WO2023275891A1 - Prolonged release tablet containing metformin hydrochloride - Google Patents
Prolonged release tablet containing metformin hydrochloride Download PDFInfo
- Publication number
- WO2023275891A1 WO2023275891A1 PCT/IN2022/050594 IN2022050594W WO2023275891A1 WO 2023275891 A1 WO2023275891 A1 WO 2023275891A1 IN 2022050594 W IN2022050594 W IN 2022050594W WO 2023275891 A1 WO2023275891 A1 WO 2023275891A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- prolonged
- release tablet
- tablet
- metformin hydrochloride
- microcrystalline cellulose
- Prior art date
Links
- XZWYZXLIPXDOLR-UHFFFAOYSA-N metformin hydrochloride Natural products CN(C)C(=N)NC(N)=N XZWYZXLIPXDOLR-UHFFFAOYSA-N 0.000 title claims abstract description 27
- 230000002035 prolonged effect Effects 0.000 title claims abstract description 27
- OETHQSJEHLVLGH-UHFFFAOYSA-N metformin hydrochloride Chemical compound Cl.CN(C)C(=N)N=C(N)N OETHQSJEHLVLGH-UHFFFAOYSA-N 0.000 title claims description 16
- 229960004329 metformin hydrochloride Drugs 0.000 title claims description 15
- 229920000168 Microcrystalline cellulose Polymers 0.000 claims abstract description 13
- 229940016286 microcrystalline cellulose Drugs 0.000 claims abstract description 13
- 235000019813 microcrystalline cellulose Nutrition 0.000 claims abstract description 13
- 239000008108 microcrystalline cellulose Substances 0.000 claims abstract description 13
- 238000000034 method Methods 0.000 claims abstract description 12
- 229960003105 metformin Drugs 0.000 claims abstract description 11
- 150000003839 salts Chemical class 0.000 claims abstract description 8
- 238000002360 preparation method Methods 0.000 claims abstract 4
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 claims description 9
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 claims description 9
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 claims description 9
- UFVKGYZPFZQRLF-UHFFFAOYSA-N hydroxypropyl methyl cellulose Chemical compound OC1C(O)C(OC)OC(CO)C1OC1C(O)C(O)C(OC2C(C(O)C(OC3C(C(O)C(O)C(CO)O3)O)C(CO)O2)O)C(CO)O1 UFVKGYZPFZQRLF-UHFFFAOYSA-N 0.000 claims description 8
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims description 6
- 229940075614 colloidal silicon dioxide Drugs 0.000 claims description 6
- MVPICKVDHDWCJQ-UHFFFAOYSA-N ethyl 3-pyrrolidin-1-ylpropanoate Chemical compound CCOC(=O)CCN1CCCC1 MVPICKVDHDWCJQ-UHFFFAOYSA-N 0.000 claims description 6
- 229940045902 sodium stearyl fumarate Drugs 0.000 claims description 6
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 3
- 238000002156 mixing Methods 0.000 claims 4
- 239000003795 chemical substances by application Substances 0.000 claims 1
- 239000000314 lubricant Substances 0.000 claims 1
- 239000003826 tablet Substances 0.000 description 20
- 238000004519 manufacturing process Methods 0.000 description 12
- 239000000203 mixture Substances 0.000 description 9
- 238000007907 direct compression Methods 0.000 description 7
- 239000002552 dosage form Substances 0.000 description 6
- 239000000463 material Substances 0.000 description 6
- 238000013459 approach Methods 0.000 description 3
- 238000004090 dissolution Methods 0.000 description 3
- 238000005550 wet granulation Methods 0.000 description 3
- 230000009471 action Effects 0.000 description 2
- 239000007891 compressed tablet Substances 0.000 description 2
- 239000003085 diluting agent Substances 0.000 description 2
- 238000009472 formulation Methods 0.000 description 2
- 230000006872 improvement Effects 0.000 description 2
- 230000007246 mechanism Effects 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 1
- 239000008186 active pharmaceutical agent Substances 0.000 description 1
- 230000000295 complement effect Effects 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 229940088679 drug related substance Drugs 0.000 description 1
- 229940095884 glucophage Drugs 0.000 description 1
- 229960003943 hypromellose Drugs 0.000 description 1
- 239000012729 immediate-release (IR) formulation Substances 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 239000007935 oral tablet Substances 0.000 description 1
- 229940096978 oral tablet Drugs 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 239000008363 phosphate buffer Substances 0.000 description 1
- 238000012545 processing Methods 0.000 description 1
- 230000000069 prophylactic effect Effects 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 230000004044 response Effects 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 239000007916 tablet composition Substances 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 238000010977 unit operation Methods 0.000 description 1
Classifications
-
- 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
- A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
- A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
Definitions
- tablets designed for the prolonged-release administration of metformin or its pharmaceutically acceptable salt are disclosed herein.
- the present invention provides tablet containing metformin or its pharmaceutically acceptable salt and grade of microcrystalline cellulose having higher compactability and lower bulk density.
- the present invention may be understood more readily by reference to the following detailed description. It is to be understood that this invention is not limited to the specific products, methods, conditions or parameters described and/or shown herein, and that the terminology used herein is for the purpose of describing particular embodiments by way of example only and is not intended to be limiting of any claimed invention.
Abstract
Provided is prolonged release tablet containing metformin or a pharmaceutically acceptable salt thereof and microcrystalline cellulose grade having higher compactability and lower bulk density. Also, provided is process for the preparation of prolonged release metformin tablet.
Description
Field of the Invention
The present invention generally relates to the field of pharmaceutical preparations, and more particularly, to prolonged release tablet of metformin hydrochloride along with microcrystalline cellulose grade having higher compatibility and lower bulk density.
Background of the Invention
Metformin hydrochloride is available as prolonged release tablet dosage forms in dosage strengths from 500mg to 1000mg. Due to its high dose, it is very difficult to achieve the desired physiochemical properties and release profile of prolonged release tablet formulations using minimum number of excipients. Drug substance has very poor flow properties and less compressibility due to its fine crystalline nature.
Due to limited scope of inclusion of diluents in Metformin hydrochloride prolonged release tablets, wet granulation technique is preferable choice of manufacturing to improve its flow properties and compressibility. However, the wet granulation technique is associated with drawbacks such as long processing time, multiple steps involved in manufacturing, requirement of sophisticated equipment’s for manufacturing, and chances of batch-to-batch variability due to more complex nature of manufacturing process.
Direct compression is preferred choice for manufacturing of solid oral tablet dosage forms, as it involves less unit operations, does not require more sophisticated equipment’s for manufacturing and cost effective than wet granulation technique. To manufacture product using direct compression approach, raw materials used in formulation should have good flow and compressibility to achieve the desired physicochemical properties of dosage form.
Due to poor flow properties and less compressibility of metformin hydrochloride, the development of prolonged release formulation using less quantity of diluents and direct compression approach is challenging.
To overcome the challenges associated with the direct compression approach for manufacturing of prolonged release tablet dosage form of metformin hydrochloride, the inventors of the present invention found that during the direct compression there is need to improve compactability of blend. The inventors have meticulously identified that grade of microcrystalline cellulose having higher compactability and lower bulk density can be used to significantly improve the overall compactability of blend to formulate prolonged release metformin hydrochloride tablets with desired physical and chemical properties using direct compression as a manufacturing process.
Summary of the Invention
The present invention provides a prolonged release tablet dosage form containing metformin or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable excipients manufactured using direct compression as a manufacturing process.
In one aspect, the present invention provides a prolonged release tablet dosage form comprising metformin or pharmaceutically acceptable salt thereof and microcrystalline cellulose having higher compactability and lower bulk density to improve the compressibility.
These and other aspects and advantages of the present invention are described in the following detailed description of the invention.
Detailed Description of the Invention
Disclosed herein are tablets designed for the prolonged-release administration of metformin or its pharmaceutically acceptable salt. To achieve the prolonged-release administration of metformin or its pharmaceutically acceptable salt, the present invention provides tablet containing metformin or its pharmaceutically acceptable salt and grade of microcrystalline cellulose having higher compactability and lower bulk density.
The present invention may be understood more readily by reference to the following detailed description. It is to be understood that this invention is not limited to the specific products, methods, conditions or parameters described and/or shown herein, and that the terminology used herein is for the purpose of describing particular embodiments by way of example only and is not intended to be limiting of any claimed invention. Similarly, unless otherwise stated, any description as to a possible mechanism or mode of action or reason for improvement is meant to be illustrative only, and the invention herein is not be constrained by the correctness or incorrectness of any such suggested mechanism or more of action or reason for improvement. Throughout this text, it is recognized that the descriptions refer both to the features and methods of making and using the compositions described herein.
In the present disclosure the singular forms “a”, “an” and “the” include the plural reference, and references to a particular numerical value includes at least that particular value, unless the context clearly indicates otherwise. Thus, for example, a reference to “a material” is a reference to at least one of such materials and equivalents thereof known to those skilled in the art, and so forth.
When a value is expressed as an approximation by use of the descriptor “about” it will be understood that the particular value forms another embodiment. In general, use of the term “about” indicates approximations that can vary depending on the desired properties sought to be obtained by the disclosed subject matter and is to be interpreted in the specific context in which it is used, based on its function. The person skilled in the art will be able to interpret this as a matter of routine. In some cases, the number of significant figures used for a particular value may be one nonlimiting method of determining the extend of the word “about”. In other cases, the gradations used in a series of values may be used to determine the intended range available to the term “about” for each value. Where present, all ranges are inclusive and combinable. That is, references to values stated in ranges include every value within that range. The term “about” as used herein means ± approximately 10% of the indicated value.
It is to be appreciated that certain features of the invention which are, for clarity, described herein in the context of separate embodiments, may also be provided in combination in a single embodiment. That is, unless obviously incompatible or excluded, each individual embodiment is deemed to be combinable with any other embodiment(s) and such a combination is considered to be another embodiment. Conversely, various features of the invention that are, for brevity, described in the context of a single embodiment, may also be provided separately or in any subcombination.
The term “prolonged-release” as used herein refers to any type of release of metformin hydrochloride from a tablet of the present invention that is appropriate to obtain a specific therapeutic or prophylactic response after administration to a subject. A person skilled in the art knows how prolonged release differs from the release of immediate release tablet.
In one embodiment, the present invention provides a prolonged-release tablet which contains metformin or a pharmaceutically acceptable salt thereof, preferably hydrochloride, and a grade of microcrystalline cellulose (MCC) having higher compactability and lower bulk density.
The bulk density is preferably 0.10 to 0.15 g/cc.
The tablet may further include colloidal silicon dioxide, sodium stearyl fumarate, and hydroxypropyl methylcellulose (Hypromellose). Hydroxypropyl methylcellulose may have single viscosity grade or combination of different viscosity grades.
The following examples are illustrative only and are not intended to be a limitation on the present invention.
Example 1
Prolonged-release metformin tablet
Table 1
Manufacturing Procedure
(a) Metformin hydrochloride and colloidal silicon dioxide were co-sifted.
(b) Microcrystalline cellulose (KG-1000) and hydroxypropyl methylcellulose (100000 cps) co-sifted with step (a).
(c) Material of step (b) was blended in a blender
(d) Sodium stearyl fumarate was sifted through appropriate screen and mixed with step (c) to obtain lubricated blend.
(e) Lubricated blend of step (d) was compressed into tablets. (f) Compressed tablets of step (e) were packed in blister pack.
Example 2
Prolonged-release metformin tablet
Table 1 Manufacturing Procedure
1. Metformin hydrochloride, Microcrystalline cellulose (KG-1000), hydroxypropyl methylcellulose (100000 cps) and hydroxypropyl methylcellulose (15 cps) were co- sifted.
2. Colloidal silicon dioxide was sifted through finer sieve.
3. Material of step (a) and step (b) were blended in a blender for suitable time
4. Sodium stearyl fumarate was sifted and mixed with step (c) to obtain lubricated blend.
5. Lubricated blend of step (d) was compressed into tablets. 6. Compressed tablets of step (e) were packed in blister pack.
Example 3 Tablets prepared according to Example 1 and Example 2 were studied in comparison with the reference product Glucophage® and exhibited the following dissolution profile when tested in a USP Type 1 apparatus at 100 rpms in 900ml media (pH 6.8 phosphate buffer) and at 37°C:
Table 2
Example 4
Tablet prepared according to example 1 exhibited the following stability dissolution profile when stored at 40° and 75% relative humidity:
Table 3
Example 5
Tablet prepared according to example 2 exhibited the following stability dissolution profile when stored at 40° and 75% relative humidity:
Table 4
It will be understood by those skilled in the art that various changes may be made and equivalents may be substituted without departing from the scope of the invention, and further those other aspects, advantages and modifications will be apparent to those skilled in the art to which the invention pertains. In addition to the embodiments described herein, the present invention contemplates and claims those inventions resulting from the combination of features of the invention cited herein
and those of the cited prior art references which complement the features of the present invention. Similarly, it will be appreciated that any described material, feature, or article may be used in combination with any other material, feature, or article, and such combinations are considered within the scope of this invention.
Claims
1 . A prolonged-release tablet comprising metformin or a pharmaceutically acceptable salt thereof, a grade of microcrystalline cellulose having higher compactability and lower bulk density, and a pharmaceutically acceptable excipient.
2. The prolonged-release tablet as claimed in claim 1 , wherein the tablet further comprises hydroxypropyl methylcellulose of single viscosity grade or combination of different viscosity grades.
3. The prolonged-release tablet as claimed in claim 1 , wherein the tablet further comprises sodium stearyl fumarate as a lubricant and colloidal silicon dioxide as a glidant.
4. A process for the preparation of prolonged-release tablet of metformin hydrochloride, the process comprises the steps of
(a) co-sifting metformin hydrochloride and colloidal silicon dioxide,
(b) co-sifting microcrystalline cellulose and hydroxypropyl methylcellulose with step (a) and mixing,
(c) blending step (b) with sodium stearyl fumarate, and
(d) compressing step (c) into tablet,
5. A process for the preparation of prolonged-release tablet of metformin hydrochloride, the process comprises the steps of
(a) co-sifting metformin hydrochloride microcrystalline cellulose and hydroxypropyl methylcellulose and sifting colloidal silicon dioxide separately and mixing
(b) blending step (a) with sodium stearyl fumarate, and
(c) compressing step (b) into tablet.
6. A prolonged-release tablet comprising metformin hydrochloride and microcrystalline cellulose having bulk density of 0.10 to 0.15 g/cc.
7. A prolonged-release tablet and process for the preparation prolonged-release tablet, substantially as described and illustrated by examples herein.
Dated this 28th day of June 2022
Varun Chhonkar Agent for the Applicant IN/PA-1269
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| IN202121029146 | 2021-06-29 | ||
| IN202121029146 | 2021-06-29 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| WO2023275891A1 true WO2023275891A1 (en) | 2023-01-05 |
Family
ID=84690905
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PCT/IN2022/050594 WO2023275891A1 (en) | 2021-06-29 | 2022-06-28 | Prolonged release tablet containing metformin hydrochloride |
Country Status (1)
| Country | Link |
|---|---|
| WO (1) | WO2023275891A1 (en) |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2004012715A1 (en) * | 2002-08-02 | 2004-02-12 | Penwest Pharmaceuticals Company | Sustained release formulations of metformin |
| US8431618B2 (en) * | 2008-03-31 | 2013-04-30 | Asahi Kasei Chemicals Corporation | Processed starch powder with excellent disintegration properties and manufacturing method thereof |
-
2022
- 2022-06-28 WO PCT/IN2022/050594 patent/WO2023275891A1/en unknown
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2004012715A1 (en) * | 2002-08-02 | 2004-02-12 | Penwest Pharmaceuticals Company | Sustained release formulations of metformin |
| US8431618B2 (en) * | 2008-03-31 | 2013-04-30 | Asahi Kasei Chemicals Corporation | Processed starch powder with excellent disintegration properties and manufacturing method thereof |
Non-Patent Citations (1)
| Title |
|---|
| DUMAREY, M. ET AL.: "COMBINING EXPERIMENTAL DESIGN AND ORTHOGONAL PROJECTIONS TO LATENT STRUCTURES TO STUDY THE INFLUENCE OF MICROCRYSTALLINE CELLULOSE PROPERTIES ON ROLL COMPACTION", INTERNATIONAL JOURNAL OF PHARMACEUTICS, vol. 416, no. 1, 2011, pages 110 - 119, XP028264517, DOI: 10.1016/j.ijpharm.2011.06.018 * |
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