled by diffusion through the matrix, and in which at least one other active agent is provided in the composition in a form available for rapid release in vivo.
  • pharmaceutical active agents for example agents having anti-diabetic activity
  • at least one ofthe active ingredients is, preferably homogenously, dispersed throughout a rate controlling polymer matrix, release of the at least one active ingredient being controlled by diffusion through the matrix, and in which at least one other active agent is provided in the composition in a form available for rapid release in vivo.
  • a pharmaceutical preparation in tablet form comprising two or more active ingredients with pre-determined release profiles, at least one active ingredient having a release profile that differs substantially from the release profile of at least one other active ingredient.
  • Each active ingredient may be disposed in a discrete layer within the tablet.
  • the at least two release profiles may comprise an extended release profile and an immediate release profile.
  • the present invention also relates to the pharmaceutical preparation of a bi-layer tablet suitable for oral administration.
  • Each tablet is preferably made up of immediate release compartment and extended release compartment.
  • the immediate release compartment may comprise a compressed blend of an active agent and one or more polymers with some super disintegrant and solubilisers.
  • the extended release compartment may comprise biodegradable/non-biodegradable or hydrophilic /hydrophobic polymers which have swelling properties within which an active ingredient is suitably blended and this allows prolonged release of active substance within the second layer.
  • the extended release compartment When the extended release compartment is in contact with the immediate release compartment it provides a dose sufficient to exceed the metabolic capacity of the body and maintains the therapeutic levels.
  • the invention is not limited as to the nature of the active ingredients.
  • Each layer may contain a different active ingredient.
  • the first layer may contain up to 50-80% of the active substance ofthe total weight ofthe first layer.
  • the second layer may contain up to 3-10% by weight ofthe active ingredient.
  • Drug efficacy generally depends on the ability ofthe drug to reach its target in sufficient quantities, to maintain desired therapeutic levels for a fixed (desired) time period.
  • Metformin and glimepiride are two active ingredients for anti-diabetic drugs that are used to treat diabetic patients (human beings).
  • the use ofthe core formulation involving both the active ingredients is advantageous to patients and physicians because both medicaments are synergistic to each other in the body when used in the management of blood glucose control. I.e.: diabetes.
  • the matrix material polymer is associated to the biguanide by forming a core within the preparation to provide a predetermined delay in the time period ofthe release ofthe biguanide.
  • compartmentalized (two compartments or more) delivery of active ingredients in the intestinal tract is facilitated by the product formulation, taking into account the physical & physiological conditions in the human GI tract and also the travelling time of the pharmaceutical preparation through the intestinal tract.
  • the immediate release ingredient releases within 45 minutes in acidic pH (stomach), and the extended release ingredient releases within 10 hrs at a different pH.
  • Orally administered drugs have to overcome several obstacles to reach their desired targets. Before orally administered drugs enter the general circulation ofthe human body they are absorbed into the capillaries and veins ofthe GI tract and are transported by the portal vein to the liver. The pH and enzymatic activities found in the GI tract fluids may inactivate the drug or cause the drug to dissolve poorly. Thus the amount of drugs in the blood stream is significantly lower than the amount administered. This metabolic elimination ofthe given dose results in bioavailability.
  • Formulations capable of immediate and sustained release are suitable for once daily administration.
  • the tablets ofthe invention are prepared by a method including the steps of granulation, followed by compression.
  • the present invention further provides a method for forming a tablet-form pharmaceutical composition
  • a method for forming a tablet-form pharmaceutical composition comprising: providing a first pulverulent component comprising a first pharmaceutically active agent and a matrix material; providing a second pulverulent component comprising a second pharmaceutically active agent; and compressing the first and second pulverulent components together as discrete layers to form a tablet-form pharmaceutical composition having a first layer comprising the matrix material having the first pharmaceutically active agent dispersed therein, the dispersion ofthe first agent within the matrix material being effective to delay the release profile on administration of the pharmaceutical composition with respect to the release profile of the second pharmaceutically active agent provided in the composition as a second discrete layer.
  • the method of preparation comprises the steps of: a) preparing granules of a first active substance from a pulverulent mixture of the said first active substance and one or more biodegradable inert polymeric materials, and optionally one or more additives suitable for the prolonged release ofthe said first active substance; b) preparing granules of second active substance from a pulverulent mixture of the said second active substance, a disintegrating agent, a solubilising agent, optionally one or more additives such as binding agent and polymers for the preparation ofthe immediate release ofthe second active substance; and c) combining, by compressing, in a manner known per se the two types of granules obtained in steps a) and b) above so as to obtain tablets in which the lower layer, affording prolonged release, results from the compression of granules obtained in step a) and in which the upper layer, affording immediate release, results from the compression ofthe granules in step b).
  • the first step (a) is designed to provide granules based on the first active substance, which will lead , through compression, to the lower layer, designated as the prolonged release layer.
  • the constituents of this layer are those of the biodegradable inert polymeric matrix defined above.
  • the second step (b) is designed to provide granules based on a different active substance, which will lead, through compression, to the upper layer, designated the immediate release layer.
  • Step c) leads to successive compression of the granules obtained in the preceding steps a) and b) to form a tablet.
  • Steps a) and b) involve the granulation of powder of amorphous or crystallized particles. This granulation may be carried out by a wet granulation method.
  • the compression step is suitably achieved using 19 x 9 mm flat bevelled capsule shaped punches.
  • the method of granulation comprises five essential steps:
  • the dry mixing consists of mixing the pulverulent excipients entering into the composition of the granules.
  • the wetting consists in adding to the pulverulent mixture, various constituents, an aqueous solution of binder or hydroalcoholic solution of binder or alcoholic solution of binder.
  • the granulation procedure is carried out by kneading in a planetary or a rapid type mixer granulator.
  • the drying procedure is carried out in a fluidised bed dryer or tray dryer to achieve desired loss on drying. Sizing is done in multimill by using suitable size distribution ofthe granules.
  • a process for producing a multi-layered pharmaceutical product with an immediate release and controlled release of two or more active ingredients comprising the steps of: a) producing a core comprising at least one or more polymers which absorbs water and swells, selected from the group consisting of hydroxypropyl methyl cellulose, hydroxypropyl cellulose, carbomer, hydroxypropyl methyl cellulose phthalate; and b) inserting a lower layer comprising a biguanide and upper layer comprising a sulfonylurea.
  • Figure 1 is a graph illustrating the results of the in vitro release of metformin over 12 hours from a pharmaceutical preparation produced in Example 1;
  • Figure 2 is a graph illustrating the results of the in vitro release of metformin over 12 hours from a pharmaceutical preparation produced in Examples 2, 3 and 4.
  • a pharmaceutical preparation was produced with two active ingredients (metformin and glimepiride), each of which was held in a separate layer in the tablet.
  • the lower layer was produced from the following components:
  • magnesium stearate was mixed with the powder.
  • the upper layer was produced from the following components:
  • magnesium stearate part of the sodium lauryl sulphate and colloidal silicon dioxide, were mixed together and were granulated using a paste containing polyvinylpyrrolidone and the granules were dried and screened, to obtain a suitable size distribution and mixed with colloidal silicon dioxide and croscarmellose sodium in a blender. After this had been effectively blended, magnesium stearate was mixed in with the powder.
  • the resultant bi-layer tablets each contained 500mg of metformin hydrochloride and 1 mg of glimepiride.
  • Each tablet weighed 1150mg and contained 890mg of lower layer and 260mg of upper layer and were 19 9 mm in dimension.
  • the tablets were produced on a tablet press by a two stage pressing procedure, thereby tablets of lower layer were formed in the press and then the upper layer was added and the press operated again.
  • a pharmaceutical preparation was produced with two active ingredients (metformin and glimepiride), each of which was held in a separate layer in the tablet.
  • the lower layer was produced from the following components:
  • magnesium stearate was mixed with the powder.
  • Upper Layer The components, except magnesium stearate were mixed together in a blender and then granulated, using a paste containing polyvinlypyrrolidone. The granules were dried and screened to obtain suitable particle size distribution and mixed with hydroxypropyl methyl cellulose. When this had been effectively blended, magnesium stearate was mixed with the powder.
  • Upper Layer
  • the upper layer was produced from the following components:
  • magnesium stearate part of the sodium lauryl sulphate and colloidal silicon dioxide, were mixed together and were granulated using a paste containing polyvinylpyrrolidone. The granules were dried and screened, to obtain a suitable size distribution and mixed with colloidal silicon dioxide and croscarmellose sodium in a blender. When this has been effectively blended, magnesium stearate was mixed with the powder.
  • Each bi-layer tablet contained 500mg of metformin hydrochloride and 1 mg of glimepiride.
  • Each tablet weighed 1130mg and containing 900mg of lower layer and 230mg of upper layer and were 19 x 9 mm in dimension.
  • the tablets were produced on a tablet press by a two stage pressing procedure, thereby tablets of lower layer were formed in the press and then the upper layer was added and the press operated again.
  • a pharmaceutical preparation was produced with two active ingredients (metformin and glimepiride), each of which was held in a separate layer in the tablet.
  • the lower layer was produced from the following components:
  • magnesium stearate was mixed with the powder.
  • the upper layer was produced from the following components:
  • magnesium stearate part of the sodium lauryl sulphate and the colloidal silicon dioxide, were mixed together and were granulated using a paste containing Starch and the granules were dried and screened, to obtain a suitable size distribution.
  • the mixture was then mixed with colloidal silicon dioxide and croscarmellose sodium in a blender. When this has been effectively blended, magnesium stearate were mixed with the powder.
  • Each bi-layer tablets contains 500mg of metformin hydrochloride and 1 mg of glimepiride.
  • Each tablet weighs HOOmg and contains 900mg of lower layer and 200mg of upper layer and is 19 x 9 mm in dimension.
  • the tablets were produced on a tablet press by a two stage pressing procedure, thereby tablets of lower layer were formed in the press and then the upper layer were added and the press operated again.
  • a pharmaceutical preparation was produced with two active ingredients (metformin and glimepiride), each of which was held in a separate layer in the tablet.
  • the lower layer was produced from the following components:
  • magnesium stearate was mixed with the powder.
  • the upper layer was produced from the following components:
  • the mixture is mixed with colloidal silicon dioxide and croscarmellose sodium in a blender. When this has been effectively blended, magnesium stearate were mixed with the powder.
  • the bi-layer tablets each contained 500mg of metformin hydrochloride and 1 mg of glimepiride.
  • Each tabled weighed llOOmg and contained 900mg of lower layer and 200mg of upper layer and were 19 x 9 mm in dimension.
  • the tablets were produced on a tablet press by a two stage pressing procedure, thereby tablets of lower layer were formed in the press and then the upper layer was added and the press operated again.

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  • Health & Medical Sciences (AREA)
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  • Chemical & Material Sciences (AREA)
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  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Abstract

L'invention concerne un procédé permettant la libération double d'une combinaison d'agents actifs pharmaceutiques, en particulier, des médicaments anti-diabète, un des agents actifs étant dispersé de manière homogène par l'intermédiaire d'une matrice polymère régulant le débit et la libération du médicament étant régulée par la diffusion à travers la matrice.
PCT/IN2003/000311 2003-04-17 2003-09-17 Liberation multiple de medicaments anti-diabete et procede de production associe WO2004091587A1 (fr)

Priority Applications (1)

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AU2003282374A AU2003282374A1 (en) 2003-04-17 2003-09-17 Multiple release anti-diabetic drugs and process of production thereof

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IN383/MUM/2003 2003-04-17
IN338MU2003 2003-04-17

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WO2004091587A1 true WO2004091587A1 (fr) 2004-10-28

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2007072992A3 (fr) * 2005-12-22 2007-12-06 Takeda Pharmaceutical Preparation solide
CN108509751A (zh) * 2018-04-27 2018-09-07 东南大学 一种考虑延时矩阵的电力信息物理耦合系统动态建模方法

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE19860698A1 (de) * 1998-12-30 2000-07-06 Hexal Ag Neue pharmazeutische Zusammensetzung
WO2003005991A1 (fr) * 2001-07-10 2003-01-23 Aeropharm Technology Incorporated Formulation de noyau

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE19860698A1 (de) * 1998-12-30 2000-07-06 Hexal Ag Neue pharmazeutische Zusammensetzung
WO2003005991A1 (fr) * 2001-07-10 2003-01-23 Aeropharm Technology Incorporated Formulation de noyau

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2007072992A3 (fr) * 2005-12-22 2007-12-06 Takeda Pharmaceutical Preparation solide
US8071130B2 (en) 2005-12-22 2011-12-06 Takeda Pharmaceutical Company Limited Solid preparation
AU2006328328B2 (en) * 2005-12-22 2012-08-30 Takeda Pharmaceutical Company Limited Solid preparation containing an insulin sensitizer
CN101384251B (zh) * 2005-12-22 2014-09-03 武田药品工业株式会社 含胰岛素敏化剂的固体制剂
CN108509751A (zh) * 2018-04-27 2018-09-07 东南大学 一种考虑延时矩阵的电力信息物理耦合系统动态建模方法
CN108509751B (zh) * 2018-04-27 2022-02-15 东南大学 一种考虑延时矩阵的电力信息物理耦合系统动态建模方法

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