OA16217A - Novel pharmaceutical formulation containing a biguanide and a thiazolidinedione derivative. - Google Patents

Novel pharmaceutical formulation containing a biguanide and a thiazolidinedione derivative. Download PDF

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Publication number
OA16217A
OA16217A OA1200700373 OA16217A OA 16217 A OA16217 A OA 16217A OA 1200700373 OA1200700373 OA 1200700373 OA 16217 A OA16217 A OA 16217A
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OA
OAPI
Prior art keywords
dosage form
thiazolidinedione
tablet
dérivative
release
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Application number
OA1200700373
Inventor
Kazuhiro Okochi
Avinash Nangia
Unchalee Lodin
Jack R. Cardinal
Original Assignee
Takeda Pharmaceutical Company, Limited
Watson Pharmaceuticals, Inc.
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Application filed by Takeda Pharmaceutical Company, Limited, Watson Pharmaceuticals, Inc. filed Critical Takeda Pharmaceutical Company, Limited
Publication of OA16217A publication Critical patent/OA16217A/en

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Abstract

A pharmaceutical dosage form comprising a controlled release component comprising an antihyperglycemic drug in combination with a second component comprising a thiazolidinedione derivative is herein disclosed and described.

Description

Titre :Novel pharmaceutical formulation containing a biguanide and a thiazolidinedione dérivative.
A pharmaceutical dosage form comprising a controlled release component comprising an antihyperglycemic drug in combination with a second component comprising a thiazolidinedione dérivative is herein disclosed and described.
O.A.P.I. - B.P. 887, YAOUNDE (Cameroun) - Tel. (237) 22 20 57 00- Fax: (237) 22 20 57 27- Site web: http:/www.oapi.int - Email: oapi@oapi.int
Novel Pharmaceutical Formulation Containing a Biguanide and a Thiazolidinedione Dérivative,
This is a continuât! on-in-part application of United States Patent Application Serial No. 10/777,542 foed on February 12, 2004 which is a continuation-în-part application of United States Patent Application Serial No. 10/664,804 filed on September 19, 2003 and which daims the benefit of United States provisional patent applications Serial Nos. 60/412,180 and 60/412,181 filed on September 20, 2002.
BAÇKGROUND OF THE INVENTION
The présent invention relates to a pharmaceutical dosage form comprising an antihyperglycemic drog, in combination with a thiazolidinedione dérivative. More specifically, the présent invention relates to an oral dosage form comprising a biguanide e.g. metformin or buformin or a pharmaceutically acceptable sait thereof
e.g., metformin hydrochloride or the metformin salts described in U.S.^Pat. Nos. 3,957,853 and 4,080,472 which are incorporated herein by référencé în combination with a thiazolidinedione dérivative as described in U.S. Pat. No. 4,687,777 also incorporated herein by référencé.
Many techniques hâve been used to provide controlled and extended-release pharmaceutical dosage forms in order to maintain therapeutic sérum levels of médicaments and to minimize the effects of missed doses of drugs caused by a lack of patient compliance.
For example, extended reiease tablets hâve been described which hâve an osmoticalJy active drug core surrounded by a semipermeable membrane. These tablets fonction by allowing the aqueous component of a fluid such as gastric or intestinal fiuid to permeate the coating membrane and dissolve the active ingrédient so the résultant drug solution can be released through a passageway in the coating membrane. Altematively, if the active ingrédient is insoluble in the permeating fluid, it can be pushed through the passageway by an expanding agent such as a hydrogel. Some représentative examples of these osmotic tablet Systems can be found in U.S. Pat. Nos. 3,845,770; 3,916,899; 4,034,758; 4,077,407 and 4,783,337. U.S. Pat. No. 3,952,741 teaches an osrnotic device wherein the active agent is released from a core surrounded by a semipermeable membrane only after sufficient pressure has ’ *!·: ’-λ ; * 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 hâve been refined over time in an effort to provide greater control of the release of the active ingrédient. For example, U.S. Pat. Nos. 4,777,049 and 4,851,229 describe osmotic dosage forms comprising a semipermeable wall surrounding a core. The core contains an active ingrédient and a inodulating agent wherein the modulating agent causes the active ingrédient to be released through a passageway in the semipermeable membrane in a pulsed manner. Further refinements hâve included modifications to the semipeimeable membrane surrounding the active core such as varying the proportions of the components that form the membrane, e.g. U.S. Pat. Nos. 5,178,867,4,587,117 and 4,522,625 or increasing the number of coatings surrounding the active core, e.g. U.S. Pat. Nos. 5,650,170 and 4,892,739.
Certain ccntrolled or sustained release formulations that employ antihyperglycemic drugs such as metformin hydrochloride hâve been limited to the use of an expanding or gellîng agent to control the release of the drug from the dosage fonn. This limited research is exemplified by the teachings of WO 96/08243 and by the GLUCOPHAGE™XR product insert which is a controlled release metformin HCl product commercially available from Bristol-Myers Squibb Co.
Thiazolidinedione dérivatives hâve been described in U.S. Pat. No. 4,687,777. The theiapeutîc value of these compounds in combination therapy has further been described in U.S. Pat. Nos. 5,859,037; 5,952,356; 5,965,584; 6,150,384 and 6,172,090. However, none of these patents describe a dosage form having the advantages ofthe subject invention.
Pharmaceutical dosage forms containing combinations of antihyperglycemic drugs and thiazolidinedione dérivatives hâve been proposed in the art. For example, EPO 0 749 751 (which is incorporated herein by référence) teaches pharmaceutical compositions comprising an insulin sensitivity enhancer, which could be a thiazolidinedione compound, in combination with other antidiabetics. More specifically, EPO 0 749 751 teaches that the preferred insulin sensitivity enhancer is pïoglitazone, which can be combined with other antidiabetics such as metformin, phenformin or buformin, and further that these drugs can be associated (mîxed and/or coated) with conventional excipients to piovide taste masking or sustained release behavior. Another example of a combination of antihyperglycemic drugs and ’ 'f' ·ι· thiazolidinedione dérivatives is U.S. Pat. No. 6,011,049, (which is incorporated herein by reference). This patent teaches a single pharmaceutical composition that contains pioglitazone or trolitazone and metformin in slow release forms such as osmotic pumps or skin patches. Other combinations of aniihyperglycemic drugs and thiazolidinedione dérivatives can be found in U.S. Pat. Nos. 6,524,621; 6,475,521; 6,451,342 and 6,153,632 and PCT patent applications WO 01/3594 and WO 01/3594, which are incorporated herein by reference.
Also known in the art are WO 99/47125 and United States Patent No. 6,099,862 that disclose a metformin osmotic tablet coated with an immédiate release coating containing an antihyperglycemic or a hypoglycémie drug.
Although the prior art teaches pharmaceutical dosage formulations that contain both an antihyperglycemic compound and thiazolidinedione dérivatives, the présent invention provides numerous benefits over the prior art teachings as will be described below.
lt is an object of the présent invention to provide a dosage form comprising a first active drug, which is formulated to provide a controlled or sustained release delivery. Preferably, the first active drug is an antihyperglycemic compound. The présent invention further provides for a second active drug which preferably is a thiazolidinedione dérivative. The novel dosage form described herein provides for delivery of first and second active drugs such that the bioavailability of either drug is not decreased by.the presence of food.
h is a further object of the présent invention to provide a dosage form, as described above, comprising delivery of a first active drug as a controlled or sustained release formulation for an antihyperglycemic compound, wherein said controlled or sustained release mechanism is not regulated by an expanding polymer, in combination with delivery of a second active drug by immédiate release comprising a thiazolidinedione dérivative.
It is also a furthej· object of the présent invention to provide a dosage form as described above, comprising delivery of a first active drug as a controlled or sustained Telease formulation foi an antihyperglycemic compound in combination with delivery of a second active dmg by immédiate release comprising a thiazolidinedione dérivative that can provide continuous and non-pulsating therapeutic levels of said antihyperglycemic drug to an animal or human in need of such treatment over a eight hour to twenty-four hour period.
lt is an addhiona] object of the présent invention to provide a dosage form comprising delivery of a first active drug as a controlled or sustained release formulation for an antihyperglycemic cornpound in combination with delivery of a that obtains peak plasma levels of the antihyperglycemic cornpound approximately 612 Bouts after administration following a meal and peak plasma levels of thiazolidinedione dérivative approximately l-4 hours after dcsing.
It îs also an object of the présent invention to provide a dosage form comprising a first active drug as a controlled or sustained release pharmaceutical core 1 0 tablet having only a homogeneous osmotic core wherein the osmotic core component may be made using ordinary tablet compression techniques.
It is an additions) object of the présent invention to provide a dosage form comprising delivery of a first active drug as a controlled or sustained release formulation for an antihyperglycemic cornpound in combination with delivery of a I5 second active drug by immédiate release comprising a thiazolidinedione dérivative that obtains peak plasma levels of the antihyperglycemic cornpound approximately 612 hours after administration and peak plasma levels of thiazolidinedione dérivative approximately 1-4 hours after dosing when the product is dosed following a meal.
It is a further object of the présent invention to provide a dosage form comprising an antihyperglycemic drug as a controlled or sustained release component and a thiazolidinedione dérivative as an immédiate release component, wherein not less than 80% of the total amount of the thiazolidinedione dérivative is released from the dosage form witliin 30 minutes or less.
It is a further additional object of the présent invention to provide a shelf stable dosage form comprising an antihyperglycemic drug as a controlled or sustained release component and a thiazolidinedione dérivative as an immédiate release component, wherein the total amount of thiazolidînedicne related compounds or impurities are not more than 0.6% afteT two years of storage and no individual related cornpound or impurity is more than 0.2 %.
SUMMARY OF THE INVENTION
The présent invention relates to a pharmaceutical dosage form comprising a first active drug, preferably an antihyperglycemic drug. in combination with a second active drug, preferably a thiazolidinedione derîvatrve. More specifically, the présent
invention relates to an oral dosage form comprising a first active drug comprising a biguanide such as metfonnm or buformin or a pharmaceutically acceptable sait thereof e.g., metformin hydrochloride or the metformin salis, in combination with a second active drug comprising a thiazolidinedione dérivative.
The foregoing objectives are met by a dosage form comprising a first and second active drug, wherein tire first active drug is formulated as a controlled release core, preferably an osmotic tablet, with or without a gelling or expanding polymer. The second active ingrédient may be part of tbe controlled release core or it may preferably be combined wîth the controlled release core in a manner that provides for immédiate release of the second active ingrédient. For ezample, the second active ingrédient can be jncorporated into a membrane that is applîed to the core or the second active ingrédient may be applîed to a coated or uncoated controlled release core.
In one embodiment the second active drog, which may be the thiazolidinedione dérivative, is provided as an immédiate release formulation in the dosage form whereas the antihyperglycemic component is provided as a controlled release formulation in the dosage form. This immédiate release portion of the formulation should provide peak plasma levcls (Tm„) of 1-12 hours preferably, 1-4 hours of the thiazolidinedione dérivative, while 1he controlled release portion of the formulation may provide peak plasma levels (Tmax) of 6-J2 hours of the antihyperglycemic component when dosed following a meal,
Preferably, the dosage form according to the subject invention may be î
administered once a day, preferably with oj afler a meal, and most preferably with or after the evening meal. The subject dosage form can provide therapeutic levels of the drug throughout the day with peak plasma levels (Tmnx) of the antihyperglycemic drug being obtained between 6-12 hours afteiadministration with a meal.
PET Al LEP DESCRIPTION OF THE INVENTION
The subject invention concems a pharmaccutica] formulation or dosage form 30 comprising a first active drug comprising an antihyperglycemic drug in combination with a second active drug comprising a thiazolidinedione dérivative. Preferably, the antihyperglycemic drug is a biguanide e.g. metformin or buformin or a pharmaceutically acci^rtabJe sait thereof. The antihyperglycemic drug is delivered in a controlled release manner from a tablet core, preferably an osmotic tablet core with
I or without a gelling or swelling polymer. The tablet coie shoujd include the antihyperglycemic drug and at least one pharmaceutically acceptable excipient. In one embodiment of the présent invention the tablet core includes the antihyperglycemic drug, a binding agent and an absorption enhancer, and the tablet 5 core is preferably coated with a polymeric coating to forrn a membrane around the tablet and drilled to create one passageway on each side of the membrane. The second active drug comprises a thiazolidinedione dérivative, and is preferably applied to the membrane of the tablet core and provides for either immédiate or controlled release of said thiazolidinedione dérivative.
The terrn, antihyperglycemic drugs as used in this spécification, refers to drugs that are useful in controlling or managing noninsulin-dependent diabètes mellitus (N1DDM). Antihyperglycemic drugs include the biguanides such as metfonnin, phenformin or buformin or the like, and pharmaceutically acceptable salts, isomers or derivatîves thereof.
The terrn thiazolidinedione dérivative as used in this spécification refers to drugs that are useful for controlling or managing NIDDM. These include, but are not limited to, troglitazone, rosiglitazone, pîoglitazone, ciglitazone or the like, and pharmaceutically acceptable salts, isomers or derivatîves thereof.
The term binding agent refers to any conventionally known pharmaceutically 20 acceptable binder such as polyvinyl pyrrolidone. hydroxypropy] cellulose, hydroxyethyl ' cellulose, hydroxypropyl methylcellulose, ethylcellulose, poiymethacrylate, polyvinylalcohol and the like. Mixtures of the aforementioned binding agents may aïso be used. The preferred binding agents are water soluble matériels such as polyvinyl pyrrolidone havïng a weight average molecular weight of 25 25,000 to 3,000,000. The binding agent may comprise approximately about 0 to about
40% of the total weight of the core and preferably about 3% to about 15% of the total weight of the core. Jn one embodiment, the use of a binding agent in the core is optional.
In a preferred embodiment, the core may optionally comprise an absorption 30 enhancer. The absorption enhancer can be any type of absorption enhancer commonly known in the art such as a fatty acid, a surfactant (anionic, cationic, amphoteric), a chelating agent, a bile sait or mixtures thereof. Examples of sorne preferred absorption enhancers are lecithin, fatty acids such as capric acid, oleic acid and their monoglycerides, surfactants such as sodium lauryl sulfate, sodium taurocholate and
polysorbatc 80, chelating agents such as citric acid, phytic acid, ethylenediamine tetraacetic acid (EDTA) and ethylene glycol bis(P-amiroethy] ctbcr)-N,N,N,Ntetraacetic acid (EGTA). The core may comprise approximately 0 to about 20% of lhe absorption enhancer based on the total weight of the core and most preferably about 2% to about 10% of the total weight of the core.
In one embodiment of the présent invention, which does not cmploy a gelling or swelling polymer, the core of the présent invention is preferably formed by granulating an antihyperglycemic drug with a binding agent, and compressing the granules with the addition of a lubricant and absorption enhancer jnto a tablet. The core may aiso be formed by dry granulating the core ingrédients by passing them tlirongh a roller compacter and compressing the granules with the addition of a lubricant into tablets. Direct compression may also be employed for tablettîng. Other commonly known granulation procedures are known in the art. Additionalîy, other excipients such as lubricants, pigments or dyes may also be employed in the formulation of lhe subject invention.
The tenn gelling or swelling polymer refers to polymers that gel, swell or expand in the présence of water or biological fluids. Représentative examples of gelling or swelling polymers are high molecular weight hydroxpropyl methylcellulose (such as METHOCEL® K100M, which is commercially available from Dow Chemical) and high molecular weight polyethylene oxides (such as POLYOX WSR 301, WSR 303- or WSR COAGULANT). Ollier gelling or swelling polymers are described in United States Patent No. 4,522,625 (which is incorporated herein by reference).
The core formed as described herein, can be coated with a membrane or sustained release coating. Materiels that are usefut in forming lhe membrane or sustained release coating are ethylcellulose, cellulose esters, cellulose diesters, cellulose triesters, cellulose ethers, cellulose ester-ether, cellulose acylate, cellulose diacylate, cellulose triacylate, cellulose acetate, cellulose dîaeetate, cellulose tri acetate, cellulose acetate propionate and cellulose acetate butyrate. Other suitable polymers are described in U.S. Pat. Nos. 3,845,770; 3,916,899, 4,008,719; 4,036,228 and 4,612,008 (which are incorporated herein by reference). The most preferred membrane or sustained release coating material is cellulose acetate comprising an acetyl content of 39.3 te 40.3%, and is commercially available from Eastman Fine Chemicals.
In an alternative embodiment, the membrane or sustained release coaling can jnclude one of the above-described polymère and a flux-enhancing agent. The flux enhancing agent can increase the volume of fluid imbibed into the core to enable the dosage form to dispense substantially ajl of the antihyperglycemic drug through the passageway and/or the porous membrane. The flux-enhancing agent can be a watersoluble inatcrial or an enteric material. Examples of the preferred materials that are useful as flux enhancers are sodium chloride, potassium chloride, sucrose, sorbitol, mannitol, polyethylene glycols (PEG), propylene glycol, hydroxypropyl cellulose, hydroxypropyl methycellulose, hydroxypropyl methycellulose phthalate, cellulose acétate phthalate, pciyvînyl alcohols, melhacrylic acid copolymers, poloxamers (such as LUTROL F6S, LLJTKOL F127, LUTROL F108 which are commercially avaîlable from BASF) and mixtures thereof. A preferred flux-enhancer is PEG 400.
The flux enhancer may also be a drug that is water soluble such as metformin or its pbannaceutîcally acceptable salts, or the flux enhancer may be a drug that is soluble under intestinal conditions. If the flux enhancer is a drug, the présent dosage form has the added advanlage of providing an immédiate release of the drug that has been selected as the flux enhancer.
The flux enhancing agent comprises approximately 0 to about 40% of the total weighl of the coatîng, most preferably about 2% to about 20% of the total weight of the coatîng. The flux enhancing agent dissolves or leaches from the membrane or sustained release coaling to ïbnn channels in the membrane or sustained release coatîng which enables fluid to enter the core and dissolve the active ingrédient.
The membrane or sustained release coatîng may also be formed using a commonly known excipient such as a plasticizer. Some commonly known plasticizeis include adipate. azelate, enzoate, citrate, stéarate, isoebucate, sebacate, triethyl citrate, tri-n-butyl citrate, acetyl tri-n-butyl citrate, citric acid esters, and those described in the Encyclopédie of Polymer Science and Technology, Vol. I0 (1969), published by John Wiley & Sons. The preferred plasticizers are triacetin, polyethylene glycols (PEG) (i.e PEG 400, PEG 8000), acetylated monoglyceride, grapc seed oil, olive oil, sesame oil, acetyltributylcitrate, aceîyltriethylcitrate, glycerin sorbitol, diethyloxaiate, diethylmalate, diethylfumarate, dibutylsuccinate, diethylmalonate, dioctylphthalate, dibutylsebacate, triethylcitrate, tributylcilrate, glyceroltributyrate and the like. Depending on the particular plasticizer, ainounts from about 0 to about 25%, and preferably about 2% to about 15% of the plasticizer can be used based upon the total weight of the membrane or sustaîned relcase coating.
Generally, the membrane or sustaîned release coating around the core will comprise from about 1% to about 10% and preferably about 2% to about 5% based upon the total wejght of the core and coating.
In a prefeired embodiment, the membrane or sustaîned release coating surrounding the core further comprises a passageway that will allow for controlled release of the drug from the core. As used hereïn the terni passageway includes an >
aperture, orifice, bore, hole, weakened area or an erodible element such as a gelatin plug that erodes to form an osmotic passageway for the Telease of the antihyperglycemic drug from the dosage form. Passageways used in accordance with the subject invention are well known and are described in U.S. Pat. Nos. 3,845,770; 3,916,899; 4,034,758; 4,077,407; 4,783,337 and 5,071,607.
lndependent of the antihyperglycemic is a second active drug, preferably a thiazolidinedione dérivative. This second active drug may be formulated to provide an immédiate release of the thiazolidinedione dérivative. In one embodiment of the présent invention the thiazolidinedione dérivative is applied in the form of a layer to a controlled or sustaîned released core comprising the antihyperglycemic drug. The thiazolidinedone dérivative layer employs a binder and other conventional pharmaceutical excipients such as absorption enhancers, surfactants, plasticizers, antifoaming agents and combinations of the foregoing. An absorption enhancer may be présent in the thiazolidinedione dérivative layer in an amount up to about 30% w/w in comparison to the weight of the thiazolidinedione dérivative. A binding agent may be présent in an amount up to 150% w/w of the thiazolidinedione dérivative.
In one embodiment the binder in the thiazolidinedone dérivative layer is a water soluble binder, preferably a water soluble film forming binder, which has a low viscosity, typically less than 50 mPa.S, preferably less than 25 mPa.S, and most preferably less than 10 mPa.S, when tested as a 2% aqueous solution at 20°C. An example of such a water soluble binder is hydroxypropyl cellulose available from Nippon Soda Co., Ltd of Japan under the tradename HPC-SSL and HPC-SL which hâve a reporled viscosity of 2-3 mPa.S and 3-6 mPa.S respectively.
If a surfactant is employed in the thiazolidinedone dérivative layer h is preferred that the surfactant be a non-ionic surfactant such a polaxamer.
A second active drug immédiate release formulation may be incorporated into a single dosage fonn by coating onlo the membrane or sustained release coating of the dosage form by conventiona] methods. Altematively, it may be incorporated by any pharmaceutically acceptable method into a single dosage form with the first active drug. The incorporation of the second active drug may be performed by, but would not be limited to, the processes selected from the group consisting of drug layering, lamination, dry compression, déposition and printing.
When the thiazolidinedione dérivative is coated onto a membrane or suslained release coating of an osmotic tablet core, the thiazolidinedione coating should be applied from a coating solution or suspension that empJoys an aqueous solvent, an organic solvent or a mixture of an aqueous and an organic solvent. Typical organîc solvents include acetone, isopropyl alcohol, methanol and éthanol. If a mixture of aqueous and organic solvents is employed, the ratio of water to organic solvent should range from 98:2 to 2:98, preferably 50:50 to 2:98, most prcferably 30:70 to 20:80 and idealiy about 25:75 to 20:80. If a mixed solvent System is employed, the amount of binder requîred for coating the thiazolidinedione dérivative onto the membrane or sustained release coating may be reduced. For example, successful coalings hâve been obtained from a mixed solvent System where the ratio of binder to thiazolidinedione dérivative is I:9 to I:H. Although acceptable coatings can be obtained when the thiazolidinedione coat is applied directly to the membrane or sustained release coating, a preferred approach is to first coat the membrane or suslained release coating with a seal coat prior to the application of the thiazolidinedione coating. As used herein a seal coat is a coating that does not contain an active pharmaceutical ingrédient and that rapidly disperses or dissolves in water. It may be necessary to apply about 5 to 20% exccss, preferably about 10-15% excess of the thiazolidinedione coating solution to account for losses during the coating process.
The thiazolidinedione coating solution or suspension may also contain a surfactant and a pore forming agent. A pore forming is preferably a waler-soluble material such as sodium chloride, potassium chloride, sucrose, sorbitol, mannitol, polyethylene glycols (PEG), and propylene glycol. In an alternative embodiment, the dosage form of the présent invention may also comprise an effective immédiate release amount of the antihyperglycemic dmg. The effective immédiate release amount of antihyperglycemic drug may be coated onlo the membrane or suslained
I release coating of the dosage form 01 it may be incorporated into the membrane or sustained release coating.
I
In addition, varions diluents, excipients, ïubricants, dyes, pigments, dispersants, etc., which are disclosed in Remington's Pharmaceutical Sciences (1995), 5 may be used to optimize the above listed formulations of the snbject invention.
Biguanides, such as metformin are commonly administered in dosage forms contaîning 500 mg, 750 mg, 850 mg, and 1000 mg. Thiazolidinedione dérivatives, for example pioglitizone, are commonly administered in dosage forpns contaîning 15 mg, 30 mg and 45 mg. The présent invention is intended to encompass the above listed 10 therapeutic combinations, without providmg a spécifie example of each possible combination of compounds and their respective dosage amounts.
A preferred embodiment the dosage form will hâve the following composition:
FJRST ACTIVE DRUG
15 Core: Amount (% of core)
drug 50-98% (75-95% preferred)
binder 0.1-40% (3-15% preferred)
absorption cnhanccr 0-20% (2-10% preferred)
lubricant 0-5% (0.5-1% preferred)
20 Coating: Amount (% of coating)
polymer 50-99% (75-95% preferred)
flux enhancer 0-40% (2-20% preferred)
plasticizer 0-25% (2-1 S% preferred)
25 SECOND ACTIVE DRUG Amount (% of total dosage form)
drug 0.1-20% (1-10% preferred)
binder 0.1-30% (1-20% preferred)
surfactant. 0-20% (0.1-15% preferred)
pore former 0-25% (0.1-15% preferred)
30 plasticizer 0-20% (0.1-15% preferred)
The dosage fonns prepared according to the présent invention exhibit the following dissolution jtrofile when tested in a USP Type 2 apparatus at 75 rpm in 900 ml of simulated intestinal fluid (pH 7.5 phosphate buffet) and at 37°C.:
Release of First Active Drug
Time (hours) % release
2 0-25% (0-20% preferred)
4 10-45% (20-40% preferred)
8 30-90% (45-90% preferred)
12 NLT 50% (NLT 60% prefenred)
16 NLT 60% (NLT 70% preferred)
20 NLT 70% (NLT 80% preferred)
NLT=NOT LESS THAN i
Release of Second Active Dtur
Time (hours) % release
0.5 NLT 60% (NLT 75% prefenxd)
It bas been discovered that the sélection of the excipients for use in the thiazolidinedione component of the dosage form can greatly affect the release characteristics, potency and stability of the thiazolidinedione. Therefore, in an altemate embodiment of the présent invention, the compositîon of the ihîazolidinedione component of the présent invention should be selected so that not Jess than 85%, preferably not less than 90% and most prefetably not less than 95% of the thiazolidinedione is relcased from the dosage fonn wilhin 45 minutes, preferably wifhîn 40 minutes and most preferably within 30 minutes v/hen tested according to the United States Pharmacopeia (USP) 26, with Apparatus 1 at 100 rpm, 37 °C and 900 ml of 0.3 M KC1-HC1 Buffer, pH 2.0.
Further the excipients for use in the thîazoJidinedione component of the dosage form should be selected so that the total thiazolidinedione rclated compounds or impurities in the final dosage form are not more than G.o%, preferably not more than 0.5% and most preferably not more than 0.25% and each individnal thiazolidinedione related compound or impurity in the final dosage form is not more than 0.25%, preferably not more than 0.2% and most preferably not more than 0.1%. The thiazolidinedione related compounds or impurities in the final dosage form are
WO ÏV'?’ determined by High Performance Liquid Chromatography (HPLC) using a YMCODS-AQ, 5pm, 120Â, 4.6 x 250 mm or équivalent column, a O.l M ammonium acetate bu fier : ac et onitrile: glacial acetic acid (25:25:1) mobile phase, about a 40pL injection volume, 0.7 mL/min flow rate, 25°C column température and 269 nm wavelength for the UV detector.
EXAMPLES
The following are provided by way of example only and are in no means intended to be limiting.
EXAMPLE 1
A controlled release tablet containing 850 mg of metformin HCl and 15 mg pioglitazone is prepared as follows:
First Active Dnig
I. Cure (% composition of core)
Metformin HCl 90.54%
Povidone K-301, USP 4.38%
Sodium Tribasic Phosphate 4.58%
Magnésium stéarate 0.5%
1 approximate molecular weight = 50,000; dynamic viscosity (10% w/v solution at 20DC) = 5.5-8.5 inPas (a) Granulation
The metfonnin HCl is delumped by passing it througb a 40 mesh screcn and colJecting it in a clean, polyethylene-Iined container. The povidone, K-30, and sodium tribasic phosphate are dîssolved in purificd water. The delumped metfonnin HCl 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 température of 50-70°C; atomization air pressure of 1-3 bars and spray rate of 10-100 ml/min.
Once the binàing solution is deplcled, the granules are dried in the granulator until the loss on drying is less than 2%. The dried granules are passed through a comil equîpped with the équivalent of an 18 mesh screen.
(b) Tableting
The magnésium stéarate is passed through a 40 mesh stainless steei 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 (plein lower punch, upper punch with an approximately 1 mm indentation pin).
As stated above, the orifice may be formed by any mcans commonly employer! in the pharmaceutical industry.
(c) Seal Coating (optional)
The core tablet can be 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 tabîet using a pan coater under the following conditions: exhaust air température of 3842°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 2-4% is obtained.
Π Membrane (% composition of membrane)
Cellulose Acetate (398-10)2
Triacetin
PEG 400
85%
5%
W% 2 acetyl content 39.3-40.3% (a) Membrane Coating Process
The cellulose acetate is dissolved in acetone while stirring with a bomogenizer. The polytlhylene glycol 400 and triacetin are added to the cellulose acetate solution and stiired until a clear solution is obtained. The clear membrane coating solution is then sprayed onto the seal coated tablets using a fluidized bed coater employing the following conditions: product température of J6-22°C; atomization pressure of approximately 3 bars and spray rate of 120-150 ml/min. The sealed core tablet is coaied until a theoretical coating level of approximately 3% is obtained.
III. Second Active Drug Layering (% composition of second component)
Pioglitizone HCl
Tween 80
43.5%
2.0%
Hydroxypropyl methylcellulose 54.5%
Tween 80 and hydroxypropyl methylcellulose arc dissolved in purified water. Pioglitizone HCl is then dispersed into this solution. The resulting suspension is then sprayed onto the above-membrane-coated tablets.
EXAMPLE 2
A controlled release tablet containing 850 mg of metformin HCl and 15 mg pioglitazone is prepared as follows:
First Active Drug
1. Core
Metformin HCl
Povidone K-903, USP
Sodium LauTyl Sulfate (% composition of core)
88.555%
6.368%
4.577%
Magnésium Stéarate
0.5% 3 approxîmate moïecular weight =* 1,000,000, dynamic visccsîty (10% w/v solution) 300-700 mPas at 20°C.
(a) Granulation
The metformin HCl 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-90, is dissolved in. purified water. The delumped metformin HCl and sodium lauryl sulfate are then added to a top-spray fluidized bed granulator and granulatcd by spraying with the binding solution of povidone under the following conditions: inlet air température of 50-70°C; atomization air pressure of 1 -3 bars and spray rate of 10-100 ml/inin. _
Once the binding solution is depleted, the granules are dried in the granulator until the Joss on drying is less than 2%. The dried granules are passed through a comil equipped with the équivalent of an 18 mesh screen.
(b) Tableting
The magnésium stéarate is passed through a 40 mesh stainless steel screen and blended with the metformin HCl granules for approximately five (5) minutes. Afler blending, the granules are compressed on a rotary -press fitted with 15/32” round standard concave punches (plain lowcr punch, upper punch with an approximately 1 mm indentation pin).
As stated above, the orifice may be formed by any means commonly employer! in the pliarmaceutical industry.
(c) Seal Coating (optional)
The core tablet is seaj coated with an Opadry material or other suitable waterso lubie material by first dissolving the Opadry material, preferably Opadry Clear in purified waïer. The Opadry solution is then sprayed onto the core tablet using a pan coater under the following conditions: exhaust air température of 38-42°C; atomization pressure of 28-40 psi and spay rate of 10-15 ml/min. Jhe core tablet is coated with the sealing solution until a theoretical coating level of approximately 2% is obtained.
II Membrane (% composition of membrane)
Cellulose Acétate (398-10)4
Triacetin
PEG 400
85%
5%
10% 4 acetyl content 39.3-403% (a) Membrane Coating Process
The cellulose acetate is dissolved in acetone while stirring with a homogenizeT. The polyethylene glycol 400 and triacetin are added to the cellulose acetate solution and stirred. The coating solution is then sprayed onto the seal coated tablets ita a fluidized bed coater employing the . following conditions: product température of 16-22'C; atomizatioi pressure of approxîmately 3 bars and spray rate of 120-150 ml/min. The sealed ccore tablet is coated until a theoretical coating level of approxîmately 3% îs obtained.
III. Second Active Drug Layering Pioglîtizone HCl
Tween 80 (% composition of second component)
43.5%
2.0%
Hydroxypropyl methylcellulose 54.5%
Tween 80 and hydroxypropyl methylcellulose are dissolved in purified water. Pioglîtizone HCl is then dispersed înto this solution. Tbe rcsulting suspension is then sprayed onto the above described tablets.
EXAMPLE 3
A controlled release tablet containîng 500 mg of metformin HCl and 15 mg pioglitazone is prepared as foliows:
I. First Active Drug
A 500 mg metformin membrane coated tablet is prepared as described în Example 2 above except that compound cup footings are user! during tableting. The 500 mg metformin membrane coated tablet has the following composition:
CORE
Metformin HCl 500 mg/tablet
Povidone K-90, U SP 35.96 mg/tablet
Sodium lauryl sulfate, NF 25.84 mg/tablet
Magnésium stéarate, NF 2.82 mg/tablet
SEAL COATING
Opadry Clear (YS-1 -7006) 23.53 mg/tablet
MEMBRANE COATING
Cellulose Aaceiate, 398-10, NF 23.56 mg/tablet
Triacetin, USP 1.39 mg/tablet
Polyethylene Glycol 400, NF 2.77 mg/tablet
Total weight 615.87 mg/tablet
IL Second Active Drug Layering
An immédiate release amount of pioglitiazone HCL is applied to the 500 mg metformin HCl membrane coated table! prepared in step 1. The final tablet has the following composition:
Metformin HCI membrane coated 615.87 mg/tablet
Pioglitazone Coating
Pioglitazone HCI 16.53 mg/tablet
Tween 80 2.0 mg/tablet
Polyplasdone XL 15.0 mg/tablet
Opadry Clear (YS-1-7006) 8.47 mg/tablet
Color Coating
Opadry White 10.0 mg/tablet
Polishing Coat
Candelilla Wax Powder 2.0 mg/tablet
The pioglitazone coating is diiectly applied to the 500 mg metformin HCl membrane coated tablets. The pioglitazone coating is prepared by dissolving 0.252 kg of Opadry Clear, 0.269 kg of Polyplasdone XL and 0.036 kg of Tween 80 in 9.908 kg of purified water using a homogenizer. Once these ingrédients are dissolved, 0.296 kg of pioglitazone HCl is dispersed into the solution and homogenîzed. The homogenized dispersion is then directly applied to the 500 mg metformin HCI membrane coated tablets using a 24”O’Hara Labcoat Π1 pan coater with the following conditions:
Spray Rate 15-27 ml/min
Exhaust Température 42-47’C
Atomization Air Pressure 25 psi
Pan Speed 5-9 rpm
Inlet Air Flow 300-400 CFM
Once the pioglitazone coating has been applied to the 500 mg metformin HCl membrane coated tablet, an aesthetic or col or coating of Opadry white is applied to the pioglitazone coated tablet. The color coating is prepared by dispersing 0.179 kg of Opadry White in L791 kg of purified water. The Opadry White suspension is
applied to the pioglitazone coated tablet usîng a 24w O’Hara Labcoat III pan coater under the following conditions:
Spray Rate Exhaust Température Atomization Air Pressure 20-35 mL/min 35-45’C 25 psi
Pan Speed Inlet Air FIow 9rpm 390-500 CFM
Once the color coating is applied, the tablels are polished using 0.036 kg of Candelilla wax powder.
EXAMPLE 4
A controlled release tablet containing 500 mg of metformin HCJ and 15 mg pioglitazone is prepared as follows:
I. First Active Diur
A 500 mg membrane coated tablet is prepared as described in Example 2 above except that compound cup toolings are used during tableting. The 500 mg membrane coated tablet has the following composition:
CORE
Metformin HCl 500 mg/tablet
Povidone K-90, USP 35.96 mg/tablet
Sodium Lauryl Sulfate, NF 25.84 mg/tablet
Magnésium Stéarate, NF 2.82 mg/tablet
SEAL COATING
Opadry Clear (YS-1-7006) 23.53 mg/tablet
MEMBRANE COATING
Cellulose Acetate, 398-10, NF 23.56 mg/tablet
Triacetin, USP 1.39 mg/tablet
Polyethylene Glycol 400, NF 2.77 mg/tablet
Total weight 615.87 mg/tablet
IL Second Active Drug Laycring
An immédiate release amount of pioglitiazone HCL is applied to the 500 mg metformin HCl sea) coated tablet prepared in Step I. The final tablet bas the following composition:
Metformin HCl membrane coated tablet 615.87 mg/tablet
Seal Coat
Opadry Clear (YS-1-7006) 13.8 mg/tablet
Pioglitazone Coatîng
Pioglitazone HCl 16.53 mg/tablet
Tween 80 2.0 mg/tsblet
Sodium Chloride 4.27 mg/tablet
Opadry Clear (YS-1-7006) 2,0 mg/tablet
Color Coatîng
Opadry White 8.10 mg/tablet
Polishing Coat
Candelilla Wax 0.20 mg/tablet
The seal coatîng solution is prepared by dissolving 0.258 kg of Opadry Clear in 2.576 kg of purified wateî and spraying the solution onto approximately 12.088 kg of the 500 mg membrane coated metformin HCl tablet cores using a 24” O’Hara Labcoal III pan coater. The seal coat is applied under the following conditions:
Spray Rate Exhaust Température Atomization Air Pressure 20-35 mL/min 35-45°C 25 psi
Pan Specd Inlet AirFlow 9rpm 390-500 CFM
The pioglitazone coaling is applied to the seal coated 500 mg metformin HCl membrane coated tablets. The pioglitazone coatîng is prepared by dissolving 0.040 kg of Opadry Clear, 0.085 kg of sodium chloride and 0.040 kg of Tween 80 in 4.915 kg of purified water usîng a homogenizer. Once these ingrédients are dissolved, 0.328 kg of pioglitazone HCl is dispersed into the solution and homogenized. The homogenized dispersion is then applied to the seal coated 500 mg metformin HCl membrane coated tabtets using a 24” O’Hara Labcoat III pan coater with the following conditions:
Spray Rate
Exhaust Température
Atomization Air Pressure
Pattern Air Pressure
Pan Speed
Inlet Air Flow
10-30 mL/gun/min
35-45°C
20-40 psi
20-40 psi
8-12 rprn
250-450 CFM.
Once the pioglitazone coating has been applied to the seal coated 500 mg metformin HCl membrane coated tablets, an æsthetic or color coating of Opadry White is applîed to the pioglitazone coated tablet. The color coating is prepared by dispersing 0.159 kg of Opadry White in 1.585 kg of purificd water. The Opadry White suspension is applied to the pioglitazone coated tablet using conditions similar to those described above for application of the seal coating. Once the color coating is applied, the tablets are polished using 0.004 kg of Candelilla wax powder.
EXAMPLE 5 (% composition of core)
88.07%
6.87%
4.55%
A controlled release tablet contaîning 1000 mg of metformin HCl and 30 mg pioglitazone is prepared as follows:
First Active Drug
A. Core
Metformin HCl
Povidone K-9()\ USP
Sodium Lauryl Sulfate
Magnésium Stéarate
0.5% 3 approximate molecular weight = 1,000,000, dynamic viscosity (10% w/v solution) 300-700 mPas al 20°C.
Approximately 206.34 kg of purified water is addcd to a stainless steel tank followed by approximately J 0.86 kg of povidone K-90. The solution is mixed at about 330-360 rpms for about 45 minutes or until the povidone is completely dissolved. Approximately 139.14 kg of metformin HCl is passed through a Comil equipped with a #813 screen and no spacer at 840-850 rpms.
The screened metformin HCl is loaded inlo a GPCG-60 (Glatt) brand fluidized bed coater with Wurster insert (size 32” by 35 mm high) with 3 nozzles of size 1.5 mm. The metformin HCl is fluidized and the product température is adjusted to about 38-43°C. The povîdone solution is sprayed onto the fluidized metformin HCl with an atomization pressure of about 2.5-3.0 bars and the pump rate of:
0-15 minutes 491 -515 g/min (target 500g/min)
16-30 minutes 680-710 g/min (large! 700 g/min)
31-45 minutes 860-910 g/min (target 900 g/min)
46-60 minutes 1090-1170 g/min (target 1100 g/min)
61 minutes to end 1170-1220 g/min (target 1200 g/min).
Once the povîdone solution has been consumed, the granules aie dried in the fluidized bed at about 2)00 CFM and ôO’C inJet air température until the Joss on drying (LOD) is not more than 2%. The resulting granules are passed through a Comil equipped with a #1143 stainless steel screen and a #075 spacer at a speed of 1086-1088 rpms to produce approxjjnately 150 kg of metformin HCl granules. The granulation process is repeated a second time to produce appromixately 300 kg of metformin HÇI granules.
Approximately 300 kg of the metfonnin granules are added to a 50 eu. Ft. Slant-Cone blender along with approximately 14.38 kg of sodium lauryl sulfate and blended for about 20 minutes. About 1.58 kg of magnésium stéarate is passed tlirough a #40 mesh stainless steel screen then added to the mixture in the SlantCone blender. The resulting mixture is blended for about 5 minutes then compressed inlo tablets using a conventional tablet press equipped with a 14” round compound cup die, a pre-compression force of 6 and a main compression force of 38. The resulting tablets exhibit a weight range of 1044 g to about 1226 g with a target weight of 1135g, hardness of 20-36 kp (target of 28 kp) and a friability of ïess than or equal to 0.8%
B. Seal Coating
About 57.61 kg of the core tablets prepared above are seal coated with an Opadry material or other suitable water-soluble material by first dissolving the Opadry material, preferably about 3.98 kg of Opadry Clear YS-1-7006) in about ? ,· >
21.49 kg of purifîed water. The Opadry solution is then sprayed onto the core table! using an O’Hara Lab Coat II] pan coater with a 36” pan, 3 spray guns under the following conditions: exhaust air température of 40-47°C; atomization pressure of 50± 10 psi, and spay rate of 180±60 g/min/3 guns, pan speed of 4-8 rpms and air volume of 10001200 CFM. The core tablet is coated with the sealing solution until a Iheoretical coating level of approximately 2.8-4.4% is obtained.
C. Membrane Coating
A cellulose acetate membrane coating is applied to the seal coated metformin HCl tablet cores to produce membrane coated metformin HCl tablets with the following composition:
Metformin HCl lOOOmg Tablet 98.456%
Cellulose Acetate (398-10)4 1.313%
Triacetin 0.077%
PEG 400 1.54%
4 acetyl content 39.3-40.3%
Approximately 29.95 kg of acetone is added to a stainless steel tank followed by aborrt 0.788 kg of cellulose acetate and mixed for aboul 20 minutes until the solution becomes clear. Once the solution is clear about 0.092 kg of polyethylene glycol 400 is added to the solution and mixed for about 5 minutes followed by the addition of about 0.046 kg of triacetin. The solution is mixed for an additional 5 minutes.
About 59.07 kg of the seal coated metformin HCl tablets are loaded into a GPCG-60 (Glati) brand fluidized bed coater with Wurster însert (size J 8” by 45 mm high) with a nozzle of size 1.5 mm. The seal coated metformin HCl tablets areis fluidized and lhe product température is adjusted to about 21±3°C. The cellulose acetate solution is sprayed onto the fluidized seal coated metfonnin HCl tablets with an atomization pressure of about 2.0-3.0 bars, air volume of 1600 ± 300 CFM and a spray rate of 400±100 g/min until a weight gain of 1-2% (target 1.38%) is obtained. Once the desired amounl of membrane coating bas been applied the membrane coated tablets are dried in the fluidized bed 2l±3°C and 1350Ü00 CFM foT about 10 minutes followed by 40°C and 1350±l 00 CFM for about 5 minutes.
The resulting membrane coated tablets are laser drilled to create an orifice in the approximate center of each side of the membrane coated tablet (i.e 2 orifices) with an average diameter of 0.5 mm per orifice. The top micrometer is 6.5 ± 2 mm, bottom micrometer is 6.75 ±2 mm, the puise width of the laser is 17Q±70 and puise delay of 340 ±150 and 350 ±150 respectively.
II. Second Active Drug
An immédiate release amount of pioglitazone HCL is applied to the 1000 mg metformin HCl membrane coated tablets prepared in step 1. The final tablet has the following composition:
Metformin HCl membrane coated tablet
SeaJ Coating
Opadry Clear (Y S-1-7006)
Pioglitazone Coating
Pioglitazone HCI
Sodium Chloride
Opadry Clear (Y S-1-7006)
Color Coating
Opadry II White (Y-22-77I9)
Polishing Coat
Candelilla'Wax Powder
1201.0 mg/tablet
16.0 mg/tablet
33.06 mg/tablet
4.27 mg/tablet
3.C mg/tablet
20.27 mg/tablet
0.40 mg/tablet
The seal coating is prepared by dispersing 0.Î74 kg of Opadry Clear in 3.478 kg of éthanol and mixing the dispersion for 15 minutes The dispersion ïs than spray ed onlo approximateîy 13.174 kg of the 1000 mg metformin HCl membrane coated tablets using a 24” O’Hara Labcoat III pan coater. The seal coat is applied to the 1000 mg metformin HCI membrane coated tablets with the following conditions:
Spray Rate
Exhaust T emperature
Atomizalion Air Pressure
Pan Speed
Pattern Air Pressure
10-30 ml/gun/min
25-45’C
20-40 psi
6-12 rpms
20-40 psi ris
Inlet AirFJow
250-450 CFM
The pioglitazone coating then is applied to the seal coated 1000 mg metformin HCl membrane coated tablets. The pioglitazone coating is prepared by dissolving 0.036 kg of Opadry Clear and 0.046 kg of sodium chloride in 5.344 kg of éthanol using a homogenizer. Once the ingrédients are dispersed, 0.359 kg of pioglitazone HCl is dispersed into the solution and homogenized. The homogenized dispersion is then applied to the seal coated 1000 mg metformin HCl membrane coated tablets using a 24” O’Hara Labcoat III pan coater with the following conditions:
Spray Rate
Exhaust Température
Atomization Air Pressure
Pan Speed
Pattern Air Pressure
Inlet Air Flow
10-30 mL/gun/min
25-45°C
20-40 psi
6-12 rpm
20-40 psi
250-450 CFM
Once the pioglitazone coating bas been applied, an aesthetic or color coating of Opadry II White is applied to the pioglitazone coated tablets. The color coating is prepared by dispersing 0.220 kg of Opadry II White in 4.407 kg of éthanol. The Opadry H White suspension is than applied to the pioglitazone HCl coated tablets using a 24” O'Hara Labcoat III pan coater using conditions similar to those dcscribed above for the seal coating. Once the color coating is applied, the tablets are polished using 0.004 kg of Candehlla wax powder.
EXAMPLE 6
A controlled release tablet containing 1000 mg of metformin HCl and 30 mg pioglitazone is prepared as follows:
I. First Active Drug
A 1000 mg membrane coated tablet is prepared as described in Example 5 above. The 1000 mg membrane coated tablet has the following composition: CORE
Metformin HCl
Povidone K-90, USP
Sodium Lauryl Sulfate, NF
Magnésium Stéarate, NF
SEAL COATING
1000 mg/iablct
78.0 mg/tablet
51.69 mg/tablet
5.65 mg/tablet
Opadiy Clear (YS-l-7006)
MEMBRANE COATING
Cellulose Acetate, 398-10, NF
Triacetin, USP
Polyethylene Glycol 400, NF
Total weight
47.05 mg/tablet
15.77 mg/tablet
0.92 mg/tablet
1.85 mg/tablet
1201.0 mg/tablet
II. Second Active Drug
An immédiate release amounl of pioglitazone HCL is applied to the 1000 mg metformin HCl membrane coated tablels prepared in step 1. The final tablet bas the following composition:
Metformin HCl membrane coated tablet
Seal Coat
Opadry Clear (YS-1 -7006)
Pioglitazone Coating
Pioglitazone HCl
Sodium Chloride
Opadry Clear (YS-l-7006)
Color Coating
Opadry II White (Y-22-7719)
Polishing Coat
Candelilla Wax Powder
1201.0 mg/tablet
21.0 mg/tablet
33.06 mg/tablet
5.0 mg/tablet
3.7 mg/tablet
21.54 mg/tablet
0.40 mg/tablet
The seal coat is applied to the 1000 mg metformin HCl membrane coated tablet. The seal coating is prepared by dispersing 0229 kg of Opadry Clear in 4.573 kg of alcohol USP and mixîng the dispersion for 15 minutes. The dispersion is then sprayed onto approximatety 13 08 kg of the 1000 mg metformin HCl tablet cores using a 24” O’Hara Labcoat ΙΠ pan coater with the nozzle tip set 4±2” from the top of the static bed and the following conditions:
Spray Rate
Exhaust T emperat ure
Atomization Air Pressure
Pan Speed
Supply Air Flow ± 10 mL/gun/min
25°C ± 5°C
10-40 psi
4-9rpin
200±100CFM ..
Pattern Air Pressure
10-40 psi
The seal coating dispersion is continuously sinred until it is consumed during the coating process.
The pioglitazone coating then is applied to the seal coated 1000 mg metformin
HCl membrane coated tablets. The pioglitazone coating is prepared by mixing 4.434 kg of alcohol USP and l .250 kg of purified water (approximately a 78:22 alcohol to purified water ratio) and slowly dispersing 0,040 kg of Opadry Clear into the solvent mixture. Once the Opadry Clear is dispersed, it is homogenized for about 10 minutes.
Once the Opadry Clear dispersion is homogenized, 0.054 kg of sodium chloride is added to the dispersion and homogenized for about 2 minutes. Aller the sodium chloride is homogenized, 0.360 kg of pioglitazone HCl is slowly dispersed into the solvent mix and then homogenized for about 10 minutes. Once the pioglitazone HCl is homogenized, the homogenizer is removed from the mixing vessel and replaced 15 with an air mixer and mixed for an additional 15 minutes. The pioglitazone suspension is stirred until the suspension is consumed during the coating process. The pioglitazone HCI suspension is applied to the seal coated 1000 mg metformin HCl membrane coated tablet cores using a 24” O’Hara Labcoat 111 pan coater with the nozzle tip set 4 ±2” above the top of the static bed with the following conditions:
Spray Rate
Exhaust Température
Atomization Air Pressure
Pan Speed
Pattern Air Pressure
Supply Air Flow
25± 10 mUgun/min
25i5°C
10-40 psi
4-9 ipms a 40 psi
200±100CFM
Once the pioglitazone coating has becn applied to îhe seal coated 1000 mg metformin HCl membrane coated tablets, an æsthetic coating of Opadry II White is applied to the pioglitazone coated tablet. The aesthetie coating is prepared by 30 dispersing 0.235 kg of Opadry 11 White (Y-22-7719) in 4.691 kg of alcohol USP and mixing the dispersion for about 1 hour. The Opadry 11 White dispersion is than sprayed onto the pioglitazone HCl coated tablets using a 24” O’Hara Labcoat III pan coater with the nozzle tîp set 4±2” from the top of the static bed and the following conditions:
Spray Rate
Exhaust Température
Atomization Air Pressure Pan Speed
Supply Air Flow
Pattern Air Pressure ± 10 mL/gun/min
25°C±5OC
10-40 psi
4-9 rpm
200±100 CFM
10-40 psi
The color coating dispersion is continuously stirred until the dispersion is consumed during the coating procès:.
Once the aesthetic coating suspension is consumed, the ta blets are drîed in the coating pan for about 5 minutes with a pan speed of about 2-8 rpms and an exhaust température of 25 ± 5°C. Once the tablets are dried, the exbaust air is tumed off and the pan speed is adjusted to about 3-4 rpms and 0.004 kg of Candellia wax powder that had bcen passed through a 60 mesh screen is sprinkled onto the tablets. After the tablets hâve rolled in the wax for about 5 minutes the exhaust air is tumed on and the tablets are rolled for an additional 10 minutes.
The finished pobshed tabiet exhibited the following pioglitazone HCl dissolution profile when tested in a USP apparatus type 1 at 100 rpm in a pH 2.0 HCI0.3M KC1 buffer solution:
Time % Pioglitazone Released min. 42% min 79% min 95% min 102%
The finished polished tabiet aiso contained the following pioglitazone related compounds when tested by HPLC using a YMC-ODS-AQ, 5 pm, 120Â, 4.6 x 250 mm column, a 0.1 M ammonium acetate buffer acetonitrilerglacial acetic acid (25:25:1) mobile phase, a 40pL injection volume, 0.7 mL/min flow rate, 25°C column température and 269 nm wavelenglh for the UV dectector.
Name Relative Rétention Time Amount (%)
RS-1 0.7 N.D*.
Pioglitazone 1.0
RS-2 1.5 0.03
RS-3 3.4 0.04
RS4 1.2 0.03
RS-5 2.8 0.04
*N.D. = none detected
RS-I îs (+/-)'5']p-[2-(5-elhyl-2-pyTidyl)ethoxy]bcnzyl]-5-hydroxy-2,4- thiazolidincdîone.
RS-2 is (z)-5-rp-[2“(5“ethy)-2-pyridy])ethoxy]bcnzy]iiJcne]-2,4thiazolidinedione.
RS-3 is (+/-)-5-[p-[2-f5-ethyl-2-pyridyl)ethoxy]benzyl]-3-]2-(5-ethyl-2“ pyridyi)ethyl]-2,4-thia7.oiidinedionc.
RS-4 is (+/-)-ethyl-2-carbamoyltio-3-[4-[2-(5ethyl-2pyridyl)ethoxy]phenylJpropionate.
RS-5 is ethyl“3-p-[2-(5-ethyl-2-pyridyl)eÜioxy]pheny]-propionatc.
The final polished lablet was packaged in a 100 cc HDPE bottle containing one (1) 2g SORB-IT® desiccant canister and subjected to accelerated stability conditions of 40°C and 75% relative humidity for three (3) months. Afler storage, the final polished table! was tested and exhibited the following pioglitazone HCl dissolution profile when tesled in a USP apparatus type 1 at 100 rpm in a pH 2.0 20 HC1-0.3M KCJ butter solution:
Time % Pioglitazone Reicased
10 min. 38%
20 min 73%
30 min 92%
25 45 min 101%
The stored final polished tablet also contained the following pioglitazone related compounds when tested by HPLC using a YMC-ODS-AQ, 5pm, 120Â, 4.6 X 250 mm column, a 0.1 M ammonium acctale bufïériacelonitrile:gIacÎa) acetic acid 30 (25:25:1) mobile phase, a 40pL injection volume, 0.7 mL/miz flow rate, 25°C column température and 269 nm wavelength for the UV dectector.
Name_______Relative Rétention Time__________Amount (%)
RS-1 0.7 N.D.*
Pioglitazone 1.0
RS-2 1.5 0.03
RS-3 3.4 0.03
RS-4 1.2 0.02
RS-5 2.8 0.04
*N.D. = none detected ! i
EXAMPLE 7
A controlled release tablet containing 1000 mg of metformin HCl and 30 mg pioglitazone was prepared as follows:
A. First Active Drug Core
A cellulose acetate coated metformin HCL tablet is prepared as described ïn Example 5.
B.
Second Active Drug
An immédiate release amount of pioglitazone HCL was applied to the 1000 mg metformin HCl membrane coated tablets prepared above in step A. The final tablet had the following composition:
Metformin HCl membrane coated tablet 1201.0 mg/tablet
Seal Coat
Opadry Clear (YS-1-7006)
Pioglitazone Coating
Pioglitazone HCl
9.00 mg/tablet
33.06 mg/tablet
Hydroxypropyl Cellulose, NF (HPC-SSL) 9.0 mg/tablet
Lactose Monohydrate, NF (modified spray dried) Polyethylene Glycol 8000, NF Titanium Dioxidc. USP
Polishing Coat
Candelilla Wax Powder
30.0 mg/tablet
0.450 mg/tablet
0.90 mg/tablet
0.40 mg/tablet
The seal coat was applied to approximately 12.09 kg of the 1000 mg metformin HCl membrane coated tablet prepared m step A described above. The seal coating was prepared by dispersîng about 0.91 kg of Opadry Clear (YS-1-7006) in about 1.133 kg of purified water for 30 minutes. The dispersion was sprayed onto approximately 12.09 kg of the 1000 mg metformin HCl tablet cores using a 24” O’Hara Labcoat III pan coater with the nozzle iïp set 4±2” from the top of the static bed, 3 spray guns and the following conditions:
Spray Rate
Exhaust Température
Atomîzation Air Pressure
Pan Speed
Supply Air Flow ± 10 mL/gun/mi'n
40°C ± 5°C
10-40 pei
4-9 rpm 300±100CFM
Pattern Air Pressure
10-40 psi
The pioglitazone coating was applied to the seal coated 1000 mg metformin HCl membrane coated tablets. The pioglitazone coating was prepared by slowly dispersîng about 0.104 kg of hydroxypropyl cellulose, NF (HPC-SLL) in about 8.499 kg of purified water. The HPC-SSL and water was mixed foi about 20 minutes, then 0.347 kg of lactose monohydrate, NF (modified spray dried) was added to the HPCSSL/water mixture and mixed for about 2 minutes. After the lactose was mixed in, approximately 0.005 kg of polyethylene glycol 8000 NF and 0.010 kg of titanium dioxide, USP wcre added to the watei, HPC-SSL and lactose mixture and mixed for about 5 minutes. After about 5 minutes of mixing about 0.383 kg pioglitazone hydrochloride was dispersed into the coating solution. This coating solution contained approximately 15% excess material to compensate for material loss during the coating process. The pioglitazone suspension was stirred untîl the suspension was consumed during the coating process. The pioglitazone HCl suspension was applied to the seal coated 1000 mg metformin HCl membrane coated tablet cores using a 24” O’Hara Labcoat Π1 pan coater with the nozzle tip set 4 ±2” above the top of the static bed, 3 spray guns with the following conditions:
Spray Rate 20±!0 mL/gun/mir>
Exhaust Température 40-t5°C
Atomizalion Air Fjessure 10-40 psi
Pan Speed 49rpmS^
- -î, ' .
Patlem Air Pressure ] 0-40 psi
Supply Air Flow 30Ot 100 CFM
Once the pioglitazone tablets were dried, the exhaust air was tumed off and the pan speed was adjusted to about 3-4 rpms and 0.Q04 kg of Candellia wax powder that had been passed through a 60 mesh screen was sprinkled onto the tablets. After the tablets hâve rolled in the wax for about 5 minutes the exhaust air was tumed on and the tablets wcre rolled for an additional 10 minutes.
The fïnished polished tablet released greater than 95% of the pioglitazone when tested in a USP apparatus type 1 al 100 rpm in a pH 2.0 HCI-0.3M KC1 buffer solution. The final tablets also exhibited a hardness greater than 35 kp and a friability of 0.00%. Tbe final tablet was tested for pioglitazone related compounds by HPLC using a YMC-ODS-AQ, 5pm, 12θΑ, 4.6 x 250 mm column, a 0.1 M ammonium acétate buffer:acetonrtrile:gJacja] acctic acid (25:25:1) mobile phase, a 40pL injection volume^ 0.7 mL/min flow rate, 25°C column température and 269 nm wavelength for the UV dectector. The resnlts of the test are reported in Table 1 below.
The final polished tablet was packaged in a 100 cc HDPE bottle containing one (1) 3g SORB-1T® desiccant canister and subjected to .accelerated stability conditions of 40°C and 75% relative hunridity for fifteen days, 1 month 2 njonths, 3 months and 6 months. After storage, the final polished tablet was tested and found to contain the following pioglitazone related compounds when tested by HPLC using a YMC-ODS-AQ, 5pm, 120Â, 4.6 x 250 mm cohimn, a 0.1 M ammonium acetate buffer:acetonîtrile:glacial acetic acid (25:25:1) mobile phase, a 40pL injection volume, 0.7 mL/min flow rate, 25°C column température and 269 nm wavelength for the UV dectector.
TABLE 1
Name Initial 0.5 M IM 1%) 2M (%) 3M L%) 6M (%)
(%) (%)
RS-1 (LOI 0.01 0.01 N.D. N.D. N.D.
RS-2 0.02 0.03 0.03 0.02 0.03 0.02
RS-3 0.03 0.04 0.03 0.03 0.04 0.04
RS-4 0.03 0.02 0.03 0.03 0.02 0.02
RS-5 0.04 0.04 0.04 0.04 0.03 0 04 “M” = months
EXAMPLE8
A controlled release tablet containing 1000 mg of metformin HCl and 30 mg pioglitazone was prepared as follows:
A. First Active Drug Core
Λ cellulose acetate coated metformin HCl tablet core was prepared according to the procedure described in Example 5.
B. Second Active Drug
An immédiate release amenmt of pioglitazone HCL was applied to the 1000 mg metformin HCl membrane coated tabicts prepared above in step A. The final tablet had the following composition:
Metformin HCl membrane coated tablet 1201.0 mg/tablet
Seal Coat
Opadry Clear (YS-1-7006) 9.00 mg/tablet
Pioglitazone Coating
Pioglitazone HCl 33.06 mg/tablet
Hydroxypropyl Cellulose, NF (HPC-SSL) 9.0 mg/tablet
Lactose Monohydrate, NF 30.0 mg/tablet
(modified spray dried)
Polyethylene Glycol 8000, NF 0.450 mg/tablet
Titanium Dioxide, DSP 0.90 mg/tablet
Color Coating
Hydroxypropyl Cellulose, NF (HPC-SSL) 5.5 mg/tablel
Polyethylene Glycol 8000, NF 1.38 mg/tablet
Titanium Dioxide, USP 0.60 mg/tablet
Polishing Coat
CandeJiJJa Wax Powder 0.40 mg/tablet
-&Γ33
-a
The seal coat was applied to approximately 13.02 kg of the 1000 mg metformin HCl membrane coated tablet préparai in step A described above. The seal coating was prepared by dispersing about 0.098 kg of Opadry Clear (7S-1-7006) in about 1.220 kg of purified water for 30 minutes. The dispersion was then sprayed onto approximately 13.02 kg of the 1000 mg metformin HCl tablet cores using a 24” O’Hara Labcoat III pan coater with the nozzle tip set 4±2” tmm the top of the static bed, 3 spray guns and the following conditions:
Spray Rate
Exhaust Température
Atomization Air Pressure
Pan Speed
Supply Air Flow
Pattern Air Pressure ± 10 mL/gun/ntin
40°C ± 5°C
10-40 psî
4-9 rpm
300±J00 CFM
10-40 psi
The pioglîtazone coating then was applied to the seal coated 1000 mg metformin HCl membrane coated tablets. The pioglîtazone coating was prepared by slowly dispersing about 0.108 kg of hydroxypropyl cellulose (HPC-SLL) in about 8.753 kg of purified water. The HPC-SSL and water was mixed for about 20 minutes, after which 0.358 kg of lactose monohydrate, MF (modifiai spray dried) was added to the HPC-SSL/waler mixture and mixed for about 2 minutes. After the lactose was mixed in, approximately 0.006 kg of polyethylene glycol 8000 NF and 0.011 kg of titanium dioxide, 1JSP weie added to the water, HPC-SSL and lactose mixture and mixed for about 5 minutes. After about 5 minutes of mixing about 0.394 kg pioglitazone hydrochloride was dispersed into the coating solution. This coating solution contained approximately 10% excess material to compensate for material loss during the coating proccss. The pioglitazone suspension was stirred until the suspension was consumed during the coating process. The pioglitazone HCl suspension was applied to the seal coated 1000 mg metformin HCl membrane coated tablet cores using a 24” O’Hara Labtoat 111 pan coater with the nozzle tip set 4 ±2” above the top of the static bed, 3 spray guns, with the following conditions:
Spray Rate 20± 10 mL/gun/min
Exhaust Température 40T5DC
Atomization Air Pressure 10-40 psi
Pan Speed 4-9 rpms fi
Pattern Air Pressure
Supply Air Flow
10-40 psi
300±100 CFM
Once the pioglitazone coating was applied to the seal coated 1000 mg metformin HCl membrane coated tablets, a color or aesthetic coating was applied to the pioglitazone coated tablet The color coating was prepared by dispersing about 0.060 kg of HPC-SSL, NF 0.015 kg of poIyethylene glycol 8000, NF and 0.007 titanium dioxide, USP in 0.810 kg of purified water and mixing the dispersion for about 30 minutes. The color coating was than sprayed onto the pioglitazone HCl coated tablets using a 24” O’Hara Labcoat IJ1 pan coater with the nozzle tip set 4±2” from the top of the static bed, 3 spray gnns and the following conditions:
Spray Rate
Exhaust Température
Atomization Air Pressure
Pan Speed
SuppJy Air Flow
Pattern Air Pressure * lOmL/gun/min 40°C±5°C 10-40 psi
4-9 rpm
300*100 CFM
10-40 psi
The color coating dispersion was continuously stirred until the dispersion was consumed during the coating process.
Once the color coating suspension was consumed, the tablets were dried in the coating pan for about 5 minutes with a pan speed of about 2-8 rpms and an exhaust température of 40 ± 5°C. Once the tablets were dried, the exhaust air is tumed off and the pan speed is adjusted to about 3-4 rpms and 0.004 kg of Candeltia wax powder that had been passed through a 60 mesh screen was sprinkled onto the tablets. After the tablets were rolled in the wax for about 5 minutes the exhaust air was tumed on and the tablets were rolled for an addrtional 10 minutes.
The fïnished polished tablet released greater than 90% of the pioglitazone when tested in a USP apparatus type 1 al 100 rpm in a pH 2.0 HC1-0.3M KC1 buffer solution. The average of the 12 vesscl tested was 96% released. The final tablets also exhibited a hardness greater than 35 kp and a fiiability of 0.1%. The final tablet was tested for pioglitazone related compounds by HPLC using a YMC-ODS-AQ, 5μιη, 120Â, 4.6 x 250 mm column, a 0.1 M ammonium acetate buffer:acetonitrile;glacial acetic acid (25:25:1) mobile phase, a 40pL injection volume, 0.7 mlAnin flow rate,
V, '·· ;
25°C column température and 269 nm wavelength for the UV dectector. The results of the test are reported in Table 2 below.
The final polîshed tablet was packaged in a 100 ce HDPE bottle containing one (1) 3g SORB-1T® desiccant canister and subjected to accelerated stability conditions of 4O°C and 75% relative humidity for fifteen days, 1 month, 2 months, 3 months and 6 months. After storage, the final polîshed tabler was tested and found to contain the following pioglitazone related compounds when tested by HPLC using a YMC-ODS-AQ, 5μπι, 120Â, 4.6 x 250 mm column, a 0.1 M ammonium acetate bufïer:acetoniÎrile:glacial acetic acid (25:25:1) mobile phase, a 40pL injection volume, 0.7 mL/min flow rate, 25°C column température and 269 nm wavelength for the UV dcctector.
TABLE 2
Initial 0.5 M IM 2M 3M 6M
Naine (%) (%) (%) (%) (%) (%)
RS-1 0.01 0.01 0.01 N.D. N.D. N.D.
RS-2 0.02 0.03 0.03 0.02 0.03 0.03
RS-3 0.03 0.03 0.03 0.03 0.04 0.04
RS-4 0.02 0.02 0.03 0.02 0.02 0.01
R.S-5 0.04 0.04 0.03 0.04 0Ό4 0.04
EXAMPLE 9
A controlled release tablet containing 1000 mg of metformin HCl and 15 mg pioglitazone is prepared as follows:
1. First Active Drug
A 1000 mg membrane coated tablet is prepared as described in Example 5 above. The J 000 mg membrane coated tablet has the following composition: CORE
Metformin HCl 1000 mg/tablet
Povidone K-90, USP Sodium Lauryl Sulfate. NF 78.0 mg/tablet 51.69 mg/tablely^
Magnésium Stéarate, NF 5.65 mg/tablet
SEAL COATING
Opadry Clear (YS-1-7006) 47.05 mg/tablet
MEMBRANE COATING
Cellulose Acetate, 398-10, NF 15.77 mg/tablet
Triacetin, USP 0.92 mg/tablet
Polyethylene Glycol 400, NF 1.85 mg/tablet
Total weight 1201.0 mg/tablet
II. Second Active Drug
An immédiate relcase amount of pioglitazone HCl was applied to the 1000 mg metfonnin HCl membrane coated tablets prepared in step ï. The final tablet had the following composition:
Metfonnin HCl membrane coated tablet Seal Coat
Opadry Clear (YS-1-7006)
Pioglitazone Coating
Pioglitazone HCl
Sodium Chloridc
Opadry Oear (YS-I-7006)
Color Coating
Opadry 11 White (Y-22-7719)
Polishing Coat
Candelilla Wax Powder
1201.0 mg/tablet
21.0 mg/tablet
J 6.53 mg/tablet
2.5 mg/tablet ΐ .850 mg/tablet
21.54 mg/tablet
0.40 mg/tablet
The seal coat was applied to the 1000 mg metformin HCl membrane coated tablet. The seal coating was prepared by dispersing 0.249 kg of Opadry Clcar in 4.981 kg of alcohol USP and mixing the dispersion for 15 minutes. The dispersion was then sprayed onto approximately 14.24 kg of the 1000 mg metfonnin HCl tablet cores using a 24” O’Hara Labcoat 111 pan coater with the nozzle tjp set 4±2” from the top of the static bed, 3 spray guns and the following conditions:
Spray Rate
Exhaust Température
Atomization Air Pressure ± 10 mL/gun/min
25°C ± 5°C
Pan Speed
Supply Ak Flow
Pattern Air Pressure
4-9 rpm 3OO±Î5OCFM
10-40 psi
The seal coating dispersion was continuously stirred until it was consumed during the coating process.
The pioglitazone coating was appjied to the seal coated 1000 mg metformin HCl membrane coated tablets. The pioglitazone coating was prepared by mixing 3.793 kg of alcohol USP and 1.07 kg of purifîed water and slowly dispersing 0.024 kg of Opadry Clear into the solvent mixture. Once the Opadry Clear was dispersed, it was homogenized for about 10 minutes. Once the Opadry Clear dispersion was homogenized, 0.032 kg of sodium cbloride was added to the dispersion and homogenized for about 2 minutes. After the sodium chloride was homogenized, 0.212 kg of pioglitazone HCl was slowly dispersed into the solvent mix and then homogenized for about 10 minutes. Once the pioglitazone HCl was homogenized, the homogenizer was removed from the mixing vessel and replaced with an air mixer and mixed for an additional J 5 minutes. The pioglitazone suspension was stirred until the suspension was consumed during the coating process. This coating solution contained approximately 8% excess material to compcnsate for materiel loss during the coating process. The pioglitazone HCl suspension was applied to the seal coated 1000 mg metformin HCI membrane coated tablet cores usïng a 24” O’Hara Labcoat ΠΙ pan coatcr with the nozzJe tip set 4 ±2” above the top of the statjc bed, 3 spray guns and the following conditions:
Spray Rate
Exhanst Température
Atomization Air Pressure
Pan Speed
Pattern Air Pressure
Supply Air Flow
25±10 mL/gun/mîn
25±5°C
10-40 psi
4-9 rpms
10-40 psi
300±150 CFM
Once the pioglitazone coating was applied to the seal coated 1000 mg metformin HCl membrane coated tablets, a color or aesthetic coating of Opadry 11
White was applied to the pioglitazone coated tablet. Tne aesthetic coating was prepared by dispersing 0.255 kg of Opadry II White (Y-22-7719) in 5.109 kg of alcohol U SP and mixing the dispersion for about ] hour. The Opadry II Whîte dispersion was sprayed onto the pioglîtazone HCl coated tablets usïng a 24” O’Hara Labcoat III pan coater with the nozzle fip set 4±2” from the ιορ of the static bed, 3 spray guns and the following conditions:
Spray Rate
Exhaust Température
Alomization Air Pressure ± 10 mL/gun/min
Pan Speed
Supply Air Flow
Pattern Air Pressure
10-40 psi
4-9 rpm
3OO-H5O CFM
10-40 psi
The color coating dispersion was continnously stirred until the dispersion was consumed during the coating process.
Once the aesthetic coating suspension was consumed, the tablets was dried in the coating pan for about 5 minutes with a pan speed of about 2-8 rpms and an exhaust température of 25 ± 5°C. Once the tablets were dried, the exhaust air was' tumed off and the pan speed was adjusted to about 3-4 rpms and 0.004 kg of Candellia wax powder that had been passed through a 60 mesh screeji was sprinkled onto the tablets. Afler the tablets hâve rolled in the wax for about 5 minutes the exhaust air was tumed on and the tablets are rolled for an additional 10 minutés.
The finished polished tablet released an average of 95% of the pioglitazone when tested in a USP apparatus type 1 al 100 rpm in a pH 2.0 HC1-0.3M KC1 buffer solution The final tablets also exhibited a hardness greater than 35 kp and a friability of 0.00%. The final tablet was tested for pioglitazone related compounds by HPLC using a YMC-ODS-AQ, 5pm, 120Â, 4.6 x 250 mm column, a 0.1 M ammonium acetate buffenacetonitrileiglacial acetic acid (25:25:1) mobile phase, a 40pL injection volume, 0.7 mL/min flow rate, 25®C column température and 269 nm wavelengtli for the UV dectector. The resuits of the test are reported in Table 3 below.
The final polislied tablet was packaged in a 100 cc HDPF. bottle containing one (1) 2g SORB-IT® desiccant canister and subjected to accelerated stability conditions of 40°C and 75% relative humidity for one month. After storage, the final polished tablet was teiîted and found to contain the following pioglitazone related compounds when tested by HPLC using a YMC-ODS-AQ, 5μπι, 12θΑ, 4.6 x 250 mm column, a 0.1 M ammonium acetate birffer aceîonitriJe pJ^cial acetic acid (25:25:1) h k
mobile phase, a 40pL injection volume, 0.7 mL/min flow rate, 25°C column température and 269 nm wavelergth for the UV dectector.
TABLE3
Marne Relative Rétention Tinte Initial Amount (%) 1 morrth Amount(%)
RS-1 0.7 ND ND
Pioglitazone 1.0
RS-2 1.5 0:02 0.02
RS-3 3.4 0.03 0.05
RS-4 1.2 0.03 0.02
RS-5 2.8 0.05 0.04
EXAMPLE 10
A controlled release tablet contaîning 1000 mg of metformin HCl and 15 mg pioglitazone -was prepared as follows:
A. First Active Drug Core
A cellulose acctate coated metformin HCL tablet is prepared as described in Example 5.
B. Second Active Drug
An immédiate release amount of pioglitazone HCL was applied to the 1000 mg metformin HCl membrane coated tablets prepared above in step A. The final tablet has the following composition:
Metformin HCl membrane coated tablet
Seal Coat
Opadry Clear (YS-1-7006)
Pioglitazone Coating
Pioglitazone HCl
1201.0 mg/tablet
9.00 mg/tablel
16.53 mg/tablet
Hydroxypropyl Cellulose, NF (HPC-SSL) 4.5 mg/tablet
4*·
Lactose Monohydrate, NF (modifïed spray dried) Polyethylene Glycol 8000, NF Titanium Dioxide, USP
Color Coating
15.0 mg/tablet
0.225 mg/tablet
0.450 mg/tablet
Hydroxypropyl Cellulose, NF (ÎIPC-SSL) 5.5 mg/tablet
Polyethylene Glycol 8000, NF ï .375 mg/tablet
Titanium Dioxîde, USP 0.60 mg/tablet
Polishing Coat
Candelilla Wax Powdcr
0.40 mg/tablet
The seal coat was applied to approximately 14.36 kg of the 1000 mg metformin HCl membrane coated tablet prepared in step A described above. The seal coating was prepared by dispersing about 0.108 kg ôf Opadry Clear (YS-l-7006) in 15 about l .345 kg of purified water for 30 minutes. The dispersion was then sprayed onto approximately 14.36 kg of the 1000 mg metformin HCl tablet cores using a 24” O’Hara Labcoat ΙΠ pan coater with the nozzle tip set 4±2” from the top of the static bed, 3 spray guns and the following conditions:
Spray Raie
Exhaust T emperature
Alomization Air Pressure
Pan Speed
Supply Ait Flow
Pattern Air Pressure ± 10 mL/gun/min
40°Ο±5°Ο
10-40 psi
4-9 rpm
3001:100 CFM
10-40 psi
The pioglitazone coating was applied to the seal coated 1000 mg metformin HCl membrane coated tablets. The pioglitazone côating was prepared by slowly dispersing about 0.059 kg of hydroxypropyl cellulose (HPC-SL1,) in about 6.034 kg of purified water. The HPC-SSL and water was mixed for about 20 minutes, then 30 0.197 kg of lactose monohydrate, NF (modified spray dried) was added to the HPCSSL/water mixture and mixed for about 2 minutes. After the lactose was mixed in. approximately 0.003 kg of polyethylene glycol 8000 NF and 0.006 kg of litanium dioxîde, USP were added to the water, HPC-SSL, NF and lactose mixture and mixed for about 5 minutes. After about 5 minutes ofmixing about 0.217 kg pioglitazone hydrochloride was dispersed into the coating solution. This coatîng solution contained approximately 10% excess material to compensate for material loss during the coating process. The pioglitazone suspension was stirred untii the suspension was consumed during the coating process. The pioglitazone HCl suspension was applied to the seal coated 1000 mg metfomnin HCl membrane coated tablet cores using a 24” OTlara Labcoat 111 pan coater with the nozzle tip set 4 ±2 above the top of the static bed, 3 spray guns, with the following conditions:
Spray Rate
Exhaust Température
Atomization Air Pressure
Pan Speed
Pattern Air Pressure
Supply Air Flow
Oil 0 mI2gun/inin
40±5“C
10-40 psi
4-9 rpms
10-40 psî
300*100 CFM
Once the pioglitazone coating was applied to the seal coated 1000 mg metformin HCl membrane coated tablets, a color or aesthetic coating was applied to the pioglitazone coated tablet. The color coating was prepared by dispersing about 0.066 kg of HPC-SSL, 0.016 kg of polyethylene glycol 8000, NF and 0.007 titanium dioxide, USP in 0.894 kg of purified water and mixing the dispersion for about 30 minutes. The color coating was sprayed onto the pioglitazone HCl coated tablets using a 24” O’Hara Labcoat 111 pan conter with the nozzle tip set 4±2” from the top of the static bed, 3 spray guns and the following conditions:
Spray Rate
Exhaust Température
Atomization Air Pressure
Pan Speed
Supply Air Flow
Pattern Air Pressure
20* 10 mL/gun/min
4O°C±5°C
10-40 psi
4-9 rpm
300*100 CFM
10-40 psi
The color coaling dispersion was continuously stirred unlil the dispersion was consumed during the coaling process.
Once the color coating suspension was consumed, the tablets were dried in the coating pan for about 5 minutes with a pan speed of about 2-8 rpms and an exhaust température of 40 * 5°C. Once the tablets were dried.. the exhaust air was tumed off
and the pan speed was adjusled to about 3-4 ipms and 0.005 kg of Candellia wax powder lhat had been passed Ihrough a 60 mesh screen was sprinkled onto the tablets. After the tablets were rolled in the wax ίοτ about 5 minutes the exhaust air was tumed on and the tablets were rolled for an addiiiona] 10 minutes.
I
The finished polished table! released greater than 95% of the pioglitazone when tested in a USP apparatus type 1 at 100 rpm in a pH 2.0 HC1-0.3M KC1 buffer solution. The final tablets also exhibited a hardness greater than 35 kp and a fri ability of 0.0%. The final tablet was tested for pioglitazone related compounds by HPLC using a ;YMC-ODS-AQ, 5pm, 120Â, 4.6 x 250 mm column, a 0.1 M ammonium acetate bufïenacetonitrile.glacial acctic acid (25:25.1) mobile phase, a 40pL injection volume, 0.7 mL/min flow rate, 25°C column température and 269 nm wavelength for the UV dectector. The results of the test are reported in Table 4 below.
The final polished tablet was packaged in a 100 cc HDPE bottle containing one (1) 3 g SORB-1T® dcsiccant carrister and subjected to accclerated stability conditions of 40°C and 75% relative humidity for fifteen days, 1 rnonth, 2 months and 3 months. After storage, the final polished tablet was tested and found to contain the following pioglitazone related compounds when tested by HPLC using a YMC-ODSAQ, 5pm, 120 A, 4.6 x 250 mm column, a 0.1 M ammonium acetate buft’er:acetonitrile:glaciai acetic acid (25:25:1) mobile phase, a 40pL injection volume, 0.7 mL/min flow rate, 25°C column température and 269 nm wavelength for the UV dectector.
TABLE 4
Name Initial 0.5 Μ IM 2M (%) 3M (%)
(%) (%) (%)
RS-Ï N.D. 0.01 N.D. N.D. N.D.
RS-2 0.02 0.03 0.03 0.03 0.02
RS-3 0.03 0.04 0.04 0.04 0.03
RS-4 0.03 0.02 0.02 0.02 0.02
RS-5 0.03 0.04 0.05 0.04 0.04
EXAMPLE 11
A controiled release tablet containing 500 mg of metTonnm HCl and 15 mg pioglitazone was prepared as follows:
A. First Active Drog Core
I. Metformin Granules
Metformin HCl (% composition)
92.76%
Povidone K-90, USP 7.24%
About 139.14 kg of metformin HCl was deluroped by passing it through a comil equipped with a number 813 screen aod no spaœr at 840-850 rpm and collecting it in a clean, polyethylene-lined container. About 10.86 kg of povidone, K30 was dissolved in about 206.34 kg of purifîed water. The delumped metformin HCl was then added to a top-spray fluidized bed granulator (Glatt Brand GPCG-60) and granulated by spraying the binding solution of povidone and water under the following conditions: product température of about 38-43°C, in Jet air température of 60-95°C; atomization air pressure of 2.5-3 bars and spray rate of 500 g/min (491-515 g/min) for first 15 minutes, 700 g/min (680-710 g/min) for ] 5-30 minutes, 900 g/min (860-910 g/min) for 30-45 minutes, 1100 g/min (1090-1170 g/min) for 45-60 minutes and about 1200 g/min (1170-1220 g/min) for the remainder of the spray time. Afler the binding solution has been sprayed, the granules were dried in the fluidized bed until the loss on drying (LOD) was less than 2%.
’ Once the granules were dried, they are passed through a Comil equipped with a number 1143 stainless steel screen and a #075 spacer a( a speed of ï 086-1088 rpms.
The above process was repeated a second time to produce a lotal of about 300 kg of metformin granules.
II. Metformin Blend
Metformin HCI Granules
Sodium Lauryl Sulfate, NF
Magnésium Stéarate, NF (% composition)
94.95%
4.55%
0.50%
The about 300 kg of metformin granules prepared above in step 1 were added to a 50 eu. fl. slanl cône blender along with about 14.38 kg of sodium lauryl sulfate, , -n
NF and blended for about 20 minutes. About ] .58 kg of magnésium stéarate, NF was then passed through a 40 mesh stainless steel sieve and added to the slant cône blender and blended for an additional five minutes.
The blend was compressed into metformin uncoated cores using a rotary press fitted with 15/32” round compound cup, pre-compression force of 14 kp and main compression force of 34 kp. The resulting tablets has a weight between 523-613 g with a target weight of 568 g, hardness between 14-26 kp (target of 20 kp) and a friability of lessthan or equal to 0.8%.
III. Metformin Seal Coated Tablets (% composition)
Metformin HCl Uncoated Tablets 96.02%
OPADRY Clear (YS-1-7006) 3.98%
Approximately 57.61 kg of the uncoated tablets prepared in step II above were seal coated by applying a solution of about 2.388 kg of OPADRY Clear (YS-1-7006) and 21.50 kg of purified water onto the tablets using a pan coater. The pan coater was a 36 inch O’Hara Labcoat 111 with three (3) spray guns at a distance of 8-11 inches from the bed. The coating conditions were:
Exhaust Température: 40-4 rc
Atomizat ion Pressure Air Volume 50±10 psi 10001200 CFM
Spray Rate Pan Speed 180±60 g/inin (60±20iul/gun/iiiin) 4-8 rpm.
IV Membrane
Metformin Seal Coated Tablets
Cellulose Acetate (398-10)2
Triacetîn
PEG 400 (% composition)
95.521%
3.807%
0.145%
0289% 2 acetyl content 39.3-40.3% (a) Membrane Coating Process
Approximately 51.06 kg of acetone is added to a stainless steel tank followed by about 2.281 kg of cellulose acetate and mixed for about 20 minutes until the solution becomes clear. Once the solution is clear about 0.269 kg of polyethylene glycol 400 is added to the solution and mixed for about 5 minutes followed by the addition of about 0.135 kg of trîacetin. The solution is mixed for an additional 5 minutes.
About 59.07 kg of the seal coated metformin HCl tablets are loaded into a GPCG-60 (Giatt) brand fluidized bed coater with Wurster insert (size 18” by 45 mm high) with a nozzle of size 1.5 mm. The seal coated metformin HCl tablets areis fluidized and the product température is adjusted to about 21±3°C. The cellulose acetate solution is sprayed onto the fluidized seal coated metformin HCl tablets with an atomization pressure of about 2.0-3.0 bars, air volume of J 400 ± 300 CFM and a spray rate of 400*100 g/min until a weïght gain of 3-5% (target 3.8%) is obtained. Once the dcsired amount of membrane coating bas been applied the membrane coated tablets are dried in the fluidized bed 21±3°C and 1200*100 CFM for about 10 minutes followed by 40°C and 1200*100 CFM for about 5 minutes.
The resulting membrane coated tablets are laser drilled to create an orifice in the approximate center of each side of the membrane coaied tablet (i.e 2 orifices) with an average diameter of 0.5 mm per orifice. The top micrometer is 5.4 ± 2 mm, bottom micrometer is 6.75 ±2 mm, the puise width ôf the laser is 170*70 and puise delay of290 ±150.
B. Second Active Drug
An immédiate release amount of pioglitazone HCL was applied to the 500 mg metformin HCl membrane coated tablets prepared in step A. The final tablet had the following composition:
Metformin HCI membrane coated tablet
618.9 mg/tablet
Seal Coat
Opadry Clear (VS-1-7006)
11.5 mg/tablet
Pioglitazone Coating
Pioglitazone HCI
Sodium Chloride
Opadry Clear (VS-1-7006)
Color Coating
16.53 mg/tablet
2.5 mg/tablet
1.850 mg/tablet
ΛΌ 2tKK>/i
Opadry Π White (Y-22-7719)
Polishing Coat
Candelilla Wax Powder
10.77 mg/tablet
0.20 mg/tablet
The seal coat was applied to the 500 mg metformin HCl membrane coated tablet. The seal coating was prepared by dispersing 0.243 kg of Opadry Clear in
3.473 kg of aicohol USP and mixing the dispersion for 15 minutes. The dispersion was then sprayed onto approximately 13.08 kg of the 1000 mg metformin HCl tablet cores using a 24” O’Hara Labcoat 1Π pan coater with the nozzle tip set 4±2” from the top of the static bed, 3 spray guns and tbe following conditions:
Spray Rate
Exhaust Température
Atomization Air Pressure
Pan Speed ! 5 Supply Air FIow
Pattern Air Pressure ± 10 mL/gun/min
25ÜC + 5°C
10-40 psi
4-9 rpm
2004:100 CFM
10-40 psi
The seal coating dispersion was continuously stirred until it was consumed during the coating process.
The pioglitazone coating then was applied to the seal coated 500 mg metfonnin HCl membrane coated tablets. The pioglitazone coating was prepared by mixing 5.656 kg of alcohol DSP and 1.595 kg of purified wntcr and slowly dispersing 0.045 kg of Opadry Clear irrto tbe solvent mixture. Once the Opadry Clear was dfcpersed, il was homogenized for aboui 10 minutes. Once the Opadry Clear dispersion was homogenized, 0.061 kg of sodium chJoride was added to the dispersion and homogenized for about 2 minutes. After the sodium chloride is homogenized, 0.402 kg of pioglitazone HCl was slowly disperser! into the solvent mix and then homogenized for about 10 minutes. Once the pioglitazone HCl was homogenized, the homogenizer was removed frorn the mixing vessel and replaced
I with an air mixer and mîxed for an additional 15 minutes. The pioglitazone suspension was stirred until the suspension is consumed during the coating process. This coating solution contained approximately 15% excess material to compensate for material loss during the coating process. Tbe pioglitazone HCl suspension was applied to the seal coated 500 mg metformin HCl membrane coated tablet cores using 'Y** -’Ι’ίι/Μ a 24” O’Hara Labcoat Πl pan coater with the nozzie tip set 4 ±2” above the top of the static bed with 3 spray guns and the following conditions:
Spray Rate
Exhaust Température
Atomization Air Pressure
Pan Speed
Pattern Air Pressure
Supply Air Flow
25i 10 mL/gun/min 25±5°C
10-40 psi
4-9 rpms
10-40 psi
200±100CFM 1
Once the pioglitazone coating was applied to the seal coated 500 mg metformin HCl membrane coated tablets, a color or aesthetic coating of Opadry 11 White was applied to the pioglitazone coated tablet. The aesthetic coating was prepared by dispersing 0.228 kg of Opadry II White (Y-22-7719) in 3.253 kg of alcohol USP and mixing the dispersion for about 1 hour. The Opadry II While dispersion was than sprayed onto the pioglitazone HCI coated tablets using a 24”
O’Hara Labcoat Π1 pan coater with the nozzie tip set 4±2” from the top of the static bed, 3 spray guns and the following conditions:
Spray Rate
Exhaust Température
Atomization Air Pressure
Pan Speed
Snpply Air Flow ± 10 mL/gun/min 25OC±5OC
10-40 psi
4-9 rpm 200±100CFM
Pattern Air Pressure
10-40 psi
The color coating dispersion was continuously stirred until the dispersion was consumed during the coating process.
Once the aesthetic coating suspension was consumed, the tablets were dried in the coating pan for about 5 minutes with a pan speed of about 2-8 rpms and an exhaust température of 25 ± 5°C. Once the tablets were dried, the exhaust air was 30 tumed off and the pan speed was adjusted to about 3-4 rpms and 0.004 kg of Candellia wax powder that had been passed through a 60 mesh screen was sprinkled onto the tablets. A fier the tablets rolJed in the wax for about 5 minutes the exhaust air was tumed on and the tablets were rolied for an additional 10 minutes.
The finished polished tabiet released grealer than of 95% of the pioglitazone when tested in a USP apparatus type I at 100 ipm in a pH 2.0 HC1-0.3M KCl buffer solution The final tablets also exhibited a hardness greater than 35 kp and a friability of 0.00% The final tabiet was tested for pioglitazone related compounds by HPLC using a YMC-ODS-AQ, 5pm, 120Â, 4.6 x 250 mm column, a 0.1 M ammonium acetate buffer:acetonitrile:glaciai acctîc acid (25:25:1) mobile phase, a 40pL injection volume, 0.7 mL/min flow rate, 25°C column température and 269 nm wavelength for the UV dectector. The résulte of the test are rcported in Table 5 below.
The final polished tabiet was packaged in a 100 cc HDPE bottle containing one (1) lg SORB-ΓΓ® desiccant canister and subjected to accelerated stability conditions of 40°C and 75% relative humidity for one month. After storage, the final polished tabiet was tested and found to contain the following pioglitazone related compounds when tested by HPLC using a YMC-ODS-AQ, 5pm, 120À, 4.6 x 250 mm column, a 0.1 M ammonium acetate buffer.acetonitFiJe:g)acial acetic acid (25:25:1) mobile phase, a 40pL injection volume, 0.7 mL/min flow rate, 25°C column température and 269 nm wavelength for the UV dectector.
TABLE 5
Name Initial (%) 1 M (%)
RS-1 N.D. N.D.
RS-2 0.03 0.03
RS-3 0.04 0.05
RS-4 0.03 0.02
RS-5 0.04 0.04
EXAMPLE 12
A controlled release tabiet containing 500 mg of metformin HCl and 15 mg pioglitazone was prepared as follows:
A. First Active Drug Core
The 500 mg cellulose acetate metformin HCl core was prepared as described in Exemple 11.
B. Second Active Drug
An immédiate release amount of pioglitazone HCL was applied to the 500 mg metfoimin HCl membrane coated tablets prepared above in step A. The final tablet had the following composition:
Metformin HCl membrane ccated tablet 1 613,9 mg/tablet
Seal Coat i
' Opadry Clear (YS-1-7006) 4.50 mg/tablet
Pioglitazone Coating
Pioglitazone HCl 16.53 mg/tablet
Hydroxypropyl Cellulose (HPC-SSL) 6.0 mg/tablet
Lactose Monohydiate, NF 50.0 mg/tablet
(modified spray dried)
Polyethylene Glyco) 8000, NF 0.300 mg/tablet
Titanium Dioxide, USP 0.600 mg/tablet
Color Coating
Hydroxypropyl Cellulose (HPC-SSL) 2.75 mg/tablet
Polyethylene Glycol 8000, NF 0.688 mg/tablet
Titanium Dioxide, USP 0.300 mg/tablet
Polishing Coat
Candelîlla Wax Powder 0.20 mg/tablet
The seal coat was applied to approximately 12.36 kg of the 500 mg metformin HCl membrane coated tablet prepared in step A described above. The seal coating was prepared by dispersing about 0.090 kg of Opadry Clear (YS-1-7006) in about 1.124 kg of purified water for 30 minutes. Tbe dispersion was ihen sprayed onto approximately 12.36 kg of the 500 mg metformin HCl tablet cores using a 24” O’Hara Labcoat 111 pan coaler with the nozzle tip set 4±2” from the top of the static bed, 3 spray guns and the following conditions:
Spray Rate 20 ± 10 mL/gun/min
Exhaust Température 40°C ± 5°C
Atomization Air Pressure 10-40 psi
Pan Speed
Supply Air Flow
Pattern Air Pressure
4-9 rpm
300*100 CFM
10-40 psi
The pioglitazone coating then was applied to the seal coated 500 mg τηείΓοππιη HCl membrane coated tablets. The pioglitazone coating was prepared by slowly dispersing about 0.134 kg of hydroxypropyl cellulose (HPC-SLL) in about 13.692 kg of purifîed water. The HPC-SSL and water was mîxed for about 20 minutes, then 1.119 kg of lactose monohydrate, NF (modified spray dried) was added to the HPC-SSL/water mixture and mixed for about 2 minutes. After the lactose was mixed in, approximately 0.007 kg of polyethylene glycol 8000 NF and 0.013 kg of titanium dioxide, U SP were added to the water, HPC-SSL and lactose mixture and mixed for about 5 minutes. After about 5 minutes of mixing about 0.370 kg pioglitazone hydrochloride was dispersed into the coating solution. This coating solution contained approximately 12% excess matériel to compensate for matériel loss during the coating ptrocess. The pioglitazone suspension was stirred until the suspension is consumed during the coating process. The pioglitazone HCl suspension was applied to the seal coated 500 mg metformin HCl membrane coated tablet cores using a 24” O’Hara Labcoat Π1 pan coater with the noz21e tip set 4 ±2” above the top of the static bed, 3 spray guns, with the following conditions.
Spray Rate
Exhaust Température
Atomization Air Pressure
Pan Speed
Pattern Air Pressure
Supply Air Flow
20±10mL/gun/min 40±5°C 10-40 psi 4-9rpms
10-40 psi 300MOOCFM
Once the pioglitazone coating was applied to the seal coated 500 mg metfonnin HCl membrane coated tablels. a colcr or aesthetic coating was applied to the pioglitazone coated tablet. The color coating was prepared by dispersing about 0.055 kg of HPC-SSL, NF 0.014 kg of polyethylene glycol 8000, NF and 0.006 titanium dioxide, USP in 0.747 kg of purified water and mixing the dispersion for about 30 minutes. The color coating was than sprayed onto the pioglitazone HCI coated tablets using a 24” O’Hara Labcoat III pan coater with the nozzle tip set 4±2” from the top of the static bed, 3 spray guns and the following conditions:
Spray Rate
Exhaust Température
Atomization Air Pressure
Pan Speed
Supply Air Flow
Pattern Air Pressure + 10 mL/gun/min
40°C+5nC
10-40 psi
300*100 CFM
10-40 psi
The color coating dispersion was contirruously stirred until the dispersion was consumed during the coating process.
Once the color coating suspension was consumed, the tablets were dried in the coating pan for about 5 minutes with a pan speed of about 2-8 rpms and an exhaust température of 40 ± 5°C. Once the tablets were dried, the exhaust air was turncd off and the pan speed was adjusted to about 3-4 rpms and 0.004 kg of Candellia wax powder that had been passed through a 60 mesh screen was sprinkled onto the tablets. After the tablets rolled in the wax for about 5 minutés the exhaust air was tumed on and the tablets were rolled far an additional 10 minutes.
The finished polished tablet rekased grealer than 95% of the pioglitazone when tested in a USP apparatus type 1 at 100 rpm in a pH 2.0 HC1-0.3M KC1 buffer solution. The final tablets also exhibited a hardness grealer than 35 kp and a friability of 0.01%. The final tablet was tested for pioglitazone related compounds by HPLC using a YMC-ODS-AQ, 5pm, 120Â, 4.6 x 250 nnn column, a 0.1 M ammonium acetate buffer:acetonitrile:glacial acetic acid (25:25:1) mobile phase, a 40pL injection volume, 0.7 mL/min flow rate, 25*C column température and 269 nm wavelength for the UV decteclor. The results of Oie test are rcported in Table 6 below.
The final polished tablet was packaged in a 100 cc HDPE bottle containing one (1) 3g SORB-ÏT® desiccant canister and subjected to accelerated slability conditions of 40°C and 75% relative humidity for 1 month and 2 months. After storage. the final polished lablet was tested and found to contain the following pioglitazone related compounds when tested by HPLC using a YMC-ODS-AQ, 5pm. 120A, 4.6 x 250 mm column, a 0.1 M ammonium acetate bufferacetonitrile:glacial acetic acid (25:25:1) mobile phase, a 40pL injection volume, 0.7 mL/min flow rate. 25°C column température and 269 nm wavelength for the UV dectector.
TABLE 6
Naine Initial IM 2M (%)
(%) (%)
RS-1 N.D. N.D. ND.
RS-2 0.02 0.02 0.02
RS-3 0.03 0.03 0.04
RS-4 - 0.03 0.02 0.02
RS-5 0.04 0.03 0.04
While certain prefcrred and alternative embodiments of the invention hâve been set forth for purposes of disclosing the invention, modifications to the disclosed embodiments may occur to those who are skjlJed in the art. Accordïngly, the appended claims are intended to cover ail embodiments of the invention and 15 modifications thereof which do not départ from the spirit and scope of the invention.

Claims (46)

1. A pharmaceutical dosage fonn having a firsi and second active drug, said dosage form comprising:
(a) a controlled release core comprising an antihyperglycemic drug and at least one pharmaceutically acceptable excipient; and (b) an immédiate release thiazolidinedione dérivative containing component that comprises a thiazolidinedone dérivative and a low viscosity water soluble binder;
wherein not less than 85%, of the thiazolidinedione is reieased from the dosage form within 45 minutes when tested according to the United States Pharmacopeia (USP) 26, with Apparatus l at 100 rpm, 37 °C and 900 ml of 0.3 M KCl-HCl Buffer, pH 2.0.
2. The pharmaceutical dosage form as defined in claim l wherein not less than 90%, of the thiazolidinedione is reieased from the dosage form within 45 minutes when tested according to the United States Pharmacopeia (USP) 26, with Apparatus I at 100 rpm, 37 °C and 900 ml of 0.3 M KCl-HCl Buffer, pH 2.0.
3. The pharmaceutical dosage iorm as defined in claim 1 wherein not less than 95%, of the thiazolidinedione is reieased from the dosage form within 45 minutes when tested according to the United States Pharmacopeia (USP) 26, with Apparatus 1 at 100 rpm, 37 °C and 900 ml of 0.3 M KCl-HCl Buffer, pH 2.0.
4. The pharmaceutical dosage form as defined in claim I wherein not less than 100%, of the thiazolidinedione is reieased from the dosage form within 45 minutes when tested according to the United States Pharmacopeia (USP) 26, with Apparatus 1 at 100 rpm, 37 °C and 900 ml of 03 M KCI-HCI Buffer, pH 2.0.
5. The pharmaceutical dosage form as defined in claim 1 wherein not less than 85%, of the thmolidinedione is reieased from the dosage form within 40 minutes when tested according to the United States Pharmacopeia (USP) 26, with Apparatus 1 at 100 rpm, 37 °C and 900 ml of 0.3 M KCl-HCl Buffer, pH 2.0.
6. The pharmaceutical dosage form as defined in claim 1 wherein not less than 90%, of the thiazolidinedione is reieased from the dosage fonn within 40 minutes when tested according to the United States Pharmacopeia (USP) 26, with Apparatus 1 at 100 ipm, 37 °C and 900 ml of 0.3 M KC1-HC1 Butter, pH 2.0.
7. The pharmaceutical dosage fonn as defined in daim ! wherein not less than 95%, of the thiazolidinedione is released from the dosage form wîthin 40 minutes when tested according to the United States Pharmacopeia (USP) 26, with Apparatus 1 at 100 rpm, 37 °C and 900 ml of 0.3 M KC1-HC1 Butter, pH 2.0.
8. The pharmaceutical dosage form as defined in daim 1 wherein not less than 100%, of the thiazolidinedione is released from the dosage form wîthin 40 minutes when tested according to the United States Pharmacopeia (USP) 26, with Apparatus 1 al 100 rpm, 37 °C and 900 ml of 0.3 M KC1-HC1 Butter, pH 2.0.
9. The pharmaceutical dosage form as defined in daim 1 wherein not less than 85%, of the thiazolidinedione is released from the dosage form wîthin 30 minutes when tested according to the United States Pharmacopeia (USP) 26, with Apparatus 1 at 100 rpm, 37 °C and 900 ml of 0.3 M KCI-HC1 Butter, pH 2.0.
10. The pharmaceutical dosage form as defined in daim 1 wherein not less than 90%, of the thiazolidinedione is released from the dosage form wîthin 30 minutes when tested according to the United States Pharmacopeia (USP) 26, with Apparatus 1 at 100 rpm, 37 °C and 900 ml of 0.3 M KC1-HC1 Butter, pH 2.0.
11. The pharmaceutical dosage form as defined in daim 1 wherein not less than 95%, of the thiazolidinedione is released from the dosage form within 30 minutes when tested according to the Uniled States Pharmacopeia (USP) 26, with Apparatus 1 at 100 rpm, 37 CC and 900 ml of 0.3 M KC1-HC1 Butter, pH 2.0.
12. The pharmaceutical dosage fonn as defined in claim 1 wherein not less than 100%. of the thiazolidinedione is released from the dosage form within 30 minutes when tested according lo the United States Pharmacopeia (USP) 26, with Apparatus 1 at 100 rpm, 37 °C and 900 ml of 0.3 M KC1-HC1 Butter, pH
13. A pharmaceutical dosage fonn having a first and second active drug, said dosage fonn comprising:
(a) a controlled release core comprising an antihyperglycemic drug and at least one pharmaceutically acceptable excipient; and (b) an immédiate release thiazolîdinedione dérivative containing component tbat comprises a thiazcdidinedone dérivative and a low viscosity water soluble binder; wherein the total thiazolîdinedione related compounds or impurities in the final dosage fonn are not more than 0.6 as determined by high performance liquid chromatography.
14. The pharmaceutical dosage fonn aS defîned in claim 13 wberein Ibe total thiazolîdinedione related compounds are not more than 0.5%.
15. The pharmaceutical dosage fonn as defîned in claim 13 wherein the total thiazolîdinedione related compounds are not more than 0.5%. .
16. The pharmaceutical dosage fonn as defîned in daim 13 wberein each individuel thiazolîdinedione related compound or impurity in the final dosage form is not more than 0.25%.
17. The pharmaceutical dosage form as defîned in daim 16 wherein each individual thjazolidinedione related compound or impurity in the final dosage form is not more than 0.20%.
18. The pharmaceutical dosage form as defîned in claim 17 wherein each individual thiazolîdinedione related compound or impurity in the final dosage form is not more than 0.10%.
19. 'Πιε dosage form of claim 1 wherein saîd controlled release core is an osmotic tablet.
20. The dosage fonn of claim 19 wherein the osmotic tablet comprises:
(a) a core comprising:
(i) 50-98% of said antihyperglycemic drug;
(ii) 0. J -40% of a binding agent;
(iü) 0-20% of an absorption erihancer; and (iv) 0-5% of a lubricant;
(b) optionally a seal coat sunounding the core; and (c) a sustained release membrane comprising:
(i) 50-99% of a polymer;
(ii) 0-40% of a flux enhancer and
56 .
(iij) 0-25% of a plasticizer, said membrane having at least one passageway formed therein for release of the antihyperglycemic drug.
21. The dosage form of daim 1 wherein said antihyperglycemic drug is a biguanide.
22. 'The dosage form of daim 1 wherein said thiazolidinedione dérivative is troglitazone, rosiglitazone, pioglitazone, cigUtazone or pharmaceutically acceptable saîts, isomère or dérivatives thereof.
23. The dosage form of daim 1 wherein said core is substantially free from any gelling or expanding potymer.
24. The dosage form of daim 1 wherein said controlled rdease of said antihyperglycemic drug provides a Tmax of 6-12 houre. ,
25. The dosage form of daim 1 wherein said release of the thiazolidinedione dérivative provides a Tmax of 1-12 hours.
26. The dosage form of daim 25 wherein said rdease of the thiazolidinedione dérivative provides a Tmax of 1-4 hours.
27. The dosage form of daim 13 wherein said controlled release core is an osmotic tablet.
28. The dosage form of daim 27 whereîn the osmotic tablet comprises:
(d) a core comprising;
(i) 50-98% of said antihyperglycemic drug;
( iï) 0.1 -40% of a binding agent;
(iii) 0-20% of an absorption cnhancer; and (iv) 0-5% of a lubricant;
(e) optionaJIy a seal coat surrounding the core; and (1) a suslained release membrane comprising;
(iv) 50-99% of a polymer;
(v) 0-40% of a flux enchancer and (vi) 0-25% of a plasticizer, said membrane having at least one passageway formed therein for release of the antihyperglycemic drug.
29. The dosage form of daim 13 wherein said antihyperglycemic drug js a biguanide.
30. The dosage form of claim 13 wherein said thiazolidinedione dérivative is troglitazone, rosiglitazone, pioglitazone, dglitazone or pharmaceutically acceptable salts, isomers or dérivatives thereof.
31. The dosage form of claim 13 wherein said core is substantîally free from any gelJing or expanding polymer.
32. The dosage form of claim 13 wherein said controlled release of said antihyperglycemrc drug provides a Tmax of 6-12 hours.
33. The dosage form of claim 13 wherein said release of the thiazolidinedione dérivative provides a Tmax of 1-12 hours.
34. The dosage form of claim 33 wherein said release of the thiazolidinedione dérivative provides a Tmax of 1-4 hours.
35. The dosage form of claim 1 wherein tbe water soluble binder of the immédiate release thiazolidinedione dérivative containing component has a viscosîty of less than 50 mPa.S when tested as a 2% aqueous solution at 20°C.
36. The dosage form of claim 35 wherein the water soluble binder of the immédiate release thiazolidinedione dérivative containing component has a viscosîty of less than 25 mPa.S when tested as a 2% aqueous solution at 20eC.
37. The dosage form of claim 35 wherein tbe water soluble binder of the immédiate release thiazolidinedione dérivative containing component has a viscosîty of less than 10 mPa.S when tested as a 2% aqueous solution at 20°C.
38. The dosage form of claim 35 wherein the water soluble binder of the immédiate release thiazolidinedione dérivative containing component has a viscosîty between 2 and 6 niPa.S when tested as a 2% aqueous solution at 20’C.
39. The dosage form of claim 37 wherein the water soluble binder of the immédiate release thiazolidinedione dérivative containing component is hydroxypropyl cellulose.
40. The dosage form of claim 38 wherein the water soluble binder of the immédiate release thiazolidinedione dérivative containing component is hydroxypropyl cellulose.
41. The dosage form of claim 13 wherein the waler soluble binder of the immédiate release thiazolidinedione dérivative containing component has a viscosîty of less than 50 tnPa.S when tested as a 2% aqueous solution at 20°C.
42. The dosage form of daim 41 wherein the water soluble binder of the immédiate release thiazolidinedione dérivative containing component has a viscosity ofless than 25 mPa.S when tested as a 2% aqueous solution at 20°C.
43. The dosage form of daim 41 wharein the water soluble binder of the immédiate release thiazolidinedione dérivative containing component has a viscosity of less than 10 mPa-S when tested as a 2% aqueous solution at 20°C.
44. The dosage fonn of daim 41 wherein the water soluble binder of the immédiate release thiazolidinedione dérivative containing component has a viscosity between 2 and 6 mPB.S when tested as a 2% aqueous solution at 20°C.
45. The dosage form of daim 43 wherein the water soluble binder of the immédiate release thiazolidinedione dérivative containing component is hydroxypropyl cellulose.
46. The dosage form of daim 44 wherein the water soluble binder of the immédiate release thiazolidinedione dérivative containing component is hydroxypropyl cellulose
OA1200700373 2005-03-30 2006-03-13 Novel pharmaceutical formulation containing a biguanide and a thiazolidinedione derivative. OA16217A (en)

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