CA2324493C - Controlled release oral tablet having a unitary core - Google Patents
Controlled release oral tablet having a unitary core Download PDFInfo
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- CA2324493C CA2324493C CA002324493A CA2324493A CA2324493C CA 2324493 C CA2324493 C CA 2324493C CA 002324493 A CA002324493 A CA 002324493A CA 2324493 A CA2324493 A CA 2324493A CA 2324493 C CA2324493 C CA 2324493C
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- controlled release
- release pharmaceutical
- pharmaceutical tablet
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- 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
-
- 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
- A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
- A61K9/2806—Coating materials
- A61K9/2833—Organic macromolecular compounds
- A61K9/286—Polysaccharides, e.g. gums; Cyclodextrin
- A61K9/2866—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
-
- 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
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0002—Galenical forms characterised by the drug release technique; Application systems commanded by energy
- A61K9/0004—Osmotic delivery systems; Sustained release driven by osmosis, thermal energy or gas
-
- 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
-
- 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
- A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
- A61K9/2806—Coating materials
- A61K9/282—Organic compounds, e.g. fats
-
- 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
-
- 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
- A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
- A61K9/2886—Dragees; Coated pills or tablets, e.g. with film or compression coating having two or more different drug-free coatings; Tablets of the type inert core-drug layer-inactive layer
Abstract
A controlled release antihyperglycemic tablet that does not contain an expanding polymer and comprising a core containing the antihyperglycemic drug, a semipermeable membrane coating the core and at lea st one passageway in the membrane.
Description
WO 99/47125 PC'T/US99I06024 CONTROLLED RELEASE ORAL TABLET~HAVING A UNITARY CORE
BACKGROUND OF THE INVENTION:
The present invention relates to controlled release unit dose formulations containing an -antihyperglycemic drug. More specifically, the present invention relates to an oral dosage form comprising a biguanide such as metformin or buformin or a pharmaceutically acceptable salt thereof such as metformin hydrochloride or the metformin salts described in United States Patent Nos. 3,957,853 and 4,080,472.
In the prior art, many techniques have been used to provide controlled and extended-release pharmaceutical dosage forms in order to maintain therapeutic serum levels of medicaments and to minimize the effects of missed doses of drugs caused by a lack of patient compliance.
In the prior art are extended release tablets which have an osmotically active drug core surrounded by a semipermeable membrane. These tablets function by allowing a fluid such as'gastric or intestinal fluid to permeate the coating membrane and dissolve the active ingredient so it can be released through a passageway in the coating membrane or if the active ingredient is insoluble in the permeating fluid, pushed through the passageway by an expanding agent such as a hydrogel. Some representative examples of these osmotic tablet systems can be found in United States Patent Nos. 3,845,770, 3,916,899, 4,034,758, 4,077,407 and 4,783.337. United States Patent No.
3,952,741 teaches an osmotic device wherein the active agent is released from a core surrounded by a semipermeable membrane only after sufficient pressure has developed within the membrane to burst or rupture the membrane at a weak portion of the membrane.
The basic osmotic device described in the above cited patents have been refined over time in an effort to provide greater control of the release of the active ingredient.
For example United States Patent Nos. 4,777,049 and 4,851,229 describe an osmotic dosage form comprising a SUBSTITUTE SHEET (RULE 26) WO 99I47t25 PCT/US99/06024 semipermeable wall surrounding a core. The core contains an active ingredient and a modulating agent wherein the modulating agent causes the active ingredient to be released through a passageway in the semipermeable membrane in a pulsed manner. Further refinements have included modifications to the semipermeable membrane surrounding the active core such as varying the proportions of the components that form the membrane, i.e United States Patent Nos. 5,178,867, 4,587,117 and 4,522,625 or increasing the number of coatings surrounding the active core, i.e 5,650,170 and 4,892,739.
Although vast amounts of research has been performed on controlled or sustained release compositions and in particular on osmotic dosage forms, very little research 15 has been performed in the area of controlled or sustained release compositions that employ antihyperglycemic drugs.
The limited work on controlled or sustained release formulations that employ antihyperglycemic drugs such as metformin hydrochloride has been limited to the combination of the antihyperglycemic drug and an expanding or gelling agent to control the release of the drug from the dosage form. This limited research is exemplified by the teachings of WO 96/08243 and by the GLUCOPHAGE~ product which is a commercially available product from Bristol Myers Squibb Co. containing metformin HC1.
It is reported in the 50th Edition of the Physicians' Desk Reference, copyright 1996, p. 753, that food decreases the extent and slightly delays the absorption of metformin delivered by the GLUCOPHAGE~ dosage form. This decrease is shown by approximately a 40% lower peak concentration and a 250 lower AUC in plasma and a 35 minute prolongation of time to peak plasma concentration following administration of a single GLUCOPHAGE~ tablet containing 850 mg of metformin HCl with food compared to the similar tablet administered under fasting conditions.
It is an object of the present invention to provide a controlled or sustained release formulation for an SUBSTITUTE SHEET (RULE 2fi) antihyperglycemic drug wherein the bioavailability of the drug is not decreased by the presence of food.
It is a further object of the present invention to provide a controlled or sustained release formulation for an antihyperglycemic drug that does not employ an expanding polymer.
It is also a further object of the present invention to provide a controlled or sustained release formulation for an antihyperglycemic drug that can provide continuous and non-pulsating therapeutic levels of an antihyperglycemic drug to an animal or human in need of such treatment over a twelve hour to twenty-four hour period.
It is an additional object of the present invention to provide a controlled or sustained release formulation for an antihyperglycemic drug that obtains peak plasma levels approximately 8-12 hours after administration.
It is also an object of this invention to provide a controlled or sustained release pharmaceutical tablet having only a homogeneous osmotic core wherein the osmotic core component may be made using ordinary tablet compression techniques.
SUMMARY OF THE INVENTION
The foregoing objectives are met by a controlled release dosage form comprising:
(a) a core comprising: w '- (i) an antihyperglycemic drug;
(ii) optionally a binding agent; and (iii) optionally an absorption enhancer;
(b) a semipermeable membrane coating surrounding the core;
and (c) at least one passageway in the semipermeable membrane.
The dosage form of the present invention can provide therapeutic levels of the antihyperglycemic drug for twelve to twenty-four hour periods and does not exhibit a decrease in bioavailability if taken with food. In fact, a slight SUBSTITUTE SHEET (RULE 26) increase in the bioavailability of the antihypoglycemic drug is observed when the controlled release dosage form of the present invention is administered with food. In a preferred embodiment, the dosage form will be administered once a day, ideally with or after a meal and most preferably with or after the evening meal, and provide therapeutic levels of the drug throughout the day with peak plasma levels being obtained between e-12 hours after administration.
BRIEF DESCRIPTION OF THE DRAWINGS
FIG. 1 is a graph which depicts the dissolution profile in simulated intestinal fluid (pH 7.5 phosphate buffer) and simulated gastric fluid (SGF) of the formulation described in Example 1 as tested according to the procedure described in United States Pharmacopeia XXIII, Apparatus 2 @ 75 rpm.
FIG. 2 is a graph which depicts the dissolution profile in simulated intestinal fluid (pH 7.5 phosphate buffer) and simulated gastric fluid (SGF) of the formulation described in Example 2 as tested according to the procedure described in United States Pharmacopeia XXIII, Apparatus 2 @ 75 rpm.
FIG. 3 is a graph which depicts the dissolution profile in simulated intestinal fluid (pH 7.5 phosphate buffer) and simulated gastric fluid (SGF) of the formulation described in Example 3 as tested according to the procedure described in United States Pharmacopeia XXIII, Apparatus 2 @ 75 rpm.
FIG. 4 is a graph depicting the in vivo metformin plasma profile of the formulation described in Example 1 and the in vivo metformin plasma profile of the commercially available metformin HCl product GLUCOPHAGE~
under fasting conditions.
FIG. 5 is a graph depicting the in vivo metformin plasma profile of the formulation described in Example 2 and the in vivo metformin plasma profile of the SUBSTITUTE SHEET (RULE 26) commercially available metformin HC1 product GLUCOPHAGE~
under fasting conditions.
FIG. 6 is a graph depicting the in vivo metformin plasma profile of the formulation described in Example 2 and the in vivo metformin plasma profile of the commercially available metformin HC1 product GLUCOPHAGE~
under fed conditions.
FIG. 7 is a graph depicting the in vivo metformin plasma profile of the formulation described in Example 3 and the in vivo metformin plasma profile of the commercially available metformin HC1 product GLUCOPHAGE~
under fed conditions (after breakfast).
FIG. 8 is a graph depicting the in vivo metformin plasma profile of the formulation described in Example 3 and the in vivo metformin plasma profile of the commercially available metformin HC1 product GLUCOPHAGE~
under fed conditions (after dinner).
DETAILED DESCRIPTION OF THE INVENTION
The term antihyperglycemic drugs as used in this specification refers to drugs that are useful in controlling or managing noninsulin-dependent diabetes mellitus (NIDDMO. Preferably, the antihyperglycemic drug is a biguanide such as metformin or buformin or a pharmaceutically acceptable salt thereof such as metformin hydrochloride.
The binding agent may be any conventionally known pharmaceutically acceptable binder such as polyvinyl pyrrolidone, hydroxypropyl cellulose, hydroxyethyl cellulose, ethylcellulose, polymethacrylate, waxes and the like. Mixtures of the aforementioned binding agents may also be used. The preferred binding agents are water soluble such as polyvinyl pyrrolidone having a weight average molecular weight of 25,000 to 3,000,000. The binding agent comprises approximately about 0 to about 40%
of the total weight of the core and preferably about 3o to about 15% of the total weight of the core.
SUBSTITUTE SHEET (RULE 26) The core may optionally comprise an absorption enhancer. The absorption enhancer can be any type of absorption enhancer commonly known in the art such as a fatty acid, a surfactant, a chelating agent, a bile salt or mixtures thereof. Examples of some preferred absorption enhancers are fatty acids such as capric acid, oleic acid and their monoglycerides, surfactants such as sodium lauryl sulfate, sodium taurocholate and polysorbate 80, chelating agents such as citric acid, phytic acid, ethylenediamine tetraacetic acid (EDTA) and ethylene glycol-bis(i3 aminoethyl ether)-N,N,N,N-tetraacetic acid (EGTA). The core comprises approximately 0 to about 200 of the absorption enhancer based on the total weight of the core and most preferably about 2% to about l00 of the total weight of the core.
The core of the present invention which comprises the antihyperglycemic drug, the binder which preferably is a pharmaceutically acceptable water soluble polymer and the absorption enhancer is preferably formed by wet granulating the core ingredients and compressing the granules with the addition of a lubricant into a tablet on a rotary press.
The core may also be formed by dry granulating the core ingredients and compressing the granules with the addition of a lubricant into tablets or by direct compression.
Other commonly known excipients may also be included into the core such as lubricants, pigments or dyes.
The homogeneous core is coated with a semipermeable membrane, preferably a modified polymeric membrane to form the controlled release tablet of the invention. The semipermeable membrane is permeable to the passage of an external fluid such as water and biological fluids and is impermeable to the passage of the antihyperglycemic drug in the core. Materials that are useful in forming the semipermeable membrane are cellulose esters, cellulose diesters, cellulose triesters, cellulose ethers, cellulose ester-ether, cellulose acylate, cellulose diacylate, cellulose triacylate, cellulose acetate, cellulose SUBSTITUTE SHEET (RULE 26) diacetate, cellulose triacetate, cellulose acetate propionate, and cellulose acetate butyrate. Other suitable polymers are described in United States Patent Nos.
3,845,770, 3,916,899, 4,008,719, 4,036,228 and 4,11210.
The most preferred semipermeable membrane material is cellulose acetate comprising an acetyl content of 39.3 to 40.3%, commercially available from Eastman Fine Chemicals.
In an alternative embodiment, the semipermeable membrane can be formed from the above-described polymers and a flux enhancing agent. The flux enhancing agent increases the volume of fluid imbibed into the core to enable the dosage form to dispense substantially all of the antihyperglycemic drug through the passageway and/or the porous membrane. The flux enhancing agent can be a water soluble material or an enteric material. Some examples of the preferred materials that are useful as flux enhancers are sodium chloride, potassium chloride, sucrose, sorbitol, mannitol, polyethylene glycol (PEG), propylene glycol, hydroxypropyl cellulose, hydroxypropyl methycellulose, hydroxypropyl methycellulose phthalate, cellulose acetate phthalate, polyvinyl alcohols, methacrylic acid copolymers and mixtures thereof. The preferred flux enhancer is PEG 400.
The flux enhancer may also be a drug that is water soluble such as metformin or its pharmaceutically acceptable salts or a drug that is soluble under intestinal conditions. If the flux enhancer is a drug, the present dosage form has the added advantage of providing an immediate release of the drug which is selected as the flux enhancer.
The flux enhancing agent comprises approximately 0 to about 40% of the total weight of the coating, most preferably about 2% to about 20% of the total weight of the coating. The flux enhancing agent dissolves or leaches from the semipermeable membrane to form paths in the semipermeable membrane for the fluid to enter the core and dissolve the active ingredient.
The semipermeable membrane may also be formed with commonly known excipients such a plasticizer. Some commonly known plasticizers include adipate, azelate, enzoate, citrate, stearate, isoebucate, sebacate, triethyl citrate, tri-n-butyl citrate, acetyl tri-n-butyl citrate, citric acid esters, and those described in the Encyclopedia of Polymer Science and Technology, Vol. 10 (1969), published by John Wiley & Sons. The preferred plasticizers are triacetin, acetylated monoglyceride, grape seed oil, olive oil, sesame oil, acetyltributylcitrate, acetyltriethylcitrate, glycerin sorbitol, diethyloxalate, diethylmalate, diethylfumarate, dibutylsuccinate, diethylmalonate, dioctylphthalate, dibutylsebacate, triethylcitrate, tributylcitrate, glyceroltributyrate, and the like. Depending on the particular plasticizer, amounts of from 0 to about 250, and preferably about 2% to about 150 of the plasticizer can be used based upon the total weight of the coating.
As used herein the term passageway includes an aperture, orifice, bore, hole, weaken area or an erodible element such as a gelatin plug that erodes to form an osmotic passageway for the release of the antihyperglycemic drug from the dosage form. A detailed description of the passageway can be found in United States Patents such as 3,845,770, 3,916,899, 4,034,758, 4,077,407', 4,783,337 and 5,'71, 607.
Generally, the membrane coating around the core will comprise from about to to about 5o and preferably about 2%
to about 3o based on the total weight of the core and coating.
In an alternative embodiment, the dosage form of the present invention may also comprise an effective amount of the antihyperglycemic drug that is available for immediate release. The effective amount of antihyperglycemic drug for immediate release may be coated onto the semipermeable SUBSTITUTE SHEET (RULE 26) membrane of the dosage form or it may be incorporated into the semipermeable membrane.
In a preferred embodiment the dosage form will have the following composition:
Preferred Most Preferred CORE:
drug 50-98$ 75-95$
binder 0-40$ 3-15$
absorption enhancer 0-20$ 2-10$
COATING:
semipermeable polymer 50-99$ 75-95$
flux enhancer 0-40$ 2-20$
plasticizer 0-25$ 2-15$
The dosage forms prepared according to the present invention should exhibit the following dissolution profile when tested in a USP type 2 apparatus at 75 rpms in 900 ml of simulated intestinal fluid (pH 7.5 phosphate buffer) and at 37°C:
Preferred Most Preferred Time (hours) 2 0-25$ 0-15$
4 10-45$ 20-40$
8 30-90$ 45-90$
12 NLT 50$ NLT 60$
16 NLT 60$ NLT 70$
20 NLT 70$ NLT 80$
NLT = NOT LESS THAN
In a broad aspect, then, the present invention relates to a controlled release pharmaceutical tablet comprising:
(a) a core comprising: up to 40$ of a binding agent, up to 20$ of an absorption enhancer, the balance, up to 98$, of an antihyperglycemic drug, provided that the total percentage of binding agent and absorption enhancer <_ 50$;
(b) a semipermeable membrane coating covering said core wherein the membrane is permeable to the passage of water and biological fluids and is impermeable to the passage of the antihyperglycemic drug wherein said coating comprises up to 40~ of a flux enhancer, and the balance, up to 99$, of a polymer, provided the total percentage of flux enhancer and plasticier <- 50$; and (c) at least one passageway in the semipermeable membrane for the release of the antihyperglycemic drug.
In another broad aspect, then, the present invention relates to a controlled release antihyperglycemic tablet comprising: (a) a core consisting of: up to 40~ of a water soluble binding agent; up to 20$ of an absorption enhancer, the balance, up to 98~, of metaformin or a pharmaceutically acceptable salt thereof, provided that the total percentage of binding agent and absorption enhancer s 50$; (b) a semipermeable membrane coating covering said core comprising: up to 40$ of a flux enhancer; up to 25~ of a plasticizer, the balance, up to 99$, of cellulose acetate, provided that the total percentage of flux enhancer and plasticizer s 50~; and (c) at least one passageway in the semipermeable membrane.
In yet another broad aspect, then, the present invention relates to a controlled release pharmaceutical tablet consisting of: (a) a core comprising: from 3-15% of a binding agent; from 2-15~ of an absorption enhancer, and the balance, up to 95$, of an antihyperglycemic drug, provided that the total percentage of binding agent and absorption enhancer s 25$; (b) a semipermeable membrane coating covering said core wherein the semipermeable membrane is permeable to the passage of water and biological fluids and is impermeable to the passage of the antihyperglycemic drug and comprises: from 2-20a of a flux enhancer; from 2-15$ of a plasticizer; and the balance, up to 96$ of a polymer, provided that the total percentage of flux enhancer and plasticizer <_ 25~; and (c) at least one passageway in the semipermeable membrane for the release of the antihyperglycemic drug.
9a In a further broad aspect, then, the present invention relates to a controlled release pharmaceutical tablet comprising: (a) a core comprising: up to 40~ of a binding agent, up to 20$ of an absorption enhances, and the balance, up to 98~, of an antihyperglycemic drug, provided the total percentage of binding agent and absorption enhances <_ 50~: (b) a water soluble seal coat; (c) a semipermeable membrane coating covering said core wherein the membrane is permeable to the passage of water and biological fluids and is impermeable to the passage of the antihyperglycemic drug wherein said coating comprises up to 40$ of a flux enhances, up to 25$ of a plasticizes, and the balance, up to 99$, of a polymer, provided the total percentage of flux enhances and plasticizes < 50~; and (d) at least one passageway in the semipermeable membrane for the release of the antihyperglycemic drug.
In a still further broad aspect, then, the present invention relates to a controlled release antihyperglycemic tablet comprising: (a) a core consisting of: up to 400 of a water soluble binding agent, up to 20$ of an absorption enhances, and the balance, up to 98$, metformin or a pharmaceutically acceptable salt thereof, provided the total percentage of water soluble binding agent and absorption enhances s 50$; (b) a water soluble seal coat;
(c) a semipermeable membrane coating covering said core comprising: up to 40$ of a flux enhances, up to 25~ of a plasticizes, the balance up to 99$, of a polymer, provided the total percentage of flux enhances and plasticizes <
50$; and (d) at least one passageway in the semipermeable membrane for the release of metformin.
In the preparation of the tablets of the invention, various conventional well known solvents may be used to prepare the granules and apply the external coating to the tablets of the invention. In addition, various 9b diluents, excipients, lubricants, dyes, pigments, dispersants etc. which are disclosed in Remington's pharmaceutical Sciences, 1995 Edition may be used to optimize the formulations of the invention.
9c .
A controlled release tablet containing 850 mg of metformin HC1 and having the following formula is prepared as follows:
I Core metformin HC1 90.540 povidonel*, USP 4_380 sodium tribasic phosphate 4.58%
magnesium stearate 0.5 %
lapproximate molecular weight = 50,000; dynamic viscosity (l0ow/v solution at 20°C) - 5.5-8.5 m Pa s.
(a) Granulation The metformin HC1 is delumped by passing it through a 40 mesh screen and collecting it in a clean, polyethylene lined container. The povidone, K-30, and sodium tribasic phosphate are dissolved in purified water. The delumped metformin HC1 is then added to a top-spray fluidized bed granulator and granulated by spraying the binding solution of povidone and sodium tribasic phosphate under the following conditions: inlet air temperature of 50-70°C;
atomization air pressure of 1-3 bars; and spray rate of l0-100 ml/min.
once the binding solution is depleted, the granules are dried in the granulator until the loss on drying is less than 20. The dried granules are passed through a Comil equipped with the equivalent of an 18 mesh screen.
(b) Tableting The magnesium stearate is passed through a 40 mesh stainless steel screen and blended with the metformin HCl granules for approximately five (5) minutes_ After blending, the granules are compressed on a rotary press fitted with 15/32" round standard concave punches (plain lower punch, upper punch with an approximately 1 mm indentation pin).
(c) Seal Coatix~.g (opt3.ona1) * denotes Trade-mark l0 SUBSTITUTE SHEET (RULE 26) The core tablet is seal coated with an Opadry*
material or other suitable water-soluble material by first dissolving the Opadry* material, preferably Opadry Clear*, in purified water. The Opadry* solution is then sprayed onto the core tablet using a pan coater under the following conditions: exhaust air temperature of 38-42°C;
atomization pressure of 28-40 psi; and spray rate of 10-15 ml/min. The core tablet is coated with the sealing solution until a theoretical coating level of approximately 2% is obtained.
II ~ Sustained Release ~oatinc~
cellulose acetate (398-10)~ 850 triacetin 5a PEG 400 10%
Zacetyl content 39.3 - 40.3%
(d) Sustained Release Coating The cellulose acetate is dissolved in acetone while stirring with a homogeni2er. The polyethylene glycol 400 and triacetin are added to the cellulose acetate solution and stirred until a clear solution is obtained. The clear coating solution is then sprayed onto the seal coated tablets in a fluidized bed coater~employing the following conditions: product temperature of 16-22°C; atomization pressure of approximately 3 bars; and spray rate of 120-150 ml/min. The sealed core tablet is coated until a theoretical coating level of approximately 3o is obtained.
The resulting tablet is tested in simulated intestinal fluid (pH 7.5) and simulated gastric fluid (SGF) according to the procedure described in United States Pharmacopeia XXIII, Apparatus 2 a 75 rpm and found to have the following release profile:
TTME (hours) % Released (SGFL % Released (x~H 7.5) 2 9 ~ 12 * denotes Trade-mark SUBSTITUTE SHEET (RULE 26) The release profile in pH 7.5 and SGF of the sustained - release product prepared in this Example is shown in Figure 1.
Figure 4 depicts the in vivo metformin plasma profile of the sustained release product prepared in this Example.
Also shown in Figure 4 is the in vivo metformin plasma profile of GLUCOPHAGE~, a commercially available pharmaceutical product containing the drug metformin HC1.
A controlled release tablet containing 850 mg of metformin HCl and having the following formula is prepared as follows:
I Core metformin HC1 88.555a povidone', USP 6.368°s sodium lauryl sulfate 4.5770 magnesium stearate 0.5 0 'approximate molecular weight = 1,000,000, dynamic viscosity (10%w/v solution at 20°C) - 300-700 m Pa s.
SUBSTfTUTE SHEET (RULE 26) (a) Granulation The metformin HC1 and sodium lauryl sulfate are delumped by passing them through a 40 mesh screen and collecting them in a clean, polyethylene-lined container.
The povidone, K-90F, is dissolved in purified water. The delumped metformin HCl and sodium lauryl sulfate are then added to a top-spray fluidized bed granulator and granulated by spraying with the binding solution of povidone under the following conditions. inlet air temperature of 50-70°C; atomization air pressure of 1-3 bars; and spray rate of 10-100 ml/min.
Once the binding solution is depleted, the granules are dried in the granulator until the loss on drying is less than 20. The dried granules are passed through a Comil equipped with the equivalent of an 18 mesh screen.
(b) Tableting The magnesium stearate is passed through a 40 mesh stainless steel screen and blended with the metformin HC1 granules for approximately five (5) minutes. After blending, the coated granules are compressed on a rotary press fitted with 15/32" round standard concave punches (plain lower punch, upper punch with an approximately 1 mm indentation pin).
(c) Seal Coating (optional) The core tablet is seal coated with an Opadry material or other suitable water-soluble material by first dissolving the Opadry material, preferably Opadry Clear in purified water. The Opadry solution is then sprayed onto the core tablet using a pan coater under the following conditions: exhaust air temperature of 38-42°C;
atomization pressure of 28-40 psi; and spay rate of 10-15 ml/min. The core tablet is coated with the sealing solution until a theoretical coating level of approximately 2o is obtained.
SUBSTITUTE SHEET (RULE 26) II Sustalnea Release Coatlnd cellulose acetate (398-10)" 850 triacetin 50 PEG 400 l00 9acetyl content 39.3 - 40.30 (d) Sustained Release Coating The cellulose acetate is dissolved in acetone while stirring with a homogenizer. The polyethylene glycol 400 and triacetin are added to the cellulose acetate solution and stirred until a clear solution is obtained. The clear coating solution is then sprayed onto the seal coated tablets in a fluidized bed coater employing the following conditions: product temperature of 16-22°C; atomization pressure of approximately 3 bars; and spray rate of 120-150 ml/min. The sealed core tablet is coated until a theoretical coating level of approximately 3% is obtained.
The resulting tablet is tested in simulated intestinal fluid (pH 7.5) and simulated gastric fluid (SGF) according to the procedure described in United States Pharmacopeia XXIII, Apparatus 2 Q 75 rpm and found to have the following release profile:
TIME (hours) % Released (SGF) ~ Released (pH 7.5) 20 87 ~ 91 The release profile in pH 7.5 and SGF of the sustained release product prepared in this Example is shown in Figure 2.
Figure 5 depicts the in vivo metformin plasma profile of the sustained release product prepared in this Example under fasting conditions. Figure 5 also shows the in vivo metformin plasma profile of the GLUCOPHAGE~ product under fasting conditions.
Figure 6 depicts the in vivo metformin plasma profile of the sustained release product prepared in this Example SUBSTITUTE SHEET (RULE 26) under fed conditions. rigure 6 also shows the in vivo metformin plasma profile of the GLUCOPHAGE° product under fed conditions.
Figures 5 and 6 clearly show that the dosage forms prepared in accordance with the present invention exhibit consistent bioavailability under both fed and fasting conditions while the GLUOPHAGE~ product's bioavailability decreases in the presence of food.
A controlled release tablet containing 850 mg of metformin HC1 and having the same formula as in Example 2 is prepared as described in Example 2 except that an additional hole was drilled on the plain side of the coated tablet. The additional hole had a diameter of approximately 1 mm.
The resulting tablet is tested in simulated intestinal fluid (pH 7.5) and simulated gastric fluid (SGF) according to the procedure described in United States Pharmacopeia XXIII, Apparatus 2 C 75 rpm and found to have the following release profile: .
TIME (hours) ~ Released (SGF) ~ Released (pH 7.5) The release profile in pH 7.5 and SGF of the sustained refease product prepared in this Example is shown in Figure 3.
Figure 7 depicts the in vivo metformin plasma profile of the sustained release product prepared in this Example when administered shortly after breakfast. Figure 7 also shows the in vivo metformin plasma profile of the GLUCOPHAGE° product administered shortly after breakfast.
Figure a depicts the in vivo metformin plasma profile of the sustained release product prepared in this Example when administered shortly after dinner. Figure 8 also SUBSTITUTE SHEET (RULE 26) shows the in vivo metformin plasma profile of the GLUCOPHAGE'~ product administered shortly after dinner.
Table 1 is a summary oz the bioavailability comparision data, test/reference ratio, shown in Figures 4 8 wherein the GLUCOPHAGE~ product is the reference product in a two way crossover biostudy with n = 6.
Formula Figure Study AUC Cmax Tmax Ex. 1 4 Fasting 0.202 0.12 2.15 Ex. 2 5 Fasting 0.369 0.214 1.73 Ex. 2 6 Fed (bkft) 0.628 0.305 1.94 Ex. 3 7 Fed (bkft) 0.797 0.528 1.82 Ex. 3 8 Fed (dinner) 0.850 0.751 2.00 bkft = breakfast The results reported in Table 1 and Figures 4-8 show that dosage forms prepared in accordance with the present invention exhibit an increase in the bioavailability of the antihyperglycemic drug in the presence of food, especially when taken with or shortly after the evening meal.
While certain preferred and alternative embodiments of the invention have been set forth for purposes of disclosing the invention, modifications to the disclosed embodiments may occur to those who are skilled in the art.
Accordingly, the appended claims are intended to cover all embodiments of the invention and modifications thereof which do not depart from the spirit and scope of the invention.
SUBSTITUTE SHEET (RULE 26)
BACKGROUND OF THE INVENTION:
The present invention relates to controlled release unit dose formulations containing an -antihyperglycemic drug. More specifically, the present invention relates to an oral dosage form comprising a biguanide such as metformin or buformin or a pharmaceutically acceptable salt thereof such as metformin hydrochloride or the metformin salts described in United States Patent Nos. 3,957,853 and 4,080,472.
In the prior art, many techniques have been used to provide controlled and extended-release pharmaceutical dosage forms in order to maintain therapeutic serum levels of medicaments and to minimize the effects of missed doses of drugs caused by a lack of patient compliance.
In the prior art are extended release tablets which have an osmotically active drug core surrounded by a semipermeable membrane. These tablets function by allowing a fluid such as'gastric or intestinal fluid to permeate the coating membrane and dissolve the active ingredient so it can be released through a passageway in the coating membrane or if the active ingredient is insoluble in the permeating fluid, pushed through the passageway by an expanding agent such as a hydrogel. Some representative examples of these osmotic tablet systems can be found in United States Patent Nos. 3,845,770, 3,916,899, 4,034,758, 4,077,407 and 4,783.337. United States Patent No.
3,952,741 teaches an osmotic device wherein the active agent is released from a core surrounded by a semipermeable membrane only after sufficient pressure has developed within the membrane to burst or rupture the membrane at a weak portion of the membrane.
The basic osmotic device described in the above cited patents have been refined over time in an effort to provide greater control of the release of the active ingredient.
For example United States Patent Nos. 4,777,049 and 4,851,229 describe an osmotic dosage form comprising a SUBSTITUTE SHEET (RULE 26) WO 99I47t25 PCT/US99/06024 semipermeable wall surrounding a core. The core contains an active ingredient and a modulating agent wherein the modulating agent causes the active ingredient to be released through a passageway in the semipermeable membrane in a pulsed manner. Further refinements have included modifications to the semipermeable membrane surrounding the active core such as varying the proportions of the components that form the membrane, i.e United States Patent Nos. 5,178,867, 4,587,117 and 4,522,625 or increasing the number of coatings surrounding the active core, i.e 5,650,170 and 4,892,739.
Although vast amounts of research has been performed on controlled or sustained release compositions and in particular on osmotic dosage forms, very little research 15 has been performed in the area of controlled or sustained release compositions that employ antihyperglycemic drugs.
The limited work on controlled or sustained release formulations that employ antihyperglycemic drugs such as metformin hydrochloride has been limited to the combination of the antihyperglycemic drug and an expanding or gelling agent to control the release of the drug from the dosage form. This limited research is exemplified by the teachings of WO 96/08243 and by the GLUCOPHAGE~ product which is a commercially available product from Bristol Myers Squibb Co. containing metformin HC1.
It is reported in the 50th Edition of the Physicians' Desk Reference, copyright 1996, p. 753, that food decreases the extent and slightly delays the absorption of metformin delivered by the GLUCOPHAGE~ dosage form. This decrease is shown by approximately a 40% lower peak concentration and a 250 lower AUC in plasma and a 35 minute prolongation of time to peak plasma concentration following administration of a single GLUCOPHAGE~ tablet containing 850 mg of metformin HCl with food compared to the similar tablet administered under fasting conditions.
It is an object of the present invention to provide a controlled or sustained release formulation for an SUBSTITUTE SHEET (RULE 2fi) antihyperglycemic drug wherein the bioavailability of the drug is not decreased by the presence of food.
It is a further object of the present invention to provide a controlled or sustained release formulation for an antihyperglycemic drug that does not employ an expanding polymer.
It is also a further object of the present invention to provide a controlled or sustained release formulation for an antihyperglycemic drug that can provide continuous and non-pulsating therapeutic levels of an antihyperglycemic drug to an animal or human in need of such treatment over a twelve hour to twenty-four hour period.
It is an additional object of the present invention to provide a controlled or sustained release formulation for an antihyperglycemic drug that obtains peak plasma levels approximately 8-12 hours after administration.
It is also an object of this invention to provide a controlled or sustained release pharmaceutical tablet having only a homogeneous osmotic core wherein the osmotic core component may be made using ordinary tablet compression techniques.
SUMMARY OF THE INVENTION
The foregoing objectives are met by a controlled release dosage form comprising:
(a) a core comprising: w '- (i) an antihyperglycemic drug;
(ii) optionally a binding agent; and (iii) optionally an absorption enhancer;
(b) a semipermeable membrane coating surrounding the core;
and (c) at least one passageway in the semipermeable membrane.
The dosage form of the present invention can provide therapeutic levels of the antihyperglycemic drug for twelve to twenty-four hour periods and does not exhibit a decrease in bioavailability if taken with food. In fact, a slight SUBSTITUTE SHEET (RULE 26) increase in the bioavailability of the antihypoglycemic drug is observed when the controlled release dosage form of the present invention is administered with food. In a preferred embodiment, the dosage form will be administered once a day, ideally with or after a meal and most preferably with or after the evening meal, and provide therapeutic levels of the drug throughout the day with peak plasma levels being obtained between e-12 hours after administration.
BRIEF DESCRIPTION OF THE DRAWINGS
FIG. 1 is a graph which depicts the dissolution profile in simulated intestinal fluid (pH 7.5 phosphate buffer) and simulated gastric fluid (SGF) of the formulation described in Example 1 as tested according to the procedure described in United States Pharmacopeia XXIII, Apparatus 2 @ 75 rpm.
FIG. 2 is a graph which depicts the dissolution profile in simulated intestinal fluid (pH 7.5 phosphate buffer) and simulated gastric fluid (SGF) of the formulation described in Example 2 as tested according to the procedure described in United States Pharmacopeia XXIII, Apparatus 2 @ 75 rpm.
FIG. 3 is a graph which depicts the dissolution profile in simulated intestinal fluid (pH 7.5 phosphate buffer) and simulated gastric fluid (SGF) of the formulation described in Example 3 as tested according to the procedure described in United States Pharmacopeia XXIII, Apparatus 2 @ 75 rpm.
FIG. 4 is a graph depicting the in vivo metformin plasma profile of the formulation described in Example 1 and the in vivo metformin plasma profile of the commercially available metformin HCl product GLUCOPHAGE~
under fasting conditions.
FIG. 5 is a graph depicting the in vivo metformin plasma profile of the formulation described in Example 2 and the in vivo metformin plasma profile of the SUBSTITUTE SHEET (RULE 26) commercially available metformin HC1 product GLUCOPHAGE~
under fasting conditions.
FIG. 6 is a graph depicting the in vivo metformin plasma profile of the formulation described in Example 2 and the in vivo metformin plasma profile of the commercially available metformin HC1 product GLUCOPHAGE~
under fed conditions.
FIG. 7 is a graph depicting the in vivo metformin plasma profile of the formulation described in Example 3 and the in vivo metformin plasma profile of the commercially available metformin HC1 product GLUCOPHAGE~
under fed conditions (after breakfast).
FIG. 8 is a graph depicting the in vivo metformin plasma profile of the formulation described in Example 3 and the in vivo metformin plasma profile of the commercially available metformin HC1 product GLUCOPHAGE~
under fed conditions (after dinner).
DETAILED DESCRIPTION OF THE INVENTION
The term antihyperglycemic drugs as used in this specification refers to drugs that are useful in controlling or managing noninsulin-dependent diabetes mellitus (NIDDMO. Preferably, the antihyperglycemic drug is a biguanide such as metformin or buformin or a pharmaceutically acceptable salt thereof such as metformin hydrochloride.
The binding agent may be any conventionally known pharmaceutically acceptable binder such as polyvinyl pyrrolidone, hydroxypropyl cellulose, hydroxyethyl cellulose, ethylcellulose, polymethacrylate, waxes and the like. Mixtures of the aforementioned binding agents may also be used. The preferred binding agents are water soluble such as polyvinyl pyrrolidone having a weight average molecular weight of 25,000 to 3,000,000. The binding agent comprises approximately about 0 to about 40%
of the total weight of the core and preferably about 3o to about 15% of the total weight of the core.
SUBSTITUTE SHEET (RULE 26) The core may optionally comprise an absorption enhancer. The absorption enhancer can be any type of absorption enhancer commonly known in the art such as a fatty acid, a surfactant, a chelating agent, a bile salt or mixtures thereof. Examples of some preferred absorption enhancers are fatty acids such as capric acid, oleic acid and their monoglycerides, surfactants such as sodium lauryl sulfate, sodium taurocholate and polysorbate 80, chelating agents such as citric acid, phytic acid, ethylenediamine tetraacetic acid (EDTA) and ethylene glycol-bis(i3 aminoethyl ether)-N,N,N,N-tetraacetic acid (EGTA). The core comprises approximately 0 to about 200 of the absorption enhancer based on the total weight of the core and most preferably about 2% to about l00 of the total weight of the core.
The core of the present invention which comprises the antihyperglycemic drug, the binder which preferably is a pharmaceutically acceptable water soluble polymer and the absorption enhancer is preferably formed by wet granulating the core ingredients and compressing the granules with the addition of a lubricant into a tablet on a rotary press.
The core may also be formed by dry granulating the core ingredients and compressing the granules with the addition of a lubricant into tablets or by direct compression.
Other commonly known excipients may also be included into the core such as lubricants, pigments or dyes.
The homogeneous core is coated with a semipermeable membrane, preferably a modified polymeric membrane to form the controlled release tablet of the invention. The semipermeable membrane is permeable to the passage of an external fluid such as water and biological fluids and is impermeable to the passage of the antihyperglycemic drug in the core. Materials that are useful in forming the semipermeable membrane are cellulose esters, cellulose diesters, cellulose triesters, cellulose ethers, cellulose ester-ether, cellulose acylate, cellulose diacylate, cellulose triacylate, cellulose acetate, cellulose SUBSTITUTE SHEET (RULE 26) diacetate, cellulose triacetate, cellulose acetate propionate, and cellulose acetate butyrate. Other suitable polymers are described in United States Patent Nos.
3,845,770, 3,916,899, 4,008,719, 4,036,228 and 4,11210.
The most preferred semipermeable membrane material is cellulose acetate comprising an acetyl content of 39.3 to 40.3%, commercially available from Eastman Fine Chemicals.
In an alternative embodiment, the semipermeable membrane can be formed from the above-described polymers and a flux enhancing agent. The flux enhancing agent increases the volume of fluid imbibed into the core to enable the dosage form to dispense substantially all of the antihyperglycemic drug through the passageway and/or the porous membrane. The flux enhancing agent can be a water soluble material or an enteric material. Some examples of the preferred materials that are useful as flux enhancers are sodium chloride, potassium chloride, sucrose, sorbitol, mannitol, polyethylene glycol (PEG), propylene glycol, hydroxypropyl cellulose, hydroxypropyl methycellulose, hydroxypropyl methycellulose phthalate, cellulose acetate phthalate, polyvinyl alcohols, methacrylic acid copolymers and mixtures thereof. The preferred flux enhancer is PEG 400.
The flux enhancer may also be a drug that is water soluble such as metformin or its pharmaceutically acceptable salts or a drug that is soluble under intestinal conditions. If the flux enhancer is a drug, the present dosage form has the added advantage of providing an immediate release of the drug which is selected as the flux enhancer.
The flux enhancing agent comprises approximately 0 to about 40% of the total weight of the coating, most preferably about 2% to about 20% of the total weight of the coating. The flux enhancing agent dissolves or leaches from the semipermeable membrane to form paths in the semipermeable membrane for the fluid to enter the core and dissolve the active ingredient.
The semipermeable membrane may also be formed with commonly known excipients such a plasticizer. Some commonly known plasticizers include adipate, azelate, enzoate, citrate, stearate, isoebucate, sebacate, triethyl citrate, tri-n-butyl citrate, acetyl tri-n-butyl citrate, citric acid esters, and those described in the Encyclopedia of Polymer Science and Technology, Vol. 10 (1969), published by John Wiley & Sons. The preferred plasticizers are triacetin, acetylated monoglyceride, grape seed oil, olive oil, sesame oil, acetyltributylcitrate, acetyltriethylcitrate, glycerin sorbitol, diethyloxalate, diethylmalate, diethylfumarate, dibutylsuccinate, diethylmalonate, dioctylphthalate, dibutylsebacate, triethylcitrate, tributylcitrate, glyceroltributyrate, and the like. Depending on the particular plasticizer, amounts of from 0 to about 250, and preferably about 2% to about 150 of the plasticizer can be used based upon the total weight of the coating.
As used herein the term passageway includes an aperture, orifice, bore, hole, weaken area or an erodible element such as a gelatin plug that erodes to form an osmotic passageway for the release of the antihyperglycemic drug from the dosage form. A detailed description of the passageway can be found in United States Patents such as 3,845,770, 3,916,899, 4,034,758, 4,077,407', 4,783,337 and 5,'71, 607.
Generally, the membrane coating around the core will comprise from about to to about 5o and preferably about 2%
to about 3o based on the total weight of the core and coating.
In an alternative embodiment, the dosage form of the present invention may also comprise an effective amount of the antihyperglycemic drug that is available for immediate release. The effective amount of antihyperglycemic drug for immediate release may be coated onto the semipermeable SUBSTITUTE SHEET (RULE 26) membrane of the dosage form or it may be incorporated into the semipermeable membrane.
In a preferred embodiment the dosage form will have the following composition:
Preferred Most Preferred CORE:
drug 50-98$ 75-95$
binder 0-40$ 3-15$
absorption enhancer 0-20$ 2-10$
COATING:
semipermeable polymer 50-99$ 75-95$
flux enhancer 0-40$ 2-20$
plasticizer 0-25$ 2-15$
The dosage forms prepared according to the present invention should exhibit the following dissolution profile when tested in a USP type 2 apparatus at 75 rpms in 900 ml of simulated intestinal fluid (pH 7.5 phosphate buffer) and at 37°C:
Preferred Most Preferred Time (hours) 2 0-25$ 0-15$
4 10-45$ 20-40$
8 30-90$ 45-90$
12 NLT 50$ NLT 60$
16 NLT 60$ NLT 70$
20 NLT 70$ NLT 80$
NLT = NOT LESS THAN
In a broad aspect, then, the present invention relates to a controlled release pharmaceutical tablet comprising:
(a) a core comprising: up to 40$ of a binding agent, up to 20$ of an absorption enhancer, the balance, up to 98$, of an antihyperglycemic drug, provided that the total percentage of binding agent and absorption enhancer <_ 50$;
(b) a semipermeable membrane coating covering said core wherein the membrane is permeable to the passage of water and biological fluids and is impermeable to the passage of the antihyperglycemic drug wherein said coating comprises up to 40~ of a flux enhancer, and the balance, up to 99$, of a polymer, provided the total percentage of flux enhancer and plasticier <- 50$; and (c) at least one passageway in the semipermeable membrane for the release of the antihyperglycemic drug.
In another broad aspect, then, the present invention relates to a controlled release antihyperglycemic tablet comprising: (a) a core consisting of: up to 40~ of a water soluble binding agent; up to 20$ of an absorption enhancer, the balance, up to 98~, of metaformin or a pharmaceutically acceptable salt thereof, provided that the total percentage of binding agent and absorption enhancer s 50$; (b) a semipermeable membrane coating covering said core comprising: up to 40$ of a flux enhancer; up to 25~ of a plasticizer, the balance, up to 99$, of cellulose acetate, provided that the total percentage of flux enhancer and plasticizer s 50~; and (c) at least one passageway in the semipermeable membrane.
In yet another broad aspect, then, the present invention relates to a controlled release pharmaceutical tablet consisting of: (a) a core comprising: from 3-15% of a binding agent; from 2-15~ of an absorption enhancer, and the balance, up to 95$, of an antihyperglycemic drug, provided that the total percentage of binding agent and absorption enhancer s 25$; (b) a semipermeable membrane coating covering said core wherein the semipermeable membrane is permeable to the passage of water and biological fluids and is impermeable to the passage of the antihyperglycemic drug and comprises: from 2-20a of a flux enhancer; from 2-15$ of a plasticizer; and the balance, up to 96$ of a polymer, provided that the total percentage of flux enhancer and plasticizer <_ 25~; and (c) at least one passageway in the semipermeable membrane for the release of the antihyperglycemic drug.
9a In a further broad aspect, then, the present invention relates to a controlled release pharmaceutical tablet comprising: (a) a core comprising: up to 40~ of a binding agent, up to 20$ of an absorption enhances, and the balance, up to 98~, of an antihyperglycemic drug, provided the total percentage of binding agent and absorption enhances <_ 50~: (b) a water soluble seal coat; (c) a semipermeable membrane coating covering said core wherein the membrane is permeable to the passage of water and biological fluids and is impermeable to the passage of the antihyperglycemic drug wherein said coating comprises up to 40$ of a flux enhances, up to 25$ of a plasticizes, and the balance, up to 99$, of a polymer, provided the total percentage of flux enhances and plasticizes < 50~; and (d) at least one passageway in the semipermeable membrane for the release of the antihyperglycemic drug.
In a still further broad aspect, then, the present invention relates to a controlled release antihyperglycemic tablet comprising: (a) a core consisting of: up to 400 of a water soluble binding agent, up to 20$ of an absorption enhances, and the balance, up to 98$, metformin or a pharmaceutically acceptable salt thereof, provided the total percentage of water soluble binding agent and absorption enhances s 50$; (b) a water soluble seal coat;
(c) a semipermeable membrane coating covering said core comprising: up to 40$ of a flux enhances, up to 25~ of a plasticizes, the balance up to 99$, of a polymer, provided the total percentage of flux enhances and plasticizes <
50$; and (d) at least one passageway in the semipermeable membrane for the release of metformin.
In the preparation of the tablets of the invention, various conventional well known solvents may be used to prepare the granules and apply the external coating to the tablets of the invention. In addition, various 9b diluents, excipients, lubricants, dyes, pigments, dispersants etc. which are disclosed in Remington's pharmaceutical Sciences, 1995 Edition may be used to optimize the formulations of the invention.
9c .
A controlled release tablet containing 850 mg of metformin HC1 and having the following formula is prepared as follows:
I Core metformin HC1 90.540 povidonel*, USP 4_380 sodium tribasic phosphate 4.58%
magnesium stearate 0.5 %
lapproximate molecular weight = 50,000; dynamic viscosity (l0ow/v solution at 20°C) - 5.5-8.5 m Pa s.
(a) Granulation The metformin HC1 is delumped by passing it through a 40 mesh screen and collecting it in a clean, polyethylene lined container. The povidone, K-30, and sodium tribasic phosphate are dissolved in purified water. The delumped metformin HC1 is then added to a top-spray fluidized bed granulator and granulated by spraying the binding solution of povidone and sodium tribasic phosphate under the following conditions: inlet air temperature of 50-70°C;
atomization air pressure of 1-3 bars; and spray rate of l0-100 ml/min.
once the binding solution is depleted, the granules are dried in the granulator until the loss on drying is less than 20. The dried granules are passed through a Comil equipped with the equivalent of an 18 mesh screen.
(b) Tableting The magnesium stearate is passed through a 40 mesh stainless steel screen and blended with the metformin HCl granules for approximately five (5) minutes_ After blending, the granules are compressed on a rotary press fitted with 15/32" round standard concave punches (plain lower punch, upper punch with an approximately 1 mm indentation pin).
(c) Seal Coatix~.g (opt3.ona1) * denotes Trade-mark l0 SUBSTITUTE SHEET (RULE 26) The core tablet is seal coated with an Opadry*
material or other suitable water-soluble material by first dissolving the Opadry* material, preferably Opadry Clear*, in purified water. The Opadry* solution is then sprayed onto the core tablet using a pan coater under the following conditions: exhaust air temperature of 38-42°C;
atomization pressure of 28-40 psi; and spray rate of 10-15 ml/min. The core tablet is coated with the sealing solution until a theoretical coating level of approximately 2% is obtained.
II ~ Sustained Release ~oatinc~
cellulose acetate (398-10)~ 850 triacetin 5a PEG 400 10%
Zacetyl content 39.3 - 40.3%
(d) Sustained Release Coating The cellulose acetate is dissolved in acetone while stirring with a homogeni2er. The polyethylene glycol 400 and triacetin are added to the cellulose acetate solution and stirred until a clear solution is obtained. The clear coating solution is then sprayed onto the seal coated tablets in a fluidized bed coater~employing the following conditions: product temperature of 16-22°C; atomization pressure of approximately 3 bars; and spray rate of 120-150 ml/min. The sealed core tablet is coated until a theoretical coating level of approximately 3o is obtained.
The resulting tablet is tested in simulated intestinal fluid (pH 7.5) and simulated gastric fluid (SGF) according to the procedure described in United States Pharmacopeia XXIII, Apparatus 2 a 75 rpm and found to have the following release profile:
TTME (hours) % Released (SGFL % Released (x~H 7.5) 2 9 ~ 12 * denotes Trade-mark SUBSTITUTE SHEET (RULE 26) The release profile in pH 7.5 and SGF of the sustained - release product prepared in this Example is shown in Figure 1.
Figure 4 depicts the in vivo metformin plasma profile of the sustained release product prepared in this Example.
Also shown in Figure 4 is the in vivo metformin plasma profile of GLUCOPHAGE~, a commercially available pharmaceutical product containing the drug metformin HC1.
A controlled release tablet containing 850 mg of metformin HCl and having the following formula is prepared as follows:
I Core metformin HC1 88.555a povidone', USP 6.368°s sodium lauryl sulfate 4.5770 magnesium stearate 0.5 0 'approximate molecular weight = 1,000,000, dynamic viscosity (10%w/v solution at 20°C) - 300-700 m Pa s.
SUBSTfTUTE SHEET (RULE 26) (a) Granulation The metformin HC1 and sodium lauryl sulfate are delumped by passing them through a 40 mesh screen and collecting them in a clean, polyethylene-lined container.
The povidone, K-90F, is dissolved in purified water. The delumped metformin HCl and sodium lauryl sulfate are then added to a top-spray fluidized bed granulator and granulated by spraying with the binding solution of povidone under the following conditions. inlet air temperature of 50-70°C; atomization air pressure of 1-3 bars; and spray rate of 10-100 ml/min.
Once the binding solution is depleted, the granules are dried in the granulator until the loss on drying is less than 20. The dried granules are passed through a Comil equipped with the equivalent of an 18 mesh screen.
(b) Tableting The magnesium stearate is passed through a 40 mesh stainless steel screen and blended with the metformin HC1 granules for approximately five (5) minutes. After blending, the coated granules are compressed on a rotary press fitted with 15/32" round standard concave punches (plain lower punch, upper punch with an approximately 1 mm indentation pin).
(c) Seal Coating (optional) The core tablet is seal coated with an Opadry material or other suitable water-soluble material by first dissolving the Opadry material, preferably Opadry Clear in purified water. The Opadry solution is then sprayed onto the core tablet using a pan coater under the following conditions: exhaust air temperature of 38-42°C;
atomization pressure of 28-40 psi; and spay rate of 10-15 ml/min. The core tablet is coated with the sealing solution until a theoretical coating level of approximately 2o is obtained.
SUBSTITUTE SHEET (RULE 26) II Sustalnea Release Coatlnd cellulose acetate (398-10)" 850 triacetin 50 PEG 400 l00 9acetyl content 39.3 - 40.30 (d) Sustained Release Coating The cellulose acetate is dissolved in acetone while stirring with a homogenizer. The polyethylene glycol 400 and triacetin are added to the cellulose acetate solution and stirred until a clear solution is obtained. The clear coating solution is then sprayed onto the seal coated tablets in a fluidized bed coater employing the following conditions: product temperature of 16-22°C; atomization pressure of approximately 3 bars; and spray rate of 120-150 ml/min. The sealed core tablet is coated until a theoretical coating level of approximately 3% is obtained.
The resulting tablet is tested in simulated intestinal fluid (pH 7.5) and simulated gastric fluid (SGF) according to the procedure described in United States Pharmacopeia XXIII, Apparatus 2 Q 75 rpm and found to have the following release profile:
TIME (hours) % Released (SGF) ~ Released (pH 7.5) 20 87 ~ 91 The release profile in pH 7.5 and SGF of the sustained release product prepared in this Example is shown in Figure 2.
Figure 5 depicts the in vivo metformin plasma profile of the sustained release product prepared in this Example under fasting conditions. Figure 5 also shows the in vivo metformin plasma profile of the GLUCOPHAGE~ product under fasting conditions.
Figure 6 depicts the in vivo metformin plasma profile of the sustained release product prepared in this Example SUBSTITUTE SHEET (RULE 26) under fed conditions. rigure 6 also shows the in vivo metformin plasma profile of the GLUCOPHAGE° product under fed conditions.
Figures 5 and 6 clearly show that the dosage forms prepared in accordance with the present invention exhibit consistent bioavailability under both fed and fasting conditions while the GLUOPHAGE~ product's bioavailability decreases in the presence of food.
A controlled release tablet containing 850 mg of metformin HC1 and having the same formula as in Example 2 is prepared as described in Example 2 except that an additional hole was drilled on the plain side of the coated tablet. The additional hole had a diameter of approximately 1 mm.
The resulting tablet is tested in simulated intestinal fluid (pH 7.5) and simulated gastric fluid (SGF) according to the procedure described in United States Pharmacopeia XXIII, Apparatus 2 C 75 rpm and found to have the following release profile: .
TIME (hours) ~ Released (SGF) ~ Released (pH 7.5) The release profile in pH 7.5 and SGF of the sustained refease product prepared in this Example is shown in Figure 3.
Figure 7 depicts the in vivo metformin plasma profile of the sustained release product prepared in this Example when administered shortly after breakfast. Figure 7 also shows the in vivo metformin plasma profile of the GLUCOPHAGE° product administered shortly after breakfast.
Figure a depicts the in vivo metformin plasma profile of the sustained release product prepared in this Example when administered shortly after dinner. Figure 8 also SUBSTITUTE SHEET (RULE 26) shows the in vivo metformin plasma profile of the GLUCOPHAGE'~ product administered shortly after dinner.
Table 1 is a summary oz the bioavailability comparision data, test/reference ratio, shown in Figures 4 8 wherein the GLUCOPHAGE~ product is the reference product in a two way crossover biostudy with n = 6.
Formula Figure Study AUC Cmax Tmax Ex. 1 4 Fasting 0.202 0.12 2.15 Ex. 2 5 Fasting 0.369 0.214 1.73 Ex. 2 6 Fed (bkft) 0.628 0.305 1.94 Ex. 3 7 Fed (bkft) 0.797 0.528 1.82 Ex. 3 8 Fed (dinner) 0.850 0.751 2.00 bkft = breakfast The results reported in Table 1 and Figures 4-8 show that dosage forms prepared in accordance with the present invention exhibit an increase in the bioavailability of the antihyperglycemic drug in the presence of food, especially when taken with or shortly after the evening meal.
While certain preferred and alternative embodiments of the invention have been set forth for purposes of disclosing the invention, modifications to the disclosed embodiments may occur to those who are skilled in the art.
Accordingly, the appended claims are intended to cover all embodiments of the invention and modifications thereof which do not depart from the spirit and scope of the invention.
SUBSTITUTE SHEET (RULE 26)
Claims (73)
PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:
1. A controlled release pharmaceutical tablet comprising:
(a) a core comprising:
up to 40% of a binding agent, up to 20% of an absorption enhancer, the balance, up to 98%, of an antihyper-glycemic drug, provided that the total percentage of binding agent and absorption enhancer <= 50%;
(b) a semipermeable membrane coating covering said core wherein the membrane is permeable to the passage of water and biological fluids and is impermeable to the passage of the antihyperglycemic drug wherein said coating comprises up to 40% of a flux enhancer, and the balance, up to 99%, of a polymer, provided the total percentage of flux enhancer and plasticier <= 50%: and (c) at least one passageway in the semipermeable membrane for the release of the antihyperglycemic drug.
(a) a core comprising:
up to 40% of a binding agent, up to 20% of an absorption enhancer, the balance, up to 98%, of an antihyper-glycemic drug, provided that the total percentage of binding agent and absorption enhancer <= 50%;
(b) a semipermeable membrane coating covering said core wherein the membrane is permeable to the passage of water and biological fluids and is impermeable to the passage of the antihyperglycemic drug wherein said coating comprises up to 40% of a flux enhancer, and the balance, up to 99%, of a polymer, provided the total percentage of flux enhancer and plasticier <= 50%: and (c) at least one passageway in the semipermeable membrane for the release of the antihyperglycemic drug.
2. A controlled release pharmaceutical tablet as defined in claim 1 wherein the antihyperglycemic drug is a biguanide.
3. A controlled release pharmaceutical tablet as defined in claim 2 wherein the antihyperglycemic drug is metformin or a pharmaceutically acceptable salt thereof.
4. A controlled release pharmaceutical tablet as defined in claim 2 wherein the antihyperglycemic drug is metformin or a pharmaceutically acceptable salt thereof.
5. A controlled release pharmaceutical tablet as defined in claim 1 wherein the binding agent is water soluble.
6. A controlled release pharmaceutical tablet as defined in claim 5 wherein the water soluble binding agent is polyvinyl pyrrolidone, hydroxypropyl cellulose, hydroxyethyl cellulose, waxes or mixtures thereof.
7. A controlled release pharmaceutical tablet as defined in claim 6 wherein the water soluble binding agent is polyvinyl pyrrolidone.
8. A controlled release pharmaceutical tablet as defined in claim 1 wherein the absorption enhancer is selected from the group consisting of fatty acids, surfactants, chelating agents, bile salts or mixtures thereof.
9. A controlled release pharmaceutical tablet as defined in claim 1 wherein the absorption enhancer is a fatty acid selected from the group consisting of capric acid, oleic acid or their monoglycerides.
10. A controlled release pharmaceutical tablet as defined in claim 1 wherein the absorption enhancer is a surfactant selected from the group consisting of sodium lauryl sulfate, sodium taurocholate and polysorbate 80.
11. A controlled release pharmaceutical tablet as defined in claim 1 wherein the absorption enhancer is a chelating agent selected from the group consisting of citric acid, phytic acid, ethylene diamine tetraacetic acid and ethylene glycol-bis(.beta.-aminoethyl ether)-N,N,N,N-tetraacetic acid.
12. A controlled release pharmaceutical tablet as defined in claim 1 wherein the absorption enhancer is a bile salt.
13. A controlled release pharmaceutical tablet as defined in claim 1 wherein the absorption enhancer is sodium lauryl sulfate.
14. A controlled release pharmaceutical tablet as defined in claim 1 wherein the semipermeable membrane around the core is a water insoluble cellulose derivative.
15. A controlled release pharmaceutical tablet as defined in claim 14 wherein the water insoluble cellulose derivative in the membrane around the core is cellulose acetate.
16. A controlled release pharmaceutical tablet as defined in claim 1 wherein semipermeable membrane comprises a flux enhancer.
17. A controlled release pharmaceutical tablet as defined in claim 16 wherein the flux enhancer is sodium chloride, potassium chloride, sucrose, sorbitol, mannitol, polyethylene glycol, propylene glycol, hydroxypropyl cellulose, hydroxypropyl methycellulose, hydroxypropyl methycellulose phthalate, cellulose acetate phthalate, polyvinyl alcohols, methacrylic acid copolymers or mixtures thereof.
18. A controlled release pharmaceutical tablet as defined in claim 17 wherein the flux enhancer is polyethylene glycol with an average molecular weight between 380 and 420.
19. A controlled release pharmaceutical tablet as defined in claim 1 wherein the semipermeable membrane comprises a plasticizer.
20. A controlled release pharmaceutical tablet as defined in claim 19 wherein the plasticizer is triacetin.
21. A controlled release pharmaceutical tablet as defined in claim 1 wherein at least two passageways are formed in the semipermeable membrane.
22. A controlled release pharmaceutical tablet for obtaining peak plasma level 8-12 hours after administration to a subject comprising the tablet defined in claim 1.
23. A controlled release pharmaceutical tablet as defined in claim 1 further comprising an effective amount of the antihyperglycemic drug coated onto the semipermeable membrane or mixed into the semipermeable membrane to provide an immediate release of an effective amount of the antihyperglycemic drug.
24. A controlled release pharmaceutical tablet as defined in claim 1 that exhibits the following dissolution profile when tested in a USP type 2 apparatus at 75 rpm in 900 ml of simulated intestinal fluid (pH 7.5 phosphate buffer) and at 37°C:
after 2 hours 0-25% of the drug is released;
after 4 hours 10-45% of the drug is released;
after 8 hours 30-90% of the drug is released;
after 12 hours not less than 50% of the drug is released;
after 16 hours not less than 60% of the drug is released;
and after 20 hours not less than 70% of the drug is released.
after 2 hours 0-25% of the drug is released;
after 4 hours 10-45% of the drug is released;
after 8 hours 30-90% of the drug is released;
after 12 hours not less than 50% of the drug is released;
after 16 hours not less than 60% of the drug is released;
and after 20 hours not less than 70% of the drug is released.
25. A controlled release pharmaceutical tablet as defined in claim 1 that exhibits the following dissolution profile when tested in a USP type 2 apparatus at 75 rpm in 900 ml of simulated intestinal fluid (pH 7.5 phosphate buffer) and at 37°C:
after 2 hours 0-15% of the drug is released;
after 4 hours 20-40% of the drug is released;
after 8 hours 45-90% of the drug is released;
after 12 hours not less than 60% of the drug is released;
after 16 hours not less than 70% of the drug is released;
and after 20 hours not less than 80% of the drug is released.
after 2 hours 0-15% of the drug is released;
after 4 hours 20-40% of the drug is released;
after 8 hours 45-90% of the drug is released;
after 12 hours not less than 60% of the drug is released;
after 16 hours not less than 70% of the drug is released;
and after 20 hours not less than 80% of the drug is released.
26. A controlled release antihyperglycemic tablet comprising:
(a) a core consisting of:
up to 40% of a water soluble binding agent: up to 20% of an absorption enhancer, the balance, up to 98%, of metaformin or a pharmaceutically acceptable salt thereof, provided that the total percentage of binding agent and absorption enhancer <= 50%;
(b) a semipermeable membrane coating covering said core comprising:
up to 40% of a flux enhancer: up to 25% of a plasticizer, the balance, up to 99%, of cellulose acetate, provided that the total percentage of flux enhances and plasticizer <= 50%; and (c) at least one passageway in the semipermeable membrane.
(a) a core consisting of:
up to 40% of a water soluble binding agent: up to 20% of an absorption enhancer, the balance, up to 98%, of metaformin or a pharmaceutically acceptable salt thereof, provided that the total percentage of binding agent and absorption enhancer <= 50%;
(b) a semipermeable membrane coating covering said core comprising:
up to 40% of a flux enhancer: up to 25% of a plasticizer, the balance, up to 99%, of cellulose acetate, provided that the total percentage of flux enhances and plasticizer <= 50%; and (c) at least one passageway in the semipermeable membrane.
27. A controlled release pharmaceutical tablet for obtaining peak plasma level 8-12 hours after administration to a subject, comprising the tablet as defined in claim 6.
28. A controlled release pharmaceutical tablet consisting of:
(a) a core comprising:
from 3-15% of a binding agent: from 2-15% of an absorption enhances, and the balance, up to 95%, of an antihyperglycemic drug, provided that the total percentage of binding agent and absorption enhances <=
25%;
(b) a semipermeable membrane coating covering said core wherein the semipermeable membrane is permeable to the passage of water and biological fluids and is impermeable to the passage of the antihyperglycemic drug and comprises:
from 2-20% of a flux enhances; from 2-15% of a plasticizer; and the balance, up to 96% of a polymer, provided that the total percentage of flux enhances and plasticizer <= 25%; and (c) at least one passageway in the semipermeable membrane for the release of the antihyperglycemic drug.
(a) a core comprising:
from 3-15% of a binding agent: from 2-15% of an absorption enhances, and the balance, up to 95%, of an antihyperglycemic drug, provided that the total percentage of binding agent and absorption enhances <=
25%;
(b) a semipermeable membrane coating covering said core wherein the semipermeable membrane is permeable to the passage of water and biological fluids and is impermeable to the passage of the antihyperglycemic drug and comprises:
from 2-20% of a flux enhances; from 2-15% of a plasticizer; and the balance, up to 96% of a polymer, provided that the total percentage of flux enhances and plasticizer <= 25%; and (c) at least one passageway in the semipermeable membrane for the release of the antihyperglycemic drug.
29. A controlled release pharmaceutical tablet comprising:
(a) a core comprising:
up to 40% of a binding agent, up to 20% of an absorption enhances, and the balance, up to 98%, of an antihyperglycemic drug, provided the total percentage of binding agent and absorption enhances <= 50%;
(b) a water soluble seal coat;
(c) a semipermeable membrane coating covering said core wherein the membrane is permeable to the passage of water and biological fluids and is impermeable to the passage of the antihyperglycemic drug wherein said coating comprises up to 40% of a flux enhancer, up to 25% of a plasticizer, and the balance, up to 99%, of a polymer, provided the total percentage of flux enhancer and plasticizer <= 50%; and (d) at least one passageway in the semipermeable membrane for the release of the antihyperglycemic drug.
(a) a core comprising:
up to 40% of a binding agent, up to 20% of an absorption enhances, and the balance, up to 98%, of an antihyperglycemic drug, provided the total percentage of binding agent and absorption enhances <= 50%;
(b) a water soluble seal coat;
(c) a semipermeable membrane coating covering said core wherein the membrane is permeable to the passage of water and biological fluids and is impermeable to the passage of the antihyperglycemic drug wherein said coating comprises up to 40% of a flux enhancer, up to 25% of a plasticizer, and the balance, up to 99%, of a polymer, provided the total percentage of flux enhancer and plasticizer <= 50%; and (d) at least one passageway in the semipermeable membrane for the release of the antihyperglycemic drug.
30. A controlled release pharmaceutical tablet as defined in claim 29 wherein the core consists essentially of:
75-95% of the antihyperglycemic drug;
3-15% of the binding agent; and 2-10% of the absorption enhancer; and the coating comprises:
75-95% of the polymer;
2-20% of the flux enhancer; and 2-15% of the plasticizer.
75-95% of the antihyperglycemic drug;
3-15% of the binding agent; and 2-10% of the absorption enhancer; and the coating comprises:
75-95% of the polymer;
2-20% of the flux enhancer; and 2-15% of the plasticizer.
31. A controlled release pharmaceutical tablet as defined in claim 29 that exhibits the following dissolution profile when tested in a USP type 2 apparatus at 75 rpm in 900 ml of simulated intestinal fluid (pH 7.5 phosphate buffer) and at 37°C:
after 2 hours 0-25% of the drug is released;
after 4 hours 10-45% of the drug is released;
after 8 hours 30-90% of the drug is released;
after 12 hours not less than 50% of the drug is released;
after 16 hours not less than 60% of the drug is released; and after 20 hours not less than 70% of the drug is released.
after 2 hours 0-25% of the drug is released;
after 4 hours 10-45% of the drug is released;
after 8 hours 30-90% of the drug is released;
after 12 hours not less than 50% of the drug is released;
after 16 hours not less than 60% of the drug is released; and after 20 hours not less than 70% of the drug is released.
32. A controlled release pharmaceutical tablet as defined in claim 29 that exhibits the following dissolution profile when tested in a USP type 2 apparatus at 75 rpm in 900 ml of simulated intestinal fluid (pH 7.5 phosphate buffer) and at 37°C:
after 2 hours 0-15% of the drug is released;
after 4 hours 20-40% of the drug is released;
after 8 hours 45-90% of the drug is released;
after 12 hours not less than 60% of the drug is released;
after 16 hours not less than 70% of the drug is released; and after 20 hours not less than 80% of the drug is released.
after 2 hours 0-15% of the drug is released;
after 4 hours 20-40% of the drug is released;
after 8 hours 45-90% of the drug is released;
after 12 hours not less than 60% of the drug is released;
after 16 hours not less than 70% of the drug is released; and after 20 hours not less than 80% of the drug is released.
33. A controlled release pharmaceutical tablet as defined in claim 29 wherein the binding agent is water soluble.
34. A controlled release pharmaceutical tablet as defined in claim 33 wherein the water soluble binding agent is polyvinyl pyrrolidone, hydroxypropyl cellulose, hydroxyethel cellulose, waxes or mixtures thereof.
35. A controlled release pharmaceutical tablet as defined in claim 34 wherein the water soluble binding agent is polyvinyl pyrrolidone.
36. A controlled release pharmaceutical tablet as defined in claim 29 wherein the absorption enhancer is selected from the group consisting of fatty acids, surfactants, chelating agents, bile salts or mixtures thereof.
37. A controlled release pharmaceutical tablet as defined in claim 29 wherein the absorption enhancer is a fatty acid selected from the group consisting of capric acid, oleic acid or their monoglycerides.
38. A controlled release pharmaceutical tablet as defined in claim 29 wherein the absorption enhancer is a surfactant selected form the group consisting of sodium lauryl sulfate, sodium taurocholate and polysorbate 80.
39. A controlled release pharmaceutical tablet as defined in claim 29 wherein the absorption enhancer is a chelating agent selected from the group consisting of citric acid, phytic acid, ethylene diamine tetraacetic acid and ethylene glycol-bis(.beta.-aminoethyl ether)-N,N,N,N-tetraacetic acid.
40. A controlled release pharmaceutical tablet as defined in claim 29 wherein the absorption enhancer is a bile salt.
41. A controlled release pharmaceutical tablet as defined in claim 29 wherein the absorption enhancer is sodium lauryl sulfate.
42. A controlled release pharmaceutical tablet as defined in claim 29 wherein the semipermeable membrane around the core is a water insoluble cellulose derivative.
43. A controlled release pharmaceutical tablet as defined in claim 42 wherein the water insoluble cellulose derivative in the membrane around the core is cellulose acetate.
44. A controlled release pharmaceutical tablet as defined in claim 29 wherein semipermeable membrane comprises a flux enhancer.
45. A controlled release pharmaceutical tablet as defined in claim 44 wherein the flux enhancer is sodium chloride, potassium chloride, sucrose, sorbitol, mannitol, polyethylene glycol, propylene glycol, hydroxypropyl cellulose, hydroxypropyl methycellulose, hydroxypropyl methycellulose phthalate, cellulose acetate phthalate, polyvinyl alcohols, methacrylic acid copolymers or mixtures thereof.
46. A controlled release pharmaceutical tablet as defined in claim 45 wherein the flux enhancer is polyethylene glycol with an average molecular weight between 380 and 420.
47. A controlled release pharmaceutical tablet as defined in claim 29 wherein the plasticizer is triacetin.
48. A controlled release pharmaceutical tablet as defined in claim 29 wherein at least two passageways are formed in the semipermeable membrane.
49. A controlled release pharmaceutical tablet for obtaining peak plasma levels in a subject 8-12 hours after administration, comprising the tablet as defined in claim 29.
50. A controlled release tablet as defined in claim 29 wherein the antihyperglycemic drug is a biguanide.
51. A controlled release tablet as defined in claim 29 wherein the antihyperglycemic drug is metformin or a pharmaceutically acceptable salt thereof.
52. A controlled release antihyperglycemic tablet comprising:
(a) a core consisting of:
up to 40% of a water soluble binding agent, up to 20% of an absorption enhancer, and the balance, up to 98%, metaformin or a pharmaceutically acceptable salt thereof, provided the total percentage of water soluble binding agent and absorption enhancer <= 50%;
(b) a water soluble seal coat;
(c) a semipermeable membrane coating covering said core comprising:
up to 40% of a flux enhancer, up to 25% of a plasticizer, the balance up to 99%, of a polymer, provided the total percentage of flux enhancer and plasticizer s 50%; and (d) at least one passageway in the semipermeable membrane for the release of metformin.
(a) a core consisting of:
up to 40% of a water soluble binding agent, up to 20% of an absorption enhancer, and the balance, up to 98%, metaformin or a pharmaceutically acceptable salt thereof, provided the total percentage of water soluble binding agent and absorption enhancer <= 50%;
(b) a water soluble seal coat;
(c) a semipermeable membrane coating covering said core comprising:
up to 40% of a flux enhancer, up to 25% of a plasticizer, the balance up to 99%, of a polymer, provided the total percentage of flux enhancer and plasticizer s 50%; and (d) at least one passageway in the semipermeable membrane for the release of metformin.
53. A controlled release pharmaceutical tablet as defined in claim 52 wherein the core consists of:
75-95% of the metformin of a pharmaceutically acceptable salt thereof;
3-15% of the binding agent: and 2-10% of the absorption enhancer; and the coating comprises:
75-95% of the polymer;
2-20% of the flux enhancer; and 2-15% of the plasticizer.
75-95% of the metformin of a pharmaceutically acceptable salt thereof;
3-15% of the binding agent: and 2-10% of the absorption enhancer; and the coating comprises:
75-95% of the polymer;
2-20% of the flux enhancer; and 2-15% of the plasticizer.
54. A controlled release pharmaceutical tablet as defined in claim 52 that exhibits the following dissolution profile when tested in a USP type 2 apparatus at 75 rpm in 900 ml of simulated intestinal fluid (pH 7.5 phosphate buffer) and at 37°C:
after 2 hours 0-25% of the drug is released;
after 4 hours 10-45% of the drug is released;
after 8 hours 30-90% of the drug is released;
after 12 hours not less than 50% of the drug is released;
after 16 hours not less than 60% of the drug is released; and after 20 hours not less than 70% of the drug is released.
after 2 hours 0-25% of the drug is released;
after 4 hours 10-45% of the drug is released;
after 8 hours 30-90% of the drug is released;
after 12 hours not less than 50% of the drug is released;
after 16 hours not less than 60% of the drug is released; and after 20 hours not less than 70% of the drug is released.
55. A controlled release pharmaceutical tablet as defined in claim 52 that exhibits the following dissolution profile when tested in a USP type 2 apparatus at 75 rpm in 900 ml of simulated intestinal fluid (pH 7.5 phosphate buffer) and at 37°C:
after 2 hours 0-15% of the drug is released;
after 4 hours 20-40% of the drug is released;
after 8 hours 45-90% of the drug is released;
after 12 hours not less than 60% of the drug is released;
after 16 hours not less than 70% of the drug is released; and after 20 hours not less than 80% of the drug is released.
after 2 hours 0-15% of the drug is released;
after 4 hours 20-40% of the drug is released;
after 8 hours 45-90% of the drug is released;
after 12 hours not less than 60% of the drug is released;
after 16 hours not less than 70% of the drug is released; and after 20 hours not less than 80% of the drug is released.
56. A controlled release pharmaceutical tablet as defined in claim 52 wherein the binding agent is water soluble.
57. A controlled release pharmaceutical tablet as defined in claim 52 wherein the water soluble binding agent is polyvinyl pyrrolidone, hydroxypropyl cellulose, hydroxyethyl cellulose, waxes or mixtures thereof.
58. A controlled release pharmaceutical tablet as defined in claim 57 wherein the water soluble binding agent is polyvinyl pyrrolidone.
59. A controlled release pharmaceutical tablet as defined in claim 52 wherein the absorption enhancer is selected from the group consisting of fatty acids, surfactants, chelating agents, bile salts or mixtures thereof.
60. A controlled release pharmaceutical tablet as defined in claim 52 wherein the absorption enhancer is a fatty acid selected from the group consisting of capric acid, oleic acid or their monoglycerides.
61. A controlled release pharmaceutical tablet as defined in claim 52 wherein the absorption enhancer is a surfactant selected from the group consisting of sodium lauryl sulfate, sodium taurocholate and polysorbate 80.
62. A controlled release pharmaceutical tablet as defined in claim 52 wherein the absorption enhancer is a chelating agent selected from the group consisting of citric acid, phytic acid, ethylene diamine tetraacetic acid and ethylene glycol-bis(.beta.-aminoethyl ether)-N,N,N,N-tetraacetic acid.
63. A controlled release pharmaceutical tablet as defined in claim 52 wherein the absorption enhancer is a bile salt.
64. A controlled release pharmaceutical tablet as defined in claim 52 wherein the absorption enhancer is sodium lauryl sulfate.
65. A controlled release pharmaceutical tablet as defined in claim 52 wherein the semipermeable membrane around the core is a water insoluble cellulose derivative.
66. A controlled release pharmaceutical tablet as defined in claim 65 wherein the water insoluble cellulose derivative in the membrane around the core is cellulose acetate.
67. A controlled release pharmaceutical tablet as defined in claim 52 wherein semipermeable membrane comprises a flux enhancer.
68. A controlled release pharmaceutical tablet as defined in claim 67 wherein the flux enhancer is sodium chloride, potassium chloride, sucrose, sorbitol, mannitol, polyethylene glycol, propylene glycol, hydroxypropyl cellulose, hydroxypropyl methycellulose, hydroxypropyl methycellulose phthalate, cellulose acetate phthalate, polyvinyl alcohols, methacrylic acid copolymers or mixtures thereof.
69. A controlled release pharmaceutical tablet as defined in claim 68 wherein the flux enhancer is polyethylene glycol with an average molecular weight between 380 and 420.
70. A controlled release pharmaceutical tablet as defined in claim 52 wherein the plasticizer is triacetin.
71. A controlled release pharmaceutical tablet as defined in claim 52 wherein at least two passageways are formed in the semipermeable membrane.
72. A controlled release pharmaceutical tablet for obtaining peak plasma levels in subjects 8-12 hours after administration, comprising the tablet defined in claim 52.
73. A controlled release pharmaceutical tablet as defined in claim 52 further comprising an effective amount of the metformin or pharmaceutically acceptable salt coated onto the semipermeable membrane or mixed into the semipermeable membrane to provide an immediate release of an effective amount of the metformin or pharmaceutically acceptable salt.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US09/045,330 US6099859A (en) | 1998-03-20 | 1998-03-20 | Controlled release oral tablet having a unitary core |
| US09/045,330 | 1998-03-20 | ||
| PCT/US1999/006024 WO1999047125A1 (en) | 1998-03-20 | 1999-03-19 | Controlled release oral tablet having a unitary core |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CA2324493A1 CA2324493A1 (en) | 1999-09-23 |
| CA2324493C true CA2324493C (en) | 2006-02-14 |
Family
ID=21937256
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002324493A Expired - Lifetime CA2324493C (en) | 1998-03-20 | 1999-03-19 | Controlled release oral tablet having a unitary core |
Country Status (11)
| Country | Link |
|---|---|
| US (5) | US6099859A (en) |
| EP (2) | EP2087889B1 (en) |
| JP (3) | JP4557424B2 (en) |
| KR (1) | KR20010071122A (en) |
| CN (1) | CN1158999C (en) |
| AU (1) | AU739226B2 (en) |
| CA (1) | CA2324493C (en) |
| DE (1) | DE69941115D1 (en) |
| ES (2) | ES2540972T3 (en) |
| HK (1) | HK1037963A1 (en) |
| WO (1) | WO1999047125A1 (en) |
Families Citing this family (153)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB9407386D0 (en) | 1994-04-14 | 1994-06-08 | Smithkline Beecham Plc | Pharmaceutical formulation |
| US8071128B2 (en) | 1996-06-14 | 2011-12-06 | Kyowa Hakko Kirin Co., Ltd. | Intrabuccally rapidly disintegrating tablet and a production method of the tablets |
| NZ506202A (en) | 1998-03-19 | 2003-10-31 | Bristol Myers Squibb Co | Biphasic controlled release delivery system for high solubility pharmaceuticals and method |
| US6099859A (en) * | 1998-03-20 | 2000-08-08 | Andrx Pharmaceuticals, Inc. | Controlled release oral tablet having a unitary core |
| US7303768B2 (en) * | 1998-07-24 | 2007-12-04 | Seo Hong Yoo | Preparation of aqueous clear solution dosage forms with bile acids |
| US20050158408A1 (en) * | 1998-07-24 | 2005-07-21 | Yoo Seo H. | Dried forms of aqueous solubilized bile acid dosage formulation: preparation and uses thereof |
| US7772220B2 (en) * | 2004-10-15 | 2010-08-10 | Seo Hong Yoo | Methods and compositions for reducing toxicity of a pharmaceutical compound |
| US20070072828A1 (en) * | 1998-07-24 | 2007-03-29 | Yoo Seo H | Bile preparations for colorectal disorders |
| US20040102486A1 (en) * | 1998-11-12 | 2004-05-27 | Smithkline Beecham Corporation | Novel method of treatment |
| US20040081697A1 (en) * | 1998-11-12 | 2004-04-29 | Smithkline Beecham P.L.C. | Pharmaceutical composition for modified release of an insulin sensitiser and another antidiabetic agent |
| US7250176B1 (en) | 1999-04-13 | 2007-07-31 | Beecham Pharmaceuticals (Pte) Limited | Method of treating a bacterial infection |
| US6878386B1 (en) | 1999-04-13 | 2005-04-12 | Beecham Pharmaceuticals (Pte) Limited | Method of treating a bacterial infection comprising amoxycillin and potassium clavulanate |
| US6294199B1 (en) | 1999-04-13 | 2001-09-25 | Beecham Pharmaceuticals (Pte) Limited | Method of treating a bacterial infection comprising administering amoxycillin |
| MY125516A (en) * | 1999-11-16 | 2006-08-30 | Smithkline Beecham Plc | Novel composition based on thiazolidinedione and metformin and use |
| ES2270982T3 (en) * | 2000-02-04 | 2007-04-16 | Depomed, Inc. | DOSAGE FORM OF NUCLEO AND CARCASA THAT IS APPROXIMATE TO A RELEASE OF THE ZERO ORDER PHARMACO. |
| US6627223B2 (en) | 2000-02-11 | 2003-09-30 | Eurand Pharmaceuticals Ltd. | Timed pulsatile drug delivery systems |
| US6676966B1 (en) * | 2000-05-09 | 2004-01-13 | Intellipharmaceutics Corp. | Extended release metformin hydrochloride formulations |
| US7858119B1 (en) * | 2000-05-09 | 2010-12-28 | Amina Odidi | Extended release pharmaceuticals |
| FR2811571B1 (en) | 2000-07-11 | 2002-10-11 | Flamel Tech Sa | ORAL PHARMACEUTICAL COMPOSITION FOR CONTROLLED RELEASE AND SUSTAINED ABSORPTION OF AN ACTIVE INGREDIENT |
| AU2357202A (en) | 2000-09-29 | 2002-04-08 | Solvay Pharm Bv | Ion-strength independent sustained release pharmaceutical formulation |
| EP1322158B1 (en) * | 2000-10-02 | 2012-08-08 | USV Ltd. | Sustained release pharmaceutical compositions containing metformin and method of their production |
| US6756057B2 (en) | 2000-10-12 | 2004-06-29 | Beecham Pharmaceuticals (Pte) Limited | Amoxicillin and potassium clavulanate dosage form |
| US6866866B1 (en) * | 2000-11-03 | 2005-03-15 | Andrx Labs, Llc | Controlled release metformin compositions |
| EP1335708A4 (en) | 2000-11-03 | 2005-07-13 | Andrx Corp | Controlled release metformin compositions |
| US6790459B1 (en) * | 2000-11-03 | 2004-09-14 | Andrx Labs, Llc | Methods for treating diabetes via administration of controlled release metformin |
| US20060034922A1 (en) * | 2000-11-03 | 2006-02-16 | Andrx Labs, Llc | Controlled release metformin compositions |
| AU2005239716B2 (en) * | 2000-11-03 | 2008-03-13 | Andrx Labs, Llc | Controlled Release Metformin Compositions |
| FR2816840B1 (en) | 2000-11-17 | 2004-04-09 | Flamel Tech Sa | MEDICINE BASED ON SUSTAINED RELEASE ANTI-HYPERCLYCEMIA MICROCAPSULES AND METHOD FOR PREPARING THE SAME |
| US20030175349A1 (en) * | 2001-01-30 | 2003-09-18 | Council Of Scientific And Industrial Research | Pharmaceutical compostion for extended/sustained release of a therapeutically active ingredient |
| US20020141970A1 (en) * | 2001-03-05 | 2002-10-03 | Pettit Dean K. | Stable aqueous solutions of granulocyte macrophage colony-stimulating factor |
| KR200249057Y1 (en) * | 2001-03-22 | 2001-10-19 | 김진환 | Sewage backflow integrated into the lid and base. Odor Prevention Device |
| US7323192B2 (en) * | 2001-09-28 | 2008-01-29 | Mcneil-Ppc, Inc. | Immediate release tablet |
| US7122143B2 (en) | 2001-09-28 | 2006-10-17 | Mcneil-Ppc, Inc. | Methods for manufacturing dosage forms |
| JP2005508331A (en) * | 2001-09-28 | 2005-03-31 | サン・ファーマシューティカル・インダストリーズ・リミテッド | Dosage preparation for the treatment of diabetes |
| US7838026B2 (en) | 2001-09-28 | 2010-11-23 | Mcneil-Ppc, Inc. | Burst-release polymer composition and dosage forms comprising the same |
| US9358214B2 (en) | 2001-10-04 | 2016-06-07 | Adare Pharmaceuticals, Inc. | Timed, sustained release systems for propranolol |
| US6500454B1 (en) * | 2001-10-04 | 2002-12-31 | Eurand Pharmaceuticals Ltd. | Timed, sustained release systems for propranolol |
| US6635675B2 (en) | 2001-11-05 | 2003-10-21 | Cypress Bioscience, Inc. | Method of treating chronic fatigue syndrome |
| US6602911B2 (en) | 2001-11-05 | 2003-08-05 | Cypress Bioscience, Inc. | Methods of treating fibromyalgia |
| PL369328A1 (en) * | 2001-11-06 | 2005-04-18 | Ranbaxy Laboratories Limited | Controlled release tablets of metformin |
| CA2465110A1 (en) * | 2001-11-07 | 2003-05-15 | Synthon B.V. | Tamsulosin tablets |
| US20040220240A1 (en) * | 2001-11-28 | 2004-11-04 | Pellegrini Cara A. | Method of increasing the extent of absorption of tizanidine |
| US6455557B1 (en) * | 2001-11-28 | 2002-09-24 | Elan Pharmaceuticals, Inc. | Method of reducing somnolence in patients treated with tizanidine |
| US7714006B1 (en) | 2001-12-03 | 2010-05-11 | King Pharmaceuticals Research & Development, Inc. | Methods of modifying the bioavailability of metaxalone |
| US6407128B1 (en) | 2001-12-03 | 2002-06-18 | Elan Pharmaceuticals, Inc. | Method for increasing the bioavailability of metaxalone |
| US20030118647A1 (en) * | 2001-12-04 | 2003-06-26 | Pawan Seth | Extended release tablet of metformin |
| US20030113366A1 (en) * | 2001-12-14 | 2003-06-19 | Macgregor Alexander | Reverse-micellar delivery system for controlled transportation and enhanced absorption of agents |
| US6966453B2 (en) * | 2001-12-31 | 2005-11-22 | Andrx Pharmaceuticals Llc | Apparatus and method for regulating the delivery of bulk tablets to a tablet transport system |
| US20030175346A1 (en) * | 2002-02-01 | 2003-09-18 | Anne Billotte | Osmotic delivery system |
| PE20030800A1 (en) * | 2002-02-12 | 2003-10-31 | Glaxo Group Ltd | CONTROLLED RELEASE ORAL DOSAGE FORM |
| GB0203296D0 (en) * | 2002-02-12 | 2002-03-27 | Glaxo Group Ltd | Novel composition |
| AU2003211131A1 (en) * | 2002-02-14 | 2003-09-04 | Sonus Pharmaceuticals, Inc. | Metformin salts of lipophilic acids |
| US20030187074A1 (en) * | 2002-03-04 | 2003-10-02 | Javed Hussain | Oral compositions for treatment of diabetes |
| PT1492511E (en) | 2002-04-09 | 2009-04-09 | Flamel Tech Sa | Oral pharmaceutical formulation in the form of aqueous suspension for modified release of active principle(s) |
| WO2003096968A2 (en) * | 2002-05-15 | 2003-11-27 | Sun Pharmaceutical Industries Limited | Oral osmotic controlled drug delivery system |
| WO2003099214A2 (en) * | 2002-05-23 | 2003-12-04 | Andrx Corporation | Biguanide formulations |
| US20030224046A1 (en) * | 2002-06-03 | 2003-12-04 | Vinay Rao | Unit-dose combination composition for the simultaneous delivery of a short-acting and a long-acting oral hypoglycemic agent |
| WO2003105809A1 (en) | 2002-06-17 | 2003-12-24 | Themis Laboratories Private Limited | Multilayer tablets containing thiazolidinedione and biguanides and methods for producing them |
| AU2003276688A1 (en) * | 2002-09-02 | 2004-03-19 | Sun Pharmaceutical Industries Limited | Pharmaceutical composition of metaxalone with enhanced oral bioavailability |
| US8084058B2 (en) * | 2002-09-20 | 2011-12-27 | Watson Pharmaceuticals, Inc. | Pharmaceutical formulation containing a biguanide and a thiazolidinedione derivative |
| KR101363679B1 (en) * | 2002-09-20 | 2014-02-14 | 안드렉스 랩스 엘엘씨 | Pharmaceutical tablet |
| US20050048119A1 (en) * | 2002-09-20 | 2005-03-03 | Avinash Nangia | Controlled release composition with semi-permeable membrane and poloxamer flux enhancer |
| US7959946B2 (en) | 2002-09-20 | 2011-06-14 | Watson Pharmaceuticals, Inc. | Pharmaceutical formulation containing a biguanide and a thiazolidinedione derivative |
| US7785627B2 (en) | 2002-09-20 | 2010-08-31 | Watson Pharmaceuticals, Inc. | Pharmaceutical formulation containing a biguanide and a thiazolidinedione derivative |
| US9060941B2 (en) * | 2002-09-20 | 2015-06-23 | Actavis, Inc. | Pharmaceutical formulation containing a biguanide and a thiazolidinedione derivative |
| US20050051922A1 (en) * | 2002-09-20 | 2005-03-10 | Avinash Nangia | Pharmaceutical composition with sodium lauryl sulfate as an extra-granular absorption/compression enhancer and the process to make the same |
| US20040086566A1 (en) * | 2002-11-04 | 2004-05-06 | Alpharma, Inc. | Waxy matrix dosage forms |
| US8367111B2 (en) | 2002-12-31 | 2013-02-05 | Aptalis Pharmatech, Inc. | Extended release dosage forms of propranolol hydrochloride |
| US20040131672A1 (en) * | 2003-01-07 | 2004-07-08 | Nilobon Podhipleux | Direct compression pharmaceutical composition containing a pharmaceutically active ingredient with poor flowing properties |
| US20060171970A1 (en) * | 2003-02-21 | 2006-08-03 | Cardio Combos Llc | Pharmaceutical formulation delivery system |
| US7145125B2 (en) | 2003-06-23 | 2006-12-05 | Advanced Optical Technologies, Llc | Integrating chamber cone light using LED sources |
| EP2112920B1 (en) | 2003-06-26 | 2018-07-25 | Intellipharmaceutics Corp. | Proton pump-inhibitor-containing capsules which comprise subunits differently structured for a delayed release of the active ingredient |
| KR100601249B1 (en) * | 2003-08-21 | 2006-07-13 | 한국화학연구원 | Composition for producing controllable porous membrane of oral drug delivery system |
| TW200517127A (en) * | 2003-08-07 | 2005-06-01 | Sb Pharmco Inc | Novel composition |
| EP1510208A1 (en) | 2003-08-22 | 2005-03-02 | Fournier Laboratories Ireland Limited | Pharmaceutical composition comprising a combination of metformin and statin |
| US20080031901A1 (en) * | 2004-09-24 | 2008-02-07 | Abbott Laboratories | Sustained release monoeximic formulations of opioid and nonopioid analgesics |
| RU2006118801A (en) * | 2003-10-31 | 2007-12-10 | Алза Корпорейшн (Us) | COMPOSITIONS AND MEDICINAL FORMS FOR STRENGTHENING THE ABSORPTION OF GABAPENTIN AND PREGABALIN |
| US20050095288A1 (en) * | 2003-11-03 | 2005-05-05 | Andrx Labs, Llc | Decongestant and expectorant tablets |
| US20050196447A1 (en) * | 2004-03-05 | 2005-09-08 | Huang Hai Y. | Polymeric compositions and dosage forms comprising the same |
| US20050196448A1 (en) * | 2004-03-05 | 2005-09-08 | Hai Yong Huang | Polymeric compositions and dosage forms comprising the same |
| US20050196446A1 (en) * | 2004-03-05 | 2005-09-08 | Huang Hai Y. | Polymeric compositions and dosage forms comprising the same |
| US20050196442A1 (en) * | 2004-03-05 | 2005-09-08 | Huang Hai Y. | Polymeric compositions and dosage forms comprising the same |
| MXPA06010003A (en) * | 2004-03-05 | 2007-03-21 | Johnson & Johnson | Polymeric compositions and dosage forms comprising the same. |
| HUE033015T2 (en) * | 2004-05-04 | 2017-11-28 | Innophos Inc | Directly compressible tricalcium phosphate |
| US7588779B2 (en) * | 2004-05-28 | 2009-09-15 | Andrx Labs, Llc | Pharmaceutical formulation containing a biguanide and an angiotensin antagonist |
| US20050287185A1 (en) * | 2004-06-23 | 2005-12-29 | David Wong | Extended release oxybutynin formulation |
| US8394409B2 (en) | 2004-07-01 | 2013-03-12 | Intellipharmaceutics Corp. | Controlled extended drug release technology |
| US10624858B2 (en) | 2004-08-23 | 2020-04-21 | Intellipharmaceutics Corp | Controlled release composition using transition coating, and method of preparing same |
| RU2428987C2 (en) * | 2004-08-30 | 2011-09-20 | Сео Хонг Ю | Neuroprotective action of soluble ursodeoxycholic acid in models of focal ischemia |
| US8747895B2 (en) | 2004-09-13 | 2014-06-10 | Aptalis Pharmatech, Inc. | Orally disintegrating tablets of atomoxetine |
| US8541026B2 (en) | 2004-09-24 | 2013-09-24 | Abbvie Inc. | Sustained release formulations of opioid and nonopioid analgesics |
| US9884014B2 (en) | 2004-10-12 | 2018-02-06 | Adare Pharmaceuticals, Inc. | Taste-masked pharmaceutical compositions |
| EP1809330B1 (en) * | 2004-10-15 | 2011-04-27 | Seo Hong Yoo | Compositions for reducing toxicity of cisplatin, carboplatin, and oxaliplatin |
| NZ589750A (en) | 2004-10-21 | 2012-07-27 | Aptalis Pharmatech Inc | Taste-masked pharmaceutical compositions with gastrosoluble pore-formers |
| WO2006050165A2 (en) * | 2004-11-01 | 2006-05-11 | Seo Hong Yoo | Methods and compositions for reducing neurodegeneration in amyotrophic lateral sclerosis |
| US20060121108A1 (en) * | 2004-12-02 | 2006-06-08 | Prasad C K | System and method for producing a directly compressible, high-potency formulation of metformin hydrochloride |
| PE20061245A1 (en) * | 2005-03-30 | 2007-01-06 | Generex Pharm Inc | COMPOSITIONS FOR ORAL TRANSMUCOUS TRANSMISSION OF METFORMIN |
| US9161918B2 (en) | 2005-05-02 | 2015-10-20 | Adare Pharmaceuticals, Inc. | Timed, pulsatile release systems |
| EP1959923A4 (en) * | 2005-08-30 | 2012-05-02 | Piramal Life Sciences Ltd | Extended release pharmaceutical composition of metformin and a process for producing it |
| US7994220B2 (en) * | 2005-09-28 | 2011-08-09 | Cypress Bioscience, Inc. | Milnacipran for the long-term treatment of fibromyalgia syndrome |
| EP1951710A4 (en) | 2005-11-09 | 2010-08-25 | Univ Columbia | Photochemical methods and photoactive compounds for modifying surfaces |
| US10064828B1 (en) | 2005-12-23 | 2018-09-04 | Intellipharmaceutics Corp. | Pulsed extended-pulsed and extended-pulsed pulsed drug delivery systems |
| EP2086515A2 (en) * | 2006-03-02 | 2009-08-12 | Vaunnex, Inc. | Rate-controlled bioadhesive oral dosage formulations |
| CA2648280C (en) | 2006-04-03 | 2014-03-11 | Isa Odidi | Controlled release delivery device comprising an organosol coat |
| US10960077B2 (en) | 2006-05-12 | 2021-03-30 | Intellipharmaceutics Corp. | Abuse and alcohol resistant drug composition |
| US8124598B2 (en) * | 2006-09-14 | 2012-02-28 | Sharon Sageman | 7-keto DHEA for psychiatric use |
| US20070172525A1 (en) * | 2007-03-15 | 2007-07-26 | Ramesh Sesha | Anti-diabetic combinations |
| US20080064701A1 (en) * | 2007-04-24 | 2008-03-13 | Ramesh Sesha | Anti-diabetic combinations |
| CA2681092A1 (en) * | 2007-03-15 | 2008-09-18 | Nectid, Inc. | Anti-diabetic combinations comprising a slow release biguanide composition and an immediate release dipeptidyl peptidase iv inhibitor composition |
| US20100160274A1 (en) * | 2007-09-07 | 2010-06-24 | Sharon Sageman | 7-KETO DHEA for Psychiatric Use |
| US9226907B2 (en) | 2008-02-01 | 2016-01-05 | Abbvie Inc. | Extended release hydrocodone acetaminophen and related methods and uses thereof |
| US8551524B2 (en) * | 2008-03-14 | 2013-10-08 | Iycus, Llc | Anti-diabetic combinations |
| AU2008359725A1 (en) * | 2008-07-24 | 2010-01-28 | Handa Pharmaceuticals, Llc | Stabilized atypical antipsychotic formulation |
| MX2011001384A (en) | 2008-08-06 | 2011-09-27 | Gosforth Ct Holdings Pty Ltd | Compositions and methods for treating psychiatric disorders. |
| CA2638240C (en) * | 2008-08-29 | 2010-02-02 | Alexander Macgregor | Method of treating dysglycemia and glucose excursions |
| EP2415764A4 (en) | 2009-03-31 | 2012-08-08 | Kowa Co | Prophylactic and/or therapeutic agent for anemia comprising tetrahydroquinoline compound as active ingredient |
| AU2010315414B2 (en) * | 2009-10-28 | 2015-07-09 | Mcneil-Ppc, Inc. | Fast dissolving/disintegrating coating compositions |
| CA2782285A1 (en) | 2009-12-02 | 2011-06-09 | Luigi Mapelli | Fexofenadine microcapsules and compositions containing them |
| US20110142889A1 (en) * | 2009-12-16 | 2011-06-16 | Nod Pharmaceuticals, Inc. | Compositions and methods for oral drug delivery |
| CN102552919B (en) * | 2010-12-15 | 2018-03-27 | 上海安博生物医药股份有限公司 | A kind of administration composition and its preparation and application |
| CA2792046C (en) | 2010-03-04 | 2014-12-02 | Wockhardt Limited | Modified release dosage form |
| WO2011118454A1 (en) * | 2010-03-23 | 2011-09-29 | リンテック株式会社 | Solid preparation |
| TR201802207T4 (en) | 2010-03-29 | 2018-03-21 | Astellas Pharma Inc | Controlled Release Pharmaceutical Composition. |
| US8581001B2 (en) | 2010-04-16 | 2013-11-12 | Codman & Shurtleff | Metformin-cysteine prodrug |
| BR112012032816A2 (en) * | 2010-06-22 | 2016-11-08 | Twi Pharmaceuticals | controlled release pharmaceutical composition, and methods for reducing the dietary effect of a controlled release composition, reducing the amount of time required to achieve a stable state for metformin, to improve the bioavailability of a controlled release dosage form. matrix |
| EP2611434A1 (en) | 2010-09-01 | 2013-07-10 | Lupin Limited | Pharmaceutical composition comprising metformin and pioglitazone |
| WO2013103919A2 (en) | 2012-01-06 | 2013-07-11 | Elcelyx Therapeutics, Inc. | Compositions and methods for treating metabolic disorders |
| PT2661266T (en) | 2011-01-07 | 2020-11-30 | Anji Pharma Us Llc | Chemosensory receptor ligand-based therapies |
| US9480663B2 (en) | 2011-01-07 | 2016-11-01 | Elcelyx Therapeutics, Inc. | Biguanide compositions and methods of treating metabolic disorders |
| US8796338B2 (en) | 2011-01-07 | 2014-08-05 | Elcelyx Therapeutics, Inc | Biguanide compositions and methods of treating metabolic disorders |
| US9572784B2 (en) | 2011-01-07 | 2017-02-21 | Elcelyx Therapeutics, Inc. | Compositions comprising statins, biguanides and further agents for reducing cardiometabolic risk |
| US9211263B2 (en) | 2012-01-06 | 2015-12-15 | Elcelyx Therapeutics, Inc. | Compositions and methods of treating metabolic disorders |
| US11759441B2 (en) | 2011-01-07 | 2023-09-19 | Anji Pharmaceuticals Inc. | Biguanide compositions and methods of treating metabolic disorders |
| UY33937A (en) | 2011-03-07 | 2012-09-28 | Boehringer Ingelheim Int | PHARMACEUTICAL COMPOSITIONS CONTAINING DPP-4 AND / OR SGLT-2 AND METFORMIN INHIBITORS |
| GB201111712D0 (en) | 2011-07-08 | 2011-08-24 | Gosforth Ct Holdings Pty Ltd | Pharmaceutical compositions |
| ES2832773T3 (en) | 2012-01-06 | 2021-06-11 | Anji Pharma Us Llc | Biguanide compositions and methods of treatment of metabolic disorders |
| CN102525991A (en) * | 2012-02-20 | 2012-07-04 | 中国药科大学 | Compound preparation containing pioglitazone hydrochloride and metformin hydrochloride and method for preparing compound preparation containing pioglitazone hydrochloride and metformin hydrochloride |
| US9555001B2 (en) | 2012-03-07 | 2017-01-31 | Boehringer Ingelheim International Gmbh | Pharmaceutical composition and uses thereof |
| DE102012102414A1 (en) | 2012-03-21 | 2013-10-10 | Michael Dittgen | Composition, used to treat diabetes mellitus, includes antidiabetic drug as active substance, preferably metformin or its salt, where the composition is divided into two compartments, which include drug and three groups of adjuvants |
| WO2014014427A1 (en) | 2012-07-16 | 2014-01-23 | Mahmut Bilgic | Modified release pharmaceutical tablet formulations |
| CN102920704A (en) * | 2012-11-05 | 2013-02-13 | 上海现代药物制剂工程研究中心有限公司 | Pharmaceutic preparation containing biguanide and thiazolidinedione derivatives |
| WO2014184742A1 (en) | 2013-05-13 | 2014-11-20 | Ranbaxy Laboratories Limited | Pharmaceutical compositions containing a biguanide and a low dose antidiabetic agent |
| KR101597004B1 (en) | 2013-07-25 | 2016-02-23 | 씨제이헬스케어 주식회사 | Pharmaceutical combination comprising sustained-release type metformin and immediate-release type HMG-CoA reductase inhibitor |
| WO2015073736A1 (en) | 2013-11-13 | 2015-05-21 | Arbor Pharmaceuticals, Llc | Methods and compositions for treating adhd |
| CN103622930B (en) * | 2013-12-19 | 2015-06-10 | 石家庄市华新药业有限责任公司 | Metformin hydrochloride slow release preparation and preparation method thereof |
| WO2017004526A1 (en) | 2015-07-02 | 2017-01-05 | University Of Louisville Research Foundation, Inc. | EDIBLE PLANT-DERIVED MICROVESICLE COMPOSITIONS FOR DELIVERY OF miRNA AND METHODS FOR TREATMENT OF CANCER |
| CN105232490A (en) * | 2015-11-11 | 2016-01-13 | 青岛百洋制药有限公司 | Metformin hydrochloride sustained release tablet and preparation method thereof |
| WO2018035408A1 (en) * | 2016-08-18 | 2018-02-22 | Ovid Therapeutics Inc. | Methods of treating developmental disorders with biguanides |
| US9962342B1 (en) * | 2017-03-14 | 2018-05-08 | Sunny Pharmtech Inc. | Pharmaceutical composition containing guaifenesin and application thereof |
| US11253495B2 (en) | 2018-11-21 | 2022-02-22 | Yanming Wang | Pharmaceutical composition for treating excessive lactate production and acidemia |
| CN110623933B (en) * | 2019-06-15 | 2022-07-01 | 德州德药制药有限公司 | Metformin hydrochloride controlled release tablet and preparation method thereof |
| JPWO2021171972A1 (en) * | 2020-02-28 | 2021-09-02 | ||
| CN111388438A (en) * | 2020-05-08 | 2020-07-10 | 福建东瑞制药有限公司 | Metformin hydrochloride sustained release tablet and preparation method thereof |
Family Cites Families (152)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US411210A (en) | 1889-09-17 | Water-wheel | ||
| US3174901A (en) * | 1963-01-31 | 1965-03-23 | Jan Marcel Didier Aron Samuel | Process for the oral treatment of diabetes |
| US3621097A (en) * | 1970-03-30 | 1971-11-16 | Jan Marcel Didier Aron Samuel | Method and compositions for treatment of mental illness |
| US3960949A (en) | 1971-04-02 | 1976-06-01 | Schering Aktiengesellschaft | 1,2-Biguanides |
| DE2124256A1 (en) | 1971-05-15 | 1972-11-30 | Dr Christian Brunnengraber Chemi sehe Fabrik & Co mbH 2400 Lübeck | Oral antidiabetics - contg dicarboxylic amino acids |
| US3845770A (en) * | 1972-06-05 | 1974-11-05 | Alza Corp | Osmatic dispensing device for releasing beneficial agent |
| US3916899A (en) * | 1973-04-25 | 1975-11-04 | Alza Corp | Osmotic dispensing device with maximum and minimum sizes for the passageway |
| FR2243684B1 (en) * | 1973-09-19 | 1977-01-28 | Semb | |
| DE2401879A1 (en) | 1974-01-16 | 1975-07-24 | Hoechst Ag | BENZOLSULFONAMIDOPYRIMIDINE AND THE METHOD OF MANUFACTURING THEREOF |
| US4080472A (en) * | 1974-03-22 | 1978-03-21 | Societe D'etudes Et D'exploitation De Marques Et Brevets S.E.M.S. | Metformin 2-(p-chlorophenoxy)-2-methylpropionate |
| DE2426683A1 (en) | 1974-06-01 | 1975-12-18 | Boehringer Mannheim Gmbh | BIGUANID AND METHOD FOR MANUFACTURING THEREOF |
| GB1478759A (en) * | 1974-11-18 | 1977-07-06 | Alza Corp | Process for forming outlet passageways in pills using a laser |
| US3952741A (en) * | 1975-01-09 | 1976-04-27 | Bend Research Inc. | Controlled release delivery system by an osmotic bursting mechanism |
| US4034758A (en) * | 1975-09-08 | 1977-07-12 | Alza Corporation | Osmotic therapeutic system for administering medicament |
| US4036228A (en) | 1975-09-11 | 1977-07-19 | Alza Corporation | Osmotic dispenser with gas generating means |
| US4077407A (en) * | 1975-11-24 | 1978-03-07 | Alza Corporation | Osmotic devices having composite walls |
| US4058122A (en) | 1976-02-02 | 1977-11-15 | Alza Corporation | Osmotic system with laminated wall formed of different materials |
| US4008719A (en) | 1976-02-02 | 1977-02-22 | Alza Corporation | Osmotic system having laminar arrangement for programming delivery of active agent |
| US4140755A (en) | 1976-02-13 | 1979-02-20 | Hoffmann-La Roche Inc. | Sustained release tablet formulations |
| US4063064A (en) | 1976-02-23 | 1977-12-13 | Coherent Radiation | Apparatus for tracking moving workpiece by a laser beam |
| YU43437B (en) | 1976-05-05 | 1989-08-31 | Lowey Hans | Process for obtaining tablets containing an active component with long lasting effect |
| GB1552179A (en) | 1976-11-02 | 1979-09-12 | Beecham Group Ltd | Pharmaceutical compositions for treating hyperglycaemia |
| US4111201A (en) * | 1976-11-22 | 1978-09-05 | Alza Corporation | Osmotic system for delivering selected beneficial agents having varying degrees of solubility |
| US4220648A (en) | 1979-01-22 | 1980-09-02 | The Upjohn Company | Antidiabetic 1,2-dihydro-2-oxo-6-neopentyl-nicotinic acids |
| FI63335B (en) | 1979-02-02 | 1983-02-28 | Orion Yhtymae Oy | FARING REFERENCE FOR A TABLETTER WITH A LIGHT LIGHT OF AN EFFECTIVE |
| FR2449446A1 (en) | 1979-02-22 | 1980-09-19 | Somachim | Anti-obesity compsn. contg. tri: or tetra:iodo:thyro:acetic acid - with metformine or salt to enhance activity |
| US4357469A (en) | 1979-06-14 | 1982-11-02 | Forest Laboratories, Inc. | Carrier base material for prolonged release therapeutic compositions |
| CA1146866A (en) | 1979-07-05 | 1983-05-24 | Yamanouchi Pharmaceutical Co. Ltd. | Process for the production of sustained release pharmaceutical composition of solid medical material |
| US4248858A (en) | 1979-08-09 | 1981-02-03 | American Home Products Corporation | Sustained release pharmaceutical compositions |
| US4327725A (en) | 1980-11-25 | 1982-05-04 | Alza Corporation | Osmotic device with hydrogel driving member |
| US4369172A (en) | 1981-12-18 | 1983-01-18 | Forest Laboratories Inc. | Prolonged release therapeutic compositions based on hydroxypropylmethylcellulose |
| US4389393A (en) | 1982-03-26 | 1983-06-21 | Forest Laboratories, Inc. | Sustained release therapeutic compositions based on high molecular weight hydroxypropylmethylcellulose |
| US4522625A (en) * | 1982-09-29 | 1985-06-11 | Alza Corporation | Drug dispenser comprising wall formed of semipermeable member and enteric member |
| US4673405A (en) | 1983-03-04 | 1987-06-16 | Alza Corporation | Osmotic system with instant drug availability |
| US4783337A (en) | 1983-05-11 | 1988-11-08 | Alza Corporation | Osmotic system comprising plurality of members for dispensing drug |
| US4765989A (en) | 1983-05-11 | 1988-08-23 | Alza Corporation | Osmotic device for administering certain drugs |
| US4612008A (en) * | 1983-05-11 | 1986-09-16 | Alza Corporation | Osmotic device with dual thermodynamic activity |
| US5082668A (en) | 1983-05-11 | 1992-01-21 | Alza Corporation | Controlled-release system with constant pushing source |
| US4587117A (en) * | 1983-06-06 | 1986-05-06 | Alza Corporation | Medical device for delivering drug to pH environments greater than 3.5 |
| DE3320582A1 (en) | 1983-06-08 | 1984-12-13 | Dr. Karl Thomae Gmbh, 7950 Biberach | METHODS OF PREPARATION WITH GLIQUIDONE AND METHOD FOR THE PRODUCTION THEREOF |
| DE3320583A1 (en) | 1983-06-08 | 1984-12-13 | Dr. Karl Thomae Gmbh, 7950 Biberach | NEW GALENIC PREPARATION FORMS OF ORAL ANTIDIABETICS AND METHOD FOR THE PRODUCTION THEREOF |
| US4610686A (en) | 1983-11-02 | 1986-09-09 | Alza Corporation | Controlled delivery of haloperidol by an osmotic delivery system |
| US4627850A (en) * | 1983-11-02 | 1986-12-09 | Alza Corporation | Osmotic capsule |
| JPS60100516A (en) | 1983-11-04 | 1985-06-04 | Takeda Chem Ind Ltd | Preparation of sustained release microcapsule |
| US4777049A (en) * | 1983-12-01 | 1988-10-11 | Alza Corporation | Constant release system with pulsed release |
| US4851229A (en) * | 1983-12-01 | 1989-07-25 | Alza Corporation | Composition comprising a therapeutic agent and a modulating agent |
| US4692336A (en) * | 1984-03-19 | 1987-09-08 | Alza Corporation | Self controlled release device for administering beneficial agent to recipient |
| US4615698A (en) * | 1984-03-23 | 1986-10-07 | Alza Corporation | Total agent osmotic delivery system |
| US4608048A (en) | 1984-12-06 | 1986-08-26 | Alza Corporation | Dispensing device with drug delivery patterns |
| EP0190833B1 (en) | 1985-02-07 | 1991-03-27 | Takeda Chemical Industries, Ltd. | Method for producing microcapsule |
| US4624847A (en) * | 1985-04-22 | 1986-11-25 | Alza Corporation | Drug delivery device for programmed delivery of beneficial drug |
| US4609374A (en) * | 1985-04-22 | 1986-09-02 | Alza Corporation | Osmotic device comprising means for governing initial time of agent release therefrom |
| GB8518301D0 (en) | 1985-07-19 | 1985-08-29 | Fujisawa Pharmaceutical Co | Hydrodynamically explosive systems |
| US4865598A (en) * | 1985-08-16 | 1989-09-12 | Alza Corporation | Dispensing system for administering beneficial agent |
| US4704118A (en) * | 1985-08-16 | 1987-11-03 | Alza Corporation | Ruminant dispensing device with thermo-activated memory |
| US4963141A (en) * | 1985-08-16 | 1990-10-16 | Alza Corporation | Dispensing system for administering beneficial agent formulation to ruminants |
| IT1188212B (en) | 1985-12-20 | 1988-01-07 | Paolo Colombo | SYSTEM FOR THE RELEASE SPEED OF ACTIVE SUBSTANCES |
| US4849227A (en) | 1986-03-21 | 1989-07-18 | Eurasiam Laboratories, Inc. | Pharmaceutical compositions |
| US5141752A (en) * | 1986-05-09 | 1992-08-25 | Alza Corporation | Delayed drug delivery device |
| GB8613688D0 (en) | 1986-06-05 | 1986-07-09 | Euro Celtique Sa | Pharmaceutical composition |
| GB8613689D0 (en) | 1986-06-05 | 1986-07-09 | Euro Celtique Sa | Pharmaceutical composition |
| CH668187A5 (en) | 1986-08-07 | 1988-12-15 | Ciba Geigy Ag | THERAPEUTIC SYSTEM WITH SYSTEMIC EFFECT. |
| US4803076A (en) | 1986-09-04 | 1989-02-07 | Pfizer Inc. | Controlled release device for an active substance |
| US5196410A (en) | 1986-10-31 | 1993-03-23 | Pfizer Inc. | Transdermal flux enhancing compositions |
| US4851232A (en) | 1987-02-13 | 1989-07-25 | Alza Corporation | Drug delivery system with means for obtaining desirable in vivo release rate pattern |
| FR2611500B1 (en) | 1987-03-06 | 1990-05-04 | Lipha | USE OF BIGUANIDE DERIVATIVES IN THE PREPARATION OF MEDICINES |
| US5110597A (en) * | 1987-06-25 | 1992-05-05 | Alza Corporation | Multi-unit delivery system |
| GB8724763D0 (en) * | 1987-10-22 | 1987-11-25 | Aps Research Ltd | Sustained-release formulations |
| JP2670680B2 (en) * | 1988-02-24 | 1997-10-29 | 株式会社ビーエムジー | Polylactic acid microspheres containing physiologically active substance and method for producing the same |
| US4892739A (en) * | 1988-04-25 | 1990-01-09 | Ciba-Geigy Corporation | Osmotic continuous dispensing oral delivery system containing a pharmaceutically acceptable active agent having a improved core membrane adhesion properties |
| US4857337A (en) | 1988-05-24 | 1989-08-15 | American Home Products Corp. (Del) | Enteric coated aspirin tablets |
| US5028434A (en) | 1988-07-21 | 1991-07-02 | Alza Corporation | Method for administering nilvadipine for treating cardiovascular symptoms |
| US5030452A (en) | 1989-01-12 | 1991-07-09 | Pfizer Inc. | Dispensing devices powered by lyotropic liquid crystals |
| US5108756A (en) | 1989-01-12 | 1992-04-28 | Pfizer Inc. | Dispensing devices powered by lyotropic liquid crystals |
| DD295760A5 (en) | 1989-01-31 | 1991-11-14 | Martin-Luther-Universitaet Halle Wittenberg,De | DRUG DISTRIBUTION SYSTEM WITH COTROLLED ACTIVE INGREDIENT TRANSFER |
| US5007790A (en) | 1989-04-11 | 1991-04-16 | Depomed Systems, Inc. | Sustained-release oral drug dosage form |
| US5126145A (en) | 1989-04-13 | 1992-06-30 | Upsher Smith Laboratories Inc | Controlled release tablet containing water soluble medicament |
| US5024843A (en) * | 1989-09-05 | 1991-06-18 | Alza Corporation | Oral hypoglycemic glipizide granulation |
| US5091190A (en) * | 1989-09-05 | 1992-02-25 | Alza Corporation | Delivery system for administration blood-glucose lowering drug |
| US5591454A (en) * | 1989-09-05 | 1997-01-07 | Alza Corporation | Method for lowering blood glucose |
| US5120548A (en) * | 1989-11-07 | 1992-06-09 | Merck & Co., Inc. | Swelling modulated polymeric drug delivery device |
| US5071607A (en) * | 1990-01-31 | 1991-12-10 | Alza Corporatino | Method and apparatus for forming a hole in a drug dispensing device |
| US5356913A (en) | 1990-02-09 | 1994-10-18 | The Upjohn Company | Use of insulin sensitizing agents to treat hypertension |
| US5178866A (en) * | 1990-03-23 | 1993-01-12 | Alza Corporation | Dosage form for delivering drug to the intestine |
| US5324280A (en) * | 1990-04-02 | 1994-06-28 | Alza Corporation | Osmotic dosage system for delivering a formulation comprising liquid carrier and drug |
| US5260275A (en) | 1990-08-14 | 1993-11-09 | Amylin Pharmaceuticals, Inc. | Hypoglycemics |
| NO302481B1 (en) | 1990-10-16 | 1998-03-09 | Takeda Chemical Industries Ltd | Polymer for an extended release preparation, as well as an extended release preparation |
| WO1992011843A1 (en) * | 1991-01-09 | 1992-07-23 | Alza Corporation | Bioerodible devices and compositions for diffusional release of agents |
| US5668117A (en) * | 1991-02-22 | 1997-09-16 | Shapiro; Howard K. | Methods of treating neurological diseases and etiologically related symptomology using carbonyl trapping agents in combination with previously known medicaments |
| US5576306A (en) | 1991-03-01 | 1996-11-19 | Dow Chemical Company | Pharmaceutical compositions and uses of water-soluble, high-viscosity grade cellulose ethers |
| US5178867A (en) * | 1991-08-19 | 1993-01-12 | Alza Corporation | Dosage form for delivering drug in short-time period |
| DE69220317T2 (en) | 1991-10-01 | 1997-10-16 | Takeda Chemical Industries Ltd | Microparticle summary for extended release and manufacture of the same |
| US5169638A (en) | 1991-10-23 | 1992-12-08 | E. R. Squibb & Sons, Inc. | Buoyant controlled release powder formulation |
| US5200194A (en) | 1991-12-18 | 1993-04-06 | Alza Corporation | Oral osmotic device |
| AU1193092A (en) | 1992-01-10 | 1993-08-03 | Obschestvo S Ogranichennoi Otvetstvennostju Meditsinsky Nauchno-Proizvodstvenny Komplex Biotiki | Granulated pharmaceutical composition and method of obtaining it |
| US5308348A (en) * | 1992-02-18 | 1994-05-03 | Alza Corporation | Delivery devices with pulsatile effect |
| US5185158A (en) * | 1992-02-27 | 1993-02-09 | Alza Corporation | Dosage form comprising succinimide drug for treating depressive disorders and composition comprising same |
| US5688518A (en) * | 1992-02-27 | 1997-11-18 | Alza Corporation | Antidepressive therapy |
| DK36392D0 (en) * | 1992-03-19 | 1992-03-19 | Novo Nordisk As | USE OF CHEMICAL COMPOUND |
| US5582837A (en) | 1992-03-25 | 1996-12-10 | Depomed, Inc. | Alkyl-substituted cellulose-based sustained-release oral drug dosage forms |
| US5512293A (en) * | 1992-07-23 | 1996-04-30 | Alza Corporation | Oral sustained release drug delivery device |
| AU4198793A (en) | 1992-07-24 | 1994-01-27 | Takeda Chemical Industries Ltd. | Microparticle preparation and production thereof |
| DE69316101T2 (en) | 1992-08-07 | 1998-10-22 | Takeda Chemical Industries Ltd | Manufacture of microcapsules containing water-soluble drugs |
| JP3277342B2 (en) | 1992-09-02 | 2002-04-22 | 武田薬品工業株式会社 | Manufacturing method of sustained release microcapsules |
| JP3338119B2 (en) | 1993-04-14 | 2002-10-28 | 呉羽化学工業株式会社 | Antidiabetic agent |
| ES2149250T3 (en) | 1993-04-23 | 2000-11-01 | Novartis Ag | DEVICE FOR THE ADMINISTRATION OF MEDICINES WITH CONTROLLED RELEASE. |
| DE69508985T2 (en) | 1994-02-21 | 1999-08-19 | Takeda Chemical Industries Ltd | Polyester matrix for a delayed release pharmaceutical composition |
| JP3524195B2 (en) * | 1994-02-21 | 2004-05-10 | 武田薬品工業株式会社 | Base for sustained release formulation |
| ES2188657T3 (en) | 1994-04-22 | 2003-07-01 | Yamanouchi Pharma Co Ltd | SYSTEM FOR SPECIFIC LIBERATION IN THE COLON OF A PHARMACO. |
| DE4432757A1 (en) | 1994-09-14 | 1996-03-21 | Boehringer Mannheim Gmbh | Pharmaceutical preparation containing metformin and process for its preparation |
| JP2948111B2 (en) * | 1994-09-16 | 1999-09-13 | 塩野義製薬株式会社 | Oily composition for oral administration |
| US5917052A (en) * | 1994-09-28 | 1999-06-29 | Shaman Pharmaceuticals, Inc. | Hypoglycemic agent from cryptolepis |
| ATE198152T1 (en) | 1994-09-30 | 2001-01-15 | Takeda Chemical Industries Ltd | ORAL MEDICINAL PREPARATION WITH DELAYED RELEASE OF ACTIVE INGREDIENTS |
| AUPM897594A0 (en) | 1994-10-25 | 1994-11-17 | Daratech Pty Ltd | Controlled release container |
| US5614578A (en) * | 1994-10-28 | 1997-03-25 | Alza Corporation | Injection-molded dosage form |
| US5858398A (en) * | 1994-11-03 | 1999-01-12 | Isomed Inc. | Microparticular pharmaceutical compositions |
| US5534263A (en) * | 1995-02-24 | 1996-07-09 | Alza Corporation | Active agent dosage form comprising a matrix and at least two insoluble bands |
| US5674900A (en) * | 1995-06-06 | 1997-10-07 | Shaman Pharmaceuticals, Inc. | Terpenoid-type quinones for treatment of diabetes |
| US5747527A (en) | 1995-06-06 | 1998-05-05 | Shaman Pharmaceuticals, Inc. | Furanoeremophilane and eremophilanolide sesquiterpenes for treatment of diabetes |
| US5654005A (en) | 1995-06-07 | 1997-08-05 | Andrx Pharmaceuticals, Inc. | Controlled release formulation having a preformed passageway |
| TW438587B (en) | 1995-06-20 | 2001-06-07 | Takeda Chemical Industries Ltd | A pharmaceutical composition for prophylaxis and treatment of diabetes |
| GB9516268D0 (en) * | 1995-08-08 | 1995-10-11 | Danbiosyst Uk | Compositiion for enhanced uptake of polar drugs from the colon |
| JP3902272B2 (en) * | 1995-09-04 | 2007-04-04 | 武田薬品工業株式会社 | Manufacturing method of sustained-release preparation |
| IT1276130B1 (en) * | 1995-11-14 | 1997-10-27 | Gentili Ist Spa | GLIBENCLAMIDE-METFORMIN ASSOCIATION, PHARMACEUTICAL COMPOSITIONS THAT CONTAIN IT AND THEIR USE IN THE TREATMENT OF TYPE DIABETES MELLITUS |
| US5783212A (en) | 1996-02-02 | 1998-07-21 | Temple University--of the Commonwealth System of Higher Education | Controlled release drug delivery system |
| US5716976A (en) | 1996-03-13 | 1998-02-10 | Bernstein; Richard K. | Method of treatment for carbohydrate addiction |
| US5691386A (en) * | 1996-04-16 | 1997-11-25 | Shaman Pharmaceuticals, Inc. | Triterpenoid compound for the treatment of diabetes |
| US5972389A (en) | 1996-09-19 | 1999-10-26 | Depomed, Inc. | Gastric-retentive, oral drug dosage forms for the controlled-release of sparingly soluble drugs and insoluble matter |
| US5837379A (en) | 1997-01-31 | 1998-11-17 | Andrx Pharmaceuticals, Inc. | Once daily pharmaceutical tablet having a unitary core |
| US5741926A (en) * | 1997-02-12 | 1998-04-21 | Shaman Pharmaceuticals, Inc. | Aniline derivatives having antihyperglycemic activity |
| US6011049A (en) * | 1997-02-19 | 2000-01-04 | Warner-Lambert Company | Combinations for diabetes |
| US5859037A (en) | 1997-02-19 | 1999-01-12 | Warner-Lambert Company | Sulfonylurea-glitazone combinations for diabetes |
| US6010718A (en) * | 1997-04-11 | 2000-01-04 | Abbott Laboratories | Extended release formulations of erythromycin derivatives |
| ES2248908T7 (en) | 1997-06-06 | 2014-11-24 | Depomed, Inc. | Dosage forms of drugs orally and gastric retention for continued release of highly soluble drugs |
| US6051597A (en) * | 1997-06-13 | 2000-04-18 | Merck & Co., Inc. | Indolylquinones as antidiabetic agents |
| US6287587B2 (en) | 1997-07-15 | 2001-09-11 | Takeda Chemical Industries, Ltd. | Process for producing sustained-release preparation by in-water drying |
| US5914326A (en) * | 1997-08-08 | 1999-06-22 | Ambi Inc. | Method for promoting weight and fat loss |
| JP2001527023A (en) | 1997-08-11 | 2001-12-25 | アルザ・コーポレーション | Extended release active dosage form adapted for gastric retention |
| US6056977A (en) * | 1997-10-15 | 2000-05-02 | Edward Mendell Co., Inc. | Once-a-day controlled release sulfonylurea formulation |
| US6174548B1 (en) | 1998-08-28 | 2001-01-16 | Andrx Pharmaceuticals, Inc. | Omeprazole formulation |
| NZ506202A (en) | 1998-03-19 | 2003-10-31 | Bristol Myers Squibb Co | Biphasic controlled release delivery system for high solubility pharmaceuticals and method |
| US6099859A (en) | 1998-03-20 | 2000-08-08 | Andrx Pharmaceuticals, Inc. | Controlled release oral tablet having a unitary core |
| US6100300A (en) | 1998-04-28 | 2000-08-08 | Bristol-Myers Squibb Company | Metformin formulations and method for treating intermittent claudication employing same |
| US6197340B1 (en) | 1998-05-28 | 2001-03-06 | Medical Research Institute | Controlled release lipoic acid |
| US6191162B1 (en) * | 1998-05-28 | 2001-02-20 | Medical Research Institute | Method of reducing serum glucose levels |
| US6086920A (en) | 1998-08-12 | 2000-07-11 | Fuisz Technologies Ltd. | Disintegratable microspheres |
| US6117451A (en) * | 1998-08-25 | 2000-09-12 | Pharmalogix, Inc. | Direct compression metformin hydrochloride tablets |
| US6099862A (en) | 1998-08-31 | 2000-08-08 | Andrx Corporation | Oral dosage form for the controlled release of a biguanide and sulfonylurea |
| US6790459B1 (en) * | 2000-11-03 | 2004-09-14 | Andrx Labs, Llc | Methods for treating diabetes via administration of controlled release metformin |
| US6866866B1 (en) * | 2000-11-03 | 2005-03-15 | Andrx Labs, Llc | Controlled release metformin compositions |
| US20060034922A1 (en) * | 2000-11-03 | 2006-02-16 | Andrx Labs, Llc | Controlled release metformin compositions |
| WO2003099214A2 (en) * | 2002-05-23 | 2003-12-04 | Andrx Corporation | Biguanide formulations |
-
1998
- 1998-03-20 US US09/045,330 patent/US6099859A/en not_active Expired - Lifetime
-
1999
- 1999-03-19 AU AU31019/99A patent/AU739226B2/en not_active Ceased
- 1999-03-19 EP EP09006402.3A patent/EP2087889B1/en not_active Expired - Lifetime
- 1999-03-19 KR KR1020007010441A patent/KR20010071122A/en not_active Application Discontinuation
- 1999-03-19 WO PCT/US1999/006024 patent/WO1999047125A1/en not_active Application Discontinuation
- 1999-03-19 CA CA002324493A patent/CA2324493C/en not_active Expired - Lifetime
- 1999-03-19 ES ES09006402.3T patent/ES2540972T3/en not_active Expired - Lifetime
- 1999-03-19 DE DE69941115T patent/DE69941115D1/en not_active Expired - Lifetime
- 1999-03-19 ES ES99912705T patent/ES2328308T3/en not_active Expired - Lifetime
- 1999-03-19 CN CNB998064343A patent/CN1158999C/en not_active Expired - Fee Related
- 1999-03-19 EP EP99912705A patent/EP1063971B1/en not_active Expired - Lifetime
- 1999-03-19 JP JP2000536365A patent/JP4557424B2/en not_active Expired - Fee Related
-
2000
- 2000-11-29 US US09/726,193 patent/US20010024659A1/en not_active Abandoned
-
2001
- 2001-11-01 US US10/016,556 patent/US6495162B2/en not_active Expired - Lifetime
- 2001-12-06 HK HK01108559A patent/HK1037963A1/en not_active IP Right Cessation
-
2007
- 2007-03-02 US US11/713,143 patent/US7919116B2/en not_active Expired - Fee Related
-
2010
- 2010-04-09 JP JP2010090641A patent/JP5427677B2/en not_active Expired - Fee Related
-
2011
- 2011-03-21 US US13/052,154 patent/US8475841B2/en not_active Expired - Fee Related
-
2013
- 2013-07-26 JP JP2013156106A patent/JP2013237689A/en active Pending
Also Published As
| Publication number | Publication date |
|---|---|
| JP2013237689A (en) | 2013-11-28 |
| US20110195119A1 (en) | 2011-08-11 |
| AU3101999A (en) | 1999-10-11 |
| US6099859A (en) | 2000-08-08 |
| KR20010071122A (en) | 2001-07-28 |
| WO1999047125A1 (en) | 1999-09-23 |
| US20070154548A1 (en) | 2007-07-05 |
| US20010024659A1 (en) | 2001-09-27 |
| JP2002506810A (en) | 2002-03-05 |
| US8475841B2 (en) | 2013-07-02 |
| ES2328308T3 (en) | 2009-11-11 |
| CA2324493A1 (en) | 1999-09-23 |
| US6495162B2 (en) | 2002-12-17 |
| EP1063971B1 (en) | 2009-07-15 |
| ES2540972T3 (en) | 2015-07-15 |
| EP1063971A4 (en) | 2006-05-24 |
| HK1037963A1 (en) | 2002-03-01 |
| DE69941115D1 (en) | 2009-08-27 |
| US7919116B2 (en) | 2011-04-05 |
| EP2087889A2 (en) | 2009-08-12 |
| AU739226B2 (en) | 2001-10-04 |
| JP2010159290A (en) | 2010-07-22 |
| EP2087889B1 (en) | 2015-06-17 |
| CN1308520A (en) | 2001-08-15 |
| EP1063971A1 (en) | 2001-01-03 |
| JP5427677B2 (en) | 2014-02-26 |
| JP4557424B2 (en) | 2010-10-06 |
| CN1158999C (en) | 2004-07-28 |
| EP2087889A3 (en) | 2009-09-02 |
| US20020064556A1 (en) | 2002-05-30 |
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