WO2008101943A1 - Pharmaceutical metformin hydrochloride formulation and tablet comprising said formulation - Google Patents
Pharmaceutical metformin hydrochloride formulation and tablet comprising said formulation Download PDFInfo
- Publication number
- WO2008101943A1 WO2008101943A1 PCT/EP2008/052036 EP2008052036W WO2008101943A1 WO 2008101943 A1 WO2008101943 A1 WO 2008101943A1 EP 2008052036 W EP2008052036 W EP 2008052036W WO 2008101943 A1 WO2008101943 A1 WO 2008101943A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- weight
- formulation according
- pharmaceutical formulation
- pharmaceutically acceptable
- metformin
- Prior art date
Links
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2095—Tabletting processes; Dosage units made by direct compression of powders or specially processed granules, by eliminating solvents, by melt-extrusion, by injection molding, by 3D printing
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/13—Amines
- A61K31/155—Amidines (), e.g. guanidine (H2N—C(=NH)—NH2), isourea (N=C(OH)—NH2), isothiourea (—N=C(SH)—NH2)
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2022—Organic macromolecular compounds
- A61K9/2027—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
- A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
Definitions
- the objective of modifying the original characteristics of the powder can be achieved for example by pre-compression and compaction of the drug.
- This is commonly applied to drugs such as paracetamol, ranitidine HCI, amoxicillin.
- this procedure must doubtless be regarded as a procedure additional to the direct compression process.
- larger sized particles can be used with the purpose of limiting inter-particle friction. This is precisely the case described in US 6,1 17,451 in which the formulation to be directly compressed is strictly confined to the use of metformin HCI of particle size from 400 to 600 micrometres.
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Epidemiology (AREA)
- Diabetes (AREA)
- Endocrinology (AREA)
- Emergency Medicine (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Hematology (AREA)
- Obesity (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- Medicinal Preparation (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
A formulation is described comprising micronized metformin HCI useful for the preparation of pharmaceutical tablets by simple compression.
Description
PHARMACEUTICAL METFORMIN HYDROCHLORIDE FORMULATION AND TABLET COMPRISING SAID FORMULATION
Field of the invention The present invention relates to the field of pharmaceutical formulations for tablets.
State of the art
The intrinsic properties of the product, its dosage form, the biopharmaceutical target and the economic aspects of the operations involved will determine selection of the best production process for use in the preparation of a pharmaceutical form.
The three main processes for producing tablets can be described thus: wet granulation, direct compression and dry granulation.
Dry granulation can be used when one of the constituents, primarily the drug or the diluent, has sufficient cohesive properties to form tablets. This method consists of pre-compressing the single ingredients or a mixture of two or more ingredients to obtain aggregates with good flowability, able to form tablets on addition of external excipients. This type of process is suitable for water-sensitive active ingredients, for example. The wet granulation method is used for converting a powder mixture into granules with cohesive and flow properties suitable for compression into tablets. The procedure consists of agglomerating an ingredient or a powder mixture with a granulating solvent or a solution. The wet granulate, once dried and sized, is combined with external excipients and compressed. Direct compression is regarded as a relatively quick method in which the powdered material is compressed directly without changing the chemical and physical properties of the drug.
The advantages of direct compression include: elimination of heat and moisture, restoration of primary particles during dissolution, physical stability, ease of process transfer operations, fewer manufacturing steps with cost and time advantages.
High dose drugs can be compressed directly only if the drug itself has suitable
physical characteristics (e.g. flowability and cohesiveness) for this process. Unfortunately, without excipients, most drugs particularly at high doses cannot be directly compressed into tablet form. This is mainly due to the poor flow and cohesive properties of these drugs. Generally, therefore, the applicability of direct compression is linked to medium or high dilution with excipients having a particle size greater than those of the active principle, or to the use of specific highly functional excipients.
Metformin hydrochloride is a hypoglycemic agent used in the treatment of non- insulin dependent diabetes. Metformin HCI is considered a high dose drug (normally from 400 to 1000 mg/dose), being relatively hygroscopic and not inherently compressible, hence presenting formulation problems. Consequently most tablet formulations, which comprise a quantity of 70 to 85% of the drug, adopt the wet granulation method. For direct compression formulations, the most used method is a medium or high dilution with excipients; with this method the active principle does not normally exceed 20-30% of the total. This dilution allows the poor functional properties of the drug to be overcome without the weight and size of the tablet produced being excessive. To avoid the drawbacks associated with swallowing tablets, dispersible or soluble tablets have been formulated.
WO 2004/082664 claimed soluble tablets based on a soluble salt of metformin and a soluble alcohol in high weight tablets (more than 900 mg for 500 mg of active principle). Although formulations containing up to 95% metformin are said to have been prepared, it is understandably likely that in this case the wet granulation method was used. Despite this, the characteristics of the tablets are limited (their hardness is stated as being not greater than 8 kP).
The objective of modifying the original characteristics of the powder can be achieved for example by pre-compression and compaction of the drug. This is commonly applied to drugs such as paracetamol, ranitidine HCI, amoxicillin. However this procedure must doubtless be regarded as a procedure additional to the direct compression process. In order to increase flowability, larger sized particles can be used with the purpose
of limiting inter-particle friction. This is precisely the case described in US 6,1 17,451 in which the formulation to be directly compressed is strictly confined to the use of metformin HCI of particle size from 400 to 600 micrometres. The use of components of said particle size is helpful in terms of flowability but most certainly reduces compaction properties, known to be correlated with the external surface area of the solid involved in the compaction process (no data is given on tablet performance). Moreover, segregation problems can occur as a result of the different particle sizes of the other excipients utilized in the formula. Frequently, functional excipients, able to confer appropriate characteristics on the tablets, can also be employed. These excipients should be characterized by a high compressibility at low usage percentage. These materials include cellulose derivatives in general (ethyl, hydroxyethyl, hydroxypropyl, hydroxypropylmethyl cellulose etc.), this being one of the most widely used classes though more often specified for controlled release applications (US 6,524,618). This is the case reported in US 6,1 17,451 where hydroxypropyl methylcellulose and hydroxypropyl cellulose are used to form a dynamic hydrophilic matrix which induces formation of a gel layer, delaying disintegration time and consequently active principle release. This effect is dependent to a greater or lesser extent on the content and viscosity of the polymer used. However, this should not be a characteristic of immediate release tablets (data on the behaviour of metformin HCI at release are not supplied).
Besides the active or therapeutic ingredients, the tablets can contain a number of inert materials called excipients. These can be classified according to their function. The basic components normally include: binders, diluents, lubricants, disintegrants and anti-adherents (glidants).
In direct compression particular attention must be given to the binder; it is an agent which provides the following desirable qualities to the powdered material: high compactibility, good flowability, cohesiveness. Diluents or fillers are added to increase mixture mass up to the required level for compression, but also to increase or modulate tablet properties.
Lubricants are generally added to prevent adhesion of the material to the punches and to minimize friction during compression and ejection. Said excipients are
generally included in the final mixture in small amounts, but can be increased in relation to the surface area characteristics of the powders. Disintegrants are often added to ensure an acceptable degree of disintegration. Glidants or anti-adherents are other excipients commonly added to increase flowability from the discharge hopper to the punch die. Description of the invention
The present invention relates to a metformin HCI formulation in the form of a cohesive and free-flowing powder, suitable for the preparation of tablets by means of direct compression, utilizing the least possible quantity of excipients in order to reduce the final weight of the finished product, by a simple and economical manufacturing process.
According to the invention, metformin HCI tablets can be obtained in dosage units which have a good dissolution profile, an acceptable degree of hardness and resistance to chipping as well as a short disintegration time. This is possible by using smaller active principle particles, i.e. within the range from 10 to 200 micrometres, which result in an increase in surface interactions without reducing flow characteristics. This ensures the two-fold advantage of having an effective formula with a very low quantity of excipients so as to reduce tablet size. The present invention also includes the use of a polymer, namely vinylpyrrolidone-vinyl acetate copolymer, in the form of particles also within the size range of 10-200 micrometres, presenting very high flow and compactness properties and without affecting tablet disintegration (within 15 minutes) and consequent active principle release (more than 80% within 15 minutes). In general a formulation according to the present invention comprises: a) from 70 to 85% by weight of metformin HCI having a particle size range from 10 and 200 micrometres; b) from 10 to 25% by weight of a suitable pharmaceutically acceptable binder, preferably vinylpyrrolidone-vinyl acetate copolymer with a particle size range from 10 to 200 microns; c) from 1 to 10% by weight of a suitable pharmaceutically acceptable diluent, selected from: hydroxypropyl cellulose or dibasic calcium phosphate or microcrystalline cellulose or pregelatinized starch;
d) from 1 to 5% by weight of a suitable pharmaceutically acceptable disintegrant selected from: croscarmellose sodium or sodium starch glycolate or crospovidone; e) from 0.1 to 2% of a suitable pharmaceutically acceptable glidant, preferably colloidal silica; f) from 0.1 % to 4% by weight of a pharmaceutically acceptable lubricant selected from: magnesium stearate, sodium stearyl fumarate, glyceryl docosanoate or glyceryl palmitostearate.
N,N-dimethylimidodicarbonimidic diamide hydrochloride (metformin HCI), is freely soluble in water and intrinsically non-compressible. For the purposes of the present invention, it is considered pure at 98.5-100% by weight, preferably in the form of a white crystalline powder with a particle size range from 10 to 200 microns.
The use of vinylpyrrolidone-vinyl acetate copolymer 60/40, with a particle size range from 10 to 200 microns, ensures good distribution, good compaction characteristics, slow disintegration time and a high percentage of dissolution. The very plastic behaviour of this excipient combines perfectly with the chipping characteristics of metformin HCI and, related to this, the high dilution capacity exhibited (the amount of excipient required for acceptable mixing and tablet properties). The spherical particles contribute significantly to the flowability of the metformin HCI mixture. Moreover, the binder particle sizes are so well related to those of the active principle, as to avoid all possible segregation problems. The composition can also include one or more diluents/binders preferably selected from: hydroxypropyl cellulose, dibasic calcium phosphate, microcrystalline cellulose or pregelatinized starch. These excipients can be regarded as adjuvants for flow or compaction characteristics. In general, for our formulation a quantity from 1 to 10% by weight was considered, in relation to the characteristics of the particular excipient selected,
Hydroxypropyl cellulose is chemically substituted with 50-70% hydroxypropyl groups. This chemical substitution allows for a low viscosity, i.e. within the range from 300 to 600 cps. This renders the polymer suitable for use as an auxiliary binder in standard rather than extended release matrix formulations (US 6,524,618). The particle sizes, 100% being less than 100μm, confer a good
distribution despite the low quantity used in the formula. The type and quantity of this cellulose does not alter disintegration time, a property which is strictly related to the dissolution profile. Dibasic calcium phosphate is typically used in direct compression formulations in its non-ground or otherwise crude form. It appears as a high density material, a property which reduces tablet volume. Having a nominal mean particle size of 100-200 microns, it improves flow properties. It is virtually insoluble in water, such as to help improve tablet disintegration. Microcrystalline cellulose is another excipient that may be used in these formulations. It is highly compressible and produces strong tablets even with low pressures. It can certainly help to prevent chipping and capping of metformin HCI tablets. Microcrystalline cellulose improves flow characteristics if used at a particle size range from 100-200 microns; if used as a finer material, with a nominal mean particle size of less than 70 microns, it improves compressibility. Because of this characteristic, it is also self-lubricating and so helps reduce ejection force during the tablet compression process.
Pregelatinized starch is a modified starch which has undergone chemical or mechanical treatment. This process imparts good compaction and flow properties to the starch. Having a nominal mean particle size range from 30 to 150 microns, it is perfectly suited to the particle sizes of the active principle.
In the composition of the invention, a disintegrant selected from the following can also be introduced in order to improve tablet disintegration: sodium croscarmellose, sodium starch glycolate or crospovidone. By virtue of their capillary and swelling capabilities, a quantity of 1 to 5% by weight on the final tablet can be considered adequate, depending on the formula selected.
In the present invention, colloidal silica is ideal as a glidant. It improves the flow of the powder blend from the discharge hopper to the punch die. Colloidal silica has very small particles (generally less than 20 μm), a large surface area (generally 200 m2/g) and is used in percentages of 0.1 -2% by weight. Lubricants can be divided into water-soluble and non-water-soluble types; the second type is particularly preferred for their better lubricating properties. Of these latter lubricants, the best example is magnesium stearate. It is very effective in
reducing friction between the die wall and the powder blend during compression, thus facilitating tablet ejection. Moreover it improves the flow properties of the powder blend and helps prevent adhesion to the punches and die. A level of 0.1 - 2.0% by weight of magnesium stearate can be used in these formulations. It is considered best to avoid a long mixing time, as this can lead to a reduced final tablet hardness and an increased disintegration time. For this reason other less hydrophobic lubricants can be considered, selecting them from the following group: glyceryl docosanoate, glyceryl palmitostearate (at levels of 1 -4% by weight). Formulations in accordance with the present invention are obtained by direct compression which consists only in the steps of mixing and compression. The process does not involve any preliminary procedure such as granulation or pre-compaction.
Metformin HCI and the colloidal silica are sifted and blended for a few minutes. The binder, diluent and disintegrant are added and mixed with the aforesaid. Finally the lubricant is added and mixed for the minimum time necessary. The resulting blend is compressed into final units using a rotary tablet press equipped with suitable punches, such as to provide tablets of the required shape and size. A general formula based on the aforedescribed components is given below. Using this formula, the final product obtained by means of direct compression, has the desired technological characteristics, namely: good resistance to breakage (not less than 10 kP), short disintegration time (no longer than 15 minutes), low friability (not greater than 0.5%) and no chipping, capping or lamination effect. Moreover the tablets have a good dissolution profile (more than 80% in 15 minutes) and the final product, contained within suitable packaging material, is stable over time.
COMPONENTS QUANTITY (%)
Metformin HCI 70-85
Vinylpyrrolidone-vinyl acetate copolymer 10-25
Diluents 1 -10
Disintegrants 1 -5
Colloidal silica 0.1 -2
Lubricants 0.1 -4
EXAMPLES
Some examples of reproducible formulas are given below. These formulas are based on a quantity of metformin HCI equal to 500 mg, though similar formulas can also be obtained with different doses, the invention being applicable with metformin HCI doses from 400 mg to 1000 mg. The following examples are however merely illustrative and in no way limit the present invention. Example 1
Ingredients Weight (mg) per tablet Metformin HCI 500.00
Vinylpyrrolidone-vinyl acetate copolymer 100.00
Crospovidone 10.00
Colloidal silica 5.00
Sodium stearyl fumarate 5.00 Total 620.00 Example 2
Ingredients Weight (mg) per tablet
Metformin HCI 500.00
Vinylpyrrolidone-vinyl acetate copolymer 120.00 Crospovidone 20.00
Colloidal silica 5.00
Magnesium stearate 5.00
Total 655.00 Example 3 Ingredients Weight (mg) per tablet
Metformin HCI 500.00
Vinylpyrrolidone-vinyl acetate copolymer 130.00
Crospovidone 30.00
Colloidal silica 5.00 Sodium stearyl fumarate 5.00
Total 670.00 Example 4
Ingredients Weight (mg) per tablet
Metformin HCI 500.00
Vinylpyrrolidone-vinyl acetate copolymer 120.00
Starch glycolate 25.00
Colloidal silica 5.00
Sodium stearyl fumarate 5.00
Total 655.00
Example 5
Ingredients Weight (mg) per tablet
Metformin HCI 500.00
Vinylpyrrolidone-vinyl acetate copolymer 100.00
Hydroxypropyl cellulose 25.00
Crospovidone 10.00
Colloidal silica 5.00
Glyceryl docosanoate 2.00
Total 650.00
Example 6
Ingredients Weight (mg) per tablet
Metformin HCI 500.00
Vinylpyrrolidone-vinyl acetate copolymer 96.00
Microcrystalline cellulose 20.00
Crospovidone 7.00
Colloidal silica 1.00
Sodium stearyl fumarate 1.00
Total 625.00
Example 7
Ingredients Weight (mg) per tablet
Metformin HCI 500.00
Vinylpyrrolidone-vinyl acetate copolymer 90.00
Hydroxypropyl cellulose 10.00
Microcrystalline cellulose 50.00
Crospovidone 20.00
Colloidal silica 5.00
Sodium stearyl fumarate 2.00
Total 680.00
Example 8
IInnggrreeddiieennttss Weight (mg) per tablet
MMeettffoorrmmiinn HCI 500.00
VViinnyyllppyyrrrroolliidone-vinyl acetate copolymer 95.00
CCrroossccaarrmmeellose 25.00
CCoollllooiiddaall ssiilicon dioxide 5.00
MMaaggnneessiiuunm stearate 5.00
TToottaall wweeiigglht 630.00
EExxaammppllee 99
IInnggrreeddiieennttss Weight (mg) per tablet
MMeettffoorrmmiinn HCI 500.00
VViinnyyllppyyrrrroolliidone-vinyl acetate copolymer 40.00
HHyyddrrooxxyypprrcopyl cellulose 35.00
CCaallcciiuumm pprhosphate 10.00
SSttaarrcchh ggllyyccolate 25.00
CCoollllooiiddaall ssiilica 5.00
SSooddiiuumm sstteearyl fumarate 5.00
TToottaall 620.00
EExxaammppllee 110
IInnggrreeddiieennttss Weight (mg) per tablet
MMeettffoorrmmiinn HCI 500.00
VViinnyyllppyyrrrroolliidone-vinyl acetate copolymer 100.00
PPrreeggeellaattiinniized starch 15.00
CCrroossccaarrmmeellose 20.00
CCoollllooiiddaall ssiilica 5.00
GGllyycceerryyll ddcocosanoate 20.00
TToottaall 685.00
EExxaammppllee 11 1
Ingredients Weight (mg) per tablet
Metformin HCI 500.00
Vinylpyrrolidone-vinyl acetate copolymer 1 10.00
Hydroxypropyl cellulose 10.00
Calcium phosphate 20.00
Crospovidone 10.00
Colloidal silica 5.00
Glyceryl monostearate 25.00
Total 680.00
Claims
1. Pharmaceutical formulation comprising metformin hydrochloride and at least one binder, both being in the form of particles having sizes from 10 to 200 micrometres.
2. Formulation according to claim 1 wherein said metformin HCI is 98.5-100% pure metformin HCI by weight, said binder being vinylpyrrolidone-vinyl acetate copolymer.
3. Pharmaceutical formulation based on metformin hydrochloride comprising: a) from 70 to 85% by weight of metformin HCI having a particle size range from 10 to 200 micrometres; b) from 10 to 25% by weight of a pharmaceutical grade binder, namely vinylpyrrolidone-vinyl acetate copolymer 60/40, with a particle size range from 10 to 200 micrometres together with pharmaceutically acceptable excipients.
4. Pharmaceutical formulation according to claim 3 wherein said pharmaceutically acceptable excipients comprise at least from 1 to 10% by weight of a diluent selected from the group: hydroxypropyl cellulose, dibasic calcium phosphate, microcrystalline cellulose or pregelatinized starch.
5. Pharmaceutical formulation according to claim 3 wherein said pharmaceutically acceptable excipients comprise at least from 1 to 5% by weight of a disintegrant selected from: croscarmellose sodium or sodium starch glycolate or crospovidone.
6. Pharmaceutical formulation according to claim 3 wherein said pharmaceutically acceptable excipients comprise at least from 0.1 to 2% by weight of colloidal silica as glidant.
7. Pharmaceutical formulation according to claim 3 wherein said pharmaceutically acceptable excipients comprise at least from 0.1 to 4% by weight of a lubricant selected from: magnesium stearate, sodium stearyl fumarate, glyceryl docosanoate or glyceryl palmitostearate.
8. Pharmaceutical formulation according to claims 1 -5 having the following relative weight percentage composition of its basic constituents: metformin HCI 70-85%, vinylpyrrolidone-vinyl acetate copolymer 10-25%, diluent 1 -10%, disintegrant 1 - 5%, colloidal silica 0.1 -2%, lubricant 0.1 -4%.
9. Pharmaceutical tablets consisting of a formulation according to claims 1 -8.
10. Process for producing the tablets of claim 9 wherein a formulation according to claims 1 -8 is subjected to compression.
1 1. 98.5-100% pure metformin HCI by weight, in the form of particles of size from 1 to 200 micrometres.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| IT000042A ITFI20070042A1 (en) | 2007-02-21 | 2007-02-21 | PHARMACEUTICAL FORMULATION AND COMPRESSED INCLUDING THIS FORMULATION. |
| ITFI2007A000042 | 2007-02-21 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| WO2008101943A1 true WO2008101943A1 (en) | 2008-08-28 |
Family
ID=39399182
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PCT/EP2008/052036 WO2008101943A1 (en) | 2007-02-21 | 2008-02-20 | Pharmaceutical metformin hydrochloride formulation and tablet comprising said formulation |
Country Status (2)
| Country | Link |
|---|---|
| IT (1) | ITFI20070042A1 (en) |
| WO (1) | WO2008101943A1 (en) |
Cited By (18)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2011039337A1 (en) * | 2009-10-02 | 2011-04-07 | Boehringer Ingelheim International Gmbh | Pharmaceutical composition, pharmaceutical dosage form, process for their preparation, methods for treating and uses thereof |
| WO2013074049A1 (en) * | 2011-11-03 | 2013-05-23 | Mahmut Bilgic | Micronized metformin |
| WO2013077821A1 (en) * | 2011-11-23 | 2013-05-30 | Mahmut Bilgic | Homogeneous biguanide composition |
| US8551957B2 (en) | 2007-08-16 | 2013-10-08 | Boehringer Ingelheim International Gmbh | Pharmaceutical composition comprising a glucopyranosyl-substituted benzene derivate |
| US8557782B2 (en) | 2006-05-03 | 2013-10-15 | Boehringer Ingelheim International Gmbh | Glucopyranosyl-substituted benzonitrile derivatives, pharmaceutical compositions containing such compounds, their use and process for their manufacture |
| WO2014101986A1 (en) * | 2012-12-27 | 2014-07-03 | Zentiva Sağlik Ürünleri San. Ve Tic. A.Ş. | Dry granulation process for producing tablet compositions of metformin and compositions thereof |
| US8802842B2 (en) | 2009-09-30 | 2014-08-12 | Boehringer Ingelheim International Gmbh | Method for the preparation of a crystalline form |
| US9024010B2 (en) | 2009-09-30 | 2015-05-05 | Boehringer Ingelheim International Gmbh | Processes for preparing of glucopyranosyl-substituted benzyl-benzene derivatives |
| US9127034B2 (en) | 2005-05-10 | 2015-09-08 | Boehringer Ingelheim International Gmbh | Processes for preparing of glucopyranosyl-substituted benzyl-benzene derivates and intermediates therein |
| US9192617B2 (en) | 2012-03-20 | 2015-11-24 | Boehringer Ingelheim International Gmbh | Pharmaceutical composition, methods for treating and uses thereof |
| US9555001B2 (en) | 2012-03-07 | 2017-01-31 | Boehringer Ingelheim International Gmbh | Pharmaceutical composition and uses thereof |
| US9949998B2 (en) | 2013-04-05 | 2018-04-24 | Boehringer Ingelheim International Gmbh | Pharmaceutical composition, methods for treating and uses thereof |
| US9949997B2 (en) | 2013-04-05 | 2018-04-24 | Boehringer Ingelheim International Gmbh | Pharmaceutical composition, methods for treating and uses thereof |
| US20180185291A1 (en) | 2011-03-07 | 2018-07-05 | Boehringer Ingelheim International Gmbh | Pharmaceutical compositions |
| US10406172B2 (en) | 2009-02-13 | 2019-09-10 | Boehringer Ingelheim International Gmbh | Pharmaceutical composition, methods for treating and uses thereof |
| WO2022023213A1 (en) * | 2020-07-31 | 2022-02-03 | Krka, D. D., Novo Mesto | Pharmaceutical formulation of metformin having low content of dimethylamine |
| US11666590B2 (en) | 2013-04-18 | 2023-06-06 | Boehringer Ingelheim International Gmbh | Pharmaceutical composition, methods for treating and uses thereof |
| US11813275B2 (en) | 2013-04-05 | 2023-11-14 | Boehringer Ingelheim International Gmbh | Pharmaceutical composition, methods for treating and uses thereof |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6524618B1 (en) * | 2001-06-12 | 2003-02-25 | Vijai Kumar | Directly compressible extended-release matrix formulation for metformin hydrochloride |
| WO2006038226A2 (en) * | 2004-10-08 | 2006-04-13 | Rubicon Research Pvt. Ltd. | Process for making a highly compressible controlled delivery compositions of metformin |
-
2007
- 2007-02-21 IT IT000042A patent/ITFI20070042A1/en unknown
-
2008
- 2008-02-20 WO PCT/EP2008/052036 patent/WO2008101943A1/en active Application Filing
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6524618B1 (en) * | 2001-06-12 | 2003-02-25 | Vijai Kumar | Directly compressible extended-release matrix formulation for metformin hydrochloride |
| WO2006038226A2 (en) * | 2004-10-08 | 2006-04-13 | Rubicon Research Pvt. Ltd. | Process for making a highly compressible controlled delivery compositions of metformin |
Cited By (34)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US9127034B2 (en) | 2005-05-10 | 2015-09-08 | Boehringer Ingelheim International Gmbh | Processes for preparing of glucopyranosyl-substituted benzyl-benzene derivates and intermediates therein |
| US10442795B2 (en) | 2005-05-10 | 2019-10-15 | Boehringer Ingelheim International Gmbh | Processes for preparing of glucopyranosyl-substituted benzyl-benzene derivatives and intermediates therein |
| US8557782B2 (en) | 2006-05-03 | 2013-10-15 | Boehringer Ingelheim International Gmbh | Glucopyranosyl-substituted benzonitrile derivatives, pharmaceutical compositions containing such compounds, their use and process for their manufacture |
| US8551957B2 (en) | 2007-08-16 | 2013-10-08 | Boehringer Ingelheim International Gmbh | Pharmaceutical composition comprising a glucopyranosyl-substituted benzene derivate |
| US12115179B2 (en) | 2009-02-13 | 2024-10-15 | Boehringer Ingelheim International Gmbh | Pharmaceutical composition, methods for treating and uses thereof |
| US10406172B2 (en) | 2009-02-13 | 2019-09-10 | Boehringer Ingelheim International Gmbh | Pharmaceutical composition, methods for treating and uses thereof |
| US8802842B2 (en) | 2009-09-30 | 2014-08-12 | Boehringer Ingelheim International Gmbh | Method for the preparation of a crystalline form |
| US9024010B2 (en) | 2009-09-30 | 2015-05-05 | Boehringer Ingelheim International Gmbh | Processes for preparing of glucopyranosyl-substituted benzyl-benzene derivatives |
| US9873714B2 (en) | 2009-09-30 | 2018-01-23 | Boehringer Ingelheim International Gmbh | Processes for preparing of glucopyranosyl-substituted benzyl-benzene derivatives |
| US10610489B2 (en) | 2009-10-02 | 2020-04-07 | Boehringer Ingelheim International Gmbh | Pharmaceutical composition, pharmaceutical dosage form, process for their preparation, methods for treating and uses thereof |
| AP3438A (en) * | 2009-10-02 | 2015-10-31 | Boehring Ingelheim Internat Gmbh | Pharmaceutical composition, pharmaceutical dosage form, process for their preparation, methods for treating and uses thereof |
| WO2011039337A1 (en) * | 2009-10-02 | 2011-04-07 | Boehringer Ingelheim International Gmbh | Pharmaceutical composition, pharmaceutical dosage form, process for their preparation, methods for treating and uses thereof |
| EP4371560A3 (en) * | 2009-10-02 | 2024-08-21 | Boehringer Ingelheim International GmbH | Pharmaceutical composition, pharmaceutical dosage form, process for their preparation, methods for treating and uses thereof |
| EP3150200A1 (en) * | 2009-10-02 | 2017-04-05 | Boehringer Ingelheim International GmbH | Pharmaceutical composition, pharmaceutical dosage form, process for their preparation, methods for treating and uses thereof |
| EA027181B1 (en) * | 2009-10-02 | 2017-06-30 | Бёрингер Ингельхайм Интернациональ Гмбх | Solid pharmaceutical dosage form comprising sglt-2 inhibitor and metformin hydrochloride for treating |
| CN104873974A (en) * | 2009-10-02 | 2015-09-02 | 贝林格尔·英格海姆国际有限公司 | Pharmaceutical Composition, Pharmaceutical Dosage Form, Process For Their Preparation, Methods For Treating And Uses Thereof |
| US10596120B2 (en) | 2011-03-07 | 2020-03-24 | Boehringer Ingelheim International Gmbh | Pharmaceutical compositions |
| US20180185291A1 (en) | 2011-03-07 | 2018-07-05 | Boehringer Ingelheim International Gmbh | Pharmaceutical compositions |
| US11564886B2 (en) | 2011-03-07 | 2023-01-31 | Boehringer Ingelheim International Gmbh | Pharmaceutical compositions |
| WO2013074049A1 (en) * | 2011-11-03 | 2013-05-23 | Mahmut Bilgic | Micronized metformin |
| WO2013077821A1 (en) * | 2011-11-23 | 2013-05-30 | Mahmut Bilgic | Homogeneous biguanide composition |
| US9555001B2 (en) | 2012-03-07 | 2017-01-31 | Boehringer Ingelheim International Gmbh | Pharmaceutical composition and uses thereof |
| US9192617B2 (en) | 2012-03-20 | 2015-11-24 | Boehringer Ingelheim International Gmbh | Pharmaceutical composition, methods for treating and uses thereof |
| RU2647421C2 (en) * | 2012-12-27 | 2018-03-15 | Зентива Саглык Урунлеры Сан. Ве Тыдж. А.Ш. | Dry granulation process for producing tablet compositions of metformin and compositions thereof |
| WO2014101986A1 (en) * | 2012-12-27 | 2014-07-03 | Zentiva Sağlik Ürünleri San. Ve Tic. A.Ş. | Dry granulation process for producing tablet compositions of metformin and compositions thereof |
| US11090323B2 (en) | 2013-04-05 | 2021-08-17 | Boehringer Ingelheim International Gmbh | Pharmaceutical composition, methods for treating and uses thereof |
| US10258637B2 (en) | 2013-04-05 | 2019-04-16 | Boehringer Ingelheim International Gmbh | Pharmaceutical composition, methods for treating and uses thereof |
| US11813275B2 (en) | 2013-04-05 | 2023-11-14 | Boehringer Ingelheim International Gmbh | Pharmaceutical composition, methods for treating and uses thereof |
| US11833166B2 (en) | 2013-04-05 | 2023-12-05 | Boehringer Ingelheim International Gmbh | Pharmaceutical composition, methods for treating and uses thereof |
| US11918596B2 (en) | 2013-04-05 | 2024-03-05 | Boehringer Ingelheim International Gmbh | Pharmaceutical composition, methods for treating and uses thereof |
| US9949997B2 (en) | 2013-04-05 | 2018-04-24 | Boehringer Ingelheim International Gmbh | Pharmaceutical composition, methods for treating and uses thereof |
| US9949998B2 (en) | 2013-04-05 | 2018-04-24 | Boehringer Ingelheim International Gmbh | Pharmaceutical composition, methods for treating and uses thereof |
| US11666590B2 (en) | 2013-04-18 | 2023-06-06 | Boehringer Ingelheim International Gmbh | Pharmaceutical composition, methods for treating and uses thereof |
| WO2022023213A1 (en) * | 2020-07-31 | 2022-02-03 | Krka, D. D., Novo Mesto | Pharmaceutical formulation of metformin having low content of dimethylamine |
Also Published As
| Publication number | Publication date |
|---|---|
| ITFI20070042A1 (en) | 2008-08-22 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| WO2008101943A1 (en) | Pharmaceutical metformin hydrochloride formulation and tablet comprising said formulation | |
| AU599925B2 (en) | Sustained release compositions | |
| AU599058B2 (en) | Sustained release compositions comprising hydroxypropyl cellulose ethers | |
| US5104648A (en) | High ibuprofen content granulations | |
| US6117451A (en) | Direct compression metformin hydrochloride tablets | |
| JP4394313B2 (en) | Granules based on starch and lactose | |
| US10071059B2 (en) | Co-processed tablet excipient composition its preparation and use | |
| EP3182975A1 (en) | High dosage strength tablets of rucaparib | |
| US4911921A (en) | High ibuprofen content granulations | |
| WO2007086891A1 (en) | Levetiracetam formulations and methods for their manufacture | |
| EP2804588B1 (en) | Method for producing cinacalcet compositions for direct tableting | |
| WO2008020990A1 (en) | New direct compressible excipient blend | |
| EP2379061B1 (en) | Precompacted fast-disintegrating formulations of compounds with a low oral bioavailability | |
| JP4370050B2 (en) | Clarithromycin tablets and method for producing the same | |
| KR102373089B1 (en) | Pharmaceutical composition comprising ibuprofen and acetaminophen and preparation method thereof | |
| EP2671569B1 (en) | Stable pharmaceutical compositions with fast onset | |
| US20240350414A1 (en) | Direct tableting auxiliary composition | |
| SK9912003A3 (en) | Pharmaceutical composition containing citalopram | |
| KR20060015746A (en) | Deramciclane-fumarate tablets | |
| WO2015150944A1 (en) | Solid oral pharmaceutical compositions comprising cinacalcet or a salt thereof | |
| JP2024531701A (en) | Bempedoic acid pharmaceutical composition |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| 121 | Ep: the epo has been informed by wipo that ep was designated in this application |
Ref document number: 08709118 Country of ref document: EP Kind code of ref document: A1 |
|
| NENP | Non-entry into the national phase |
Ref country code: DE |
|
| 122 | Ep: pct application non-entry in european phase |
Ref document number: 08709118 Country of ref document: EP Kind code of ref document: A1 |