KR20130014787A - A manufacturing process of composition comprising solifenacin - Google Patents
A manufacturing process of composition comprising solifenacin Download PDFInfo
- Publication number
- KR20130014787A KR20130014787A KR1020110076452A KR20110076452A KR20130014787A KR 20130014787 A KR20130014787 A KR 20130014787A KR 1020110076452 A KR1020110076452 A KR 1020110076452A KR 20110076452 A KR20110076452 A KR 20110076452A KR 20130014787 A KR20130014787 A KR 20130014787A
- Authority
- KR
- South Korea
- Prior art keywords
- solifenacin
- granules
- pharmaceutical composition
- stability
- mixture
- Prior art date
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Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/439—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom the ring forming part of a bridged ring system, e.g. quinuclidine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
-
- 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
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
Abstract
Description
The present invention relates to a method for producing a more stable solifenacin-containing pharmaceutical composition.
Solifenacin is represented by the following Chemical Formula 1, and the chemical name is (1R, 3'R) -3'-quinuclininyl-1-phenyl-1,2,3,4-tetrahydro-2-isoquinolinecarboxylate. Call.
Quinuclidin derivatives containing the solifenacin or salts thereof have excellent selective antagonism of the muscarinic M3 receptor, and urinary diseases such as neuropathy, neurogenic bladder, bladder spasm or chronic cystitis or chronic obstructive pulmonary It has been reported to be useful as a prophylactic agent for respiratory diseases such as diseases, chronic bronchitis, asthma and rhinitis (see EP801067).
However, unlike the fact that solifenacin or salt thereof is very stable in the raw material state, when the finished product is manufactured by formulating, the finished product has a problem of containing more impurities generated during the manufacturing process.
Regardless of the stability of the raw material itself, the main ingredient depends on various process conditions such as reaction temperature, pH, reaction time, mixing order, etc., depending on the formulation method, and the characteristics of excipients, binders, lubricants, etc. mixed together. There may be a variety of causes, such as interactions may occur upon contact with each other, and thus it is understood that sufficient study of formulation is required for each component.
In general, the decomposition of drugs in such formulations may include redox reactions, hydrolysis reactions, racemization, photolysis, polymerization decomposition, and the like, and these reactions may interact with heat, oxygen, light, water, and other components. It is known that the back is related. In order to obtain such a stable formulation, it is necessary to consider several causes related to the decomposition of the drug. In the case of formulation through wet granulation, as in the case of Bishcare Tablet (released by Astellas Pharmaceuticals), which is currently commercially available, As such, the main component tends to decompose over time due to interaction with organic solvents such as water or alcohol used during the manufacturing process, heating for removal of these solvents, and in the case of the direct method, On the other hand, in the preparation of a formulation with a small proportion of the active ingredient, excipients that may cause weight variation or content uniformity between tablets, and which may affect the stability of the active ingredient by random mixing with the main ingredient, There is a problem of maximizing indiscriminate exposure to the skin. Finding is not something that can be identified by simple iterations of experiments.
Therefore, in the related art, a method of limiting the amorphous content of solifenacin or its salt, or controlling the amount of water in a wet granulation method (see Korean Patent Application No. 2006-7019783), or a method of limiting the type of binder [Ref. Application 2007-7017266 has been proposed to inhibit the degradation of solifenacin over time. However, these methods also have the limitation of stability according to the wet method or the direct method, and there is still a need for improvement.
The present invention relates to a method for producing a stable solifenacin-containing pharmaceutical composition through a granulation method without using water or an organic solvent. In particular, the present invention was able to significantly improve the stability of the formulation by identifying the excipients and lubricants that adversely affect the stability of the main component in the composition and formulating them separately from the granules.
The present invention provides a more stable method for producing solifenacin and its salt-containing pharmaceutical composition.
The present invention is a mixture of the active ingredient solifenacin or a pharmaceutically acceptable salt thereof and excipients and lubricants that do not affect the stability, compression, grinding and formulation to produce a granule without using water or an organic solvent A method for producing a stable solifenacin-containing pharmaceutical composition is included.
In more detail, the process according to the present invention is mixed with only the active ingredient solifenacin or a pharmaceutically acceptable salt thereof and excipients and lubricants that do not affect the stability, and then compressed, pulverized and formulated, Alternatively, the granules may be prepared without using a solvent such as an organic solvent, and thus, decomposition of the main component by the solvent used in the wet granulation does not occur, and the main component is not subjected to a high temperature drying process to remove the used solvent. There is an advantage that does not decompose by this heat.
In addition, unlike the direct-acting method of randomly mixing and tableting, only excipients and lubricants that do not affect the main ingredient and stability are formulated into granules, and then excipients and lubricants that affect other stability are classified and granulated. There is an advantage to post-mixing after anger. As a result, not only can the thermodynamically stable state be maintained during the final manufacturing process, but also the excipients and glidants that affect stability even though the small amount of the main component is formulated to reduce the mutual contact by separating the granules from the granules Impurities can be significantly reduced, and the stability of the active ingredient is greatly improved even in the distribution storage process, which can prolong the shelf life.
In addition, the granules of the present invention preferably have a range of 30 to 100 mesh, preferably 60% or more, and more preferably 40 to 80 mesh. This can cause granules of particles larger than 30 mesh to cause weight variation or content uniformity between tablets during tablet molding, and if there are many particles smaller than 100 mesh, the granules may not have good fluidity, which may cause problems in high speed tableting. In addition, the contact with additional excipients that may affect the stability of the active ingredient may increase the adverse effect on the stability.
In addition, the main component of the composition according to the present invention includes solifenacin or a pharmaceutically acceptable salt thereof, and in particular, the pharmaceutically acceptable salt of solifenacin is most preferably succinic acid, and the content thereof is 2.5 to 20 mg. May contain
In addition, the present invention is most preferably used lactose, starch, hydroxypropyl methyl cellulose, low-substituted hydroxypropyl cellulose as an excipient that does not affect the stability used when preparing the granules, in particular microcrystalline cellulose, phosphoric acid Excipients such as calcium hydrogen, sorbitol, mannitol and the like may cause problems in the stability of the main component and are preferably not used.
In addition, the present invention confirms that the use of magnesium stearate as a lubricant in the manufacturing process has a large effect on the stability of the main component, and the type of lubricant that does not affect the stability of stearic acid, talc, except magnesium stearate , Silicon dioxide, sodium stearyl fumarate, polyethylene glycol or mixtures thereof, the content of which is most preferably limited to 0.1 to 5.0% by weight (w / w).
Then, the present invention can be prepared in the form of capsules by filling the granules prepared in the hard capsules, and recompressed in a tableting machine to produce a tablet, or by adding the excipients and lubricants, and then mixed It also includes a method of manufacturing into a tablet. The process after granule preparation is not limited to this.
The present invention provides a method for producing a more stable solifenacin-containing pharmaceutical composition without using water or an organic solvent.
Therefore, the composition prepared according to the method of the present invention, unlike the wet method using a water or organic solvent or a direct mixing method randomly mixed, does not use a solvent but also excipients or lubricants that affect the stability By formulating them separately on the outside of the granules, there are no problems in the manufacturing process compared to the preparations made by the conventional wet method or the direct batting method, and there are significantly fewer impurities immediately after the preparation, and the stability is greatly improved even during the distribution of the preparation. It can be effective to prolong the shelf life.
Hereinafter, preferred embodiments of the present invention will be described in order to facilitate understanding of the present invention. However, the following examples are provided only for the purpose of easier understanding of the present invention, and the present invention is not limited by the examples.
Example 1
5.0 g of succinic acid solifenacin succinate was mixed with 30.0 g of lactose hydrate (Pharmatose 200) and 30.0 g of corn starch and 6.0 g of hydroxypropylmethylcellulose, and then 2.0 g of talc was added to form a mixture. The mixture was compressed in a roller compactor (Roller Compactor, Fruend TF-Labo) at a pressure of 4MPa to prepare a plate compact. The compacted product was ground and sieved using an oscillator (Oscillator, ERWEKA company AR-402) using 20 mesh (standard standard KSA5101-1) to prepare granules. 0.5 g of magnesium stearate was added to the granules, mixed, and compressed into a rotary tablet press (Shanghai Tianhe Pharmaceutical Machinery, ZP198) to prepare a tablet. The tablet was 150 mg per tablet to contain 5 mg of solvenacin succinate. In addition, Opadry yellow 03F12967 was dissolved in purified water and sprayed to coat 4mg of Opadry yellow 03F12967 per tablet.
[Example 2]
5.0g of succinic acid solifenacin succinate is mixed with 50.0g of lactose (Pharmatose 200), followed by 44.5g of lactose (4), lactose starch (42.0g) and 6.0g of hydroxypropylmethylcellulose. It was. 2.0 g of stearic acid was added to the mixture, and the mixture was lubricated and then compressed into a compactor (Roller Compactor, Fruend's TF-Labo) at a pressure of 4 MPa to prepare a plate compact. The compacted product was ground and sieved using an oscillator (Oscillator, AR-402 of ERWEKA Co., Ltd.) using 20 mesh (standard specification KSA5101-1) to prepare granules. 0.5 g of magnesium stearate was added to the granules, mixed, and compressed into a rotary tablet press (Shanghai Tianhe Pharmaceutical Machinery, ZP198) to prepare a tablet. The tablet was 150 mg per tablet to contain 5 mg of solvenacin succinate. In addition, Opadry yellow 03F12967 was dissolved in purified water and sprayed to coat 4mg of Opadry yellow 03F12967 per tablet.
[Example 3]
5.0 g of succinic acid solifenacin succinate was mixed with 50.0 g of lactose (Pharmatose 200) and then mixed with 59.5 g of lactose (Pharmatose 200) and 10.0 g of corn starch. 2.0 g of stearic acid was added to the mixture, and the mixture was lubricated and then compressed into a compactor (Roller Compactor, Fruend's TF-Labo) at a pressure of 4 MPa to prepare a plate compact. The compacted product was ground and sieved using an oscillator (Oscillator, AR-402 of ERWEKA Co., Ltd.) using 20 mesh (standard specification KSA5101-1) to prepare granules.
23.0 g of microcrystalline cellulose (Vivapur 12) and 0.5 g of magnesium stearate were added to the granules, mixed, and compressed into a granulator (Shanghai Tianhe Pharmaceutical Machinery, ZP198) to prepare a tablet. The tablet was 150 mg per tablet to contain 5 mg of solvenacin succinate. In addition, Opadry yellow 03F12967 was dissolved in purified water and sprayed to coat 4mg of Opadry yellow 03F12967 per tablet.
Comparative Example 1
5.0 g of solifenacin succinate, 107.5 g of lactose hydrate (Pharmatose 200), and 30.0 g of corn starch were mixed, and then 6.0 g of hydroxypropylmethylcellulose was separately dissolved in purified water to prepare a binder solution. Put them together. After granulation through a 16 mesh sieve, the granules were dried in an oven at 60 ° C. for 2 hours so that the moisture in the granules was 2.0% or less. After sizing in a 20 mesh (mesh) mesh, 1.5 g of magnesium stearate was added to the mixture, and the mixture was lubricated and compressed into a tablet using a rotary tablet press (Shanghai Tianhe Pharmaceutical Machinery, ZP198). The tablet was 150 mg per tablet to contain 5 mg of solvenacin succinate. In addition, Opadry yellow 03F12967 was dissolved in purified water and sprayed to coat 4mg of Opadry yellow 03F12967 per tablet.
Comparative Example 2
5.0g of succinic acid solifenacin succinate is mixed with 20.0g of lactose (Pharmatose 200), followed by adding 85.5g of lactose (8), lactose starch (30.0g) and 6.0g of hydroxypropylmethylcellulose. It was. 2.0 g of colloidal silicon oxide (Aerosil 200) and 1.5 g of magnesium stearate were mixed in a mixture, and then slid and mixed in a rotary tablet press (Shanghai Tianhe Pharmaceutical Machinery, ZP198) to prepare a tablet. The tablet was 150 mg per tablet to contain 5 mg of solvenacin succinate. In addition, Opadry yellow 03F12967 was dissolved in purified water and sprayed to coat 4mg of Opadry yellow 03F12967 per tablet.
[Experimental Example 1]
The tablets prepared in each Example and Comparative Example were put in a bottle made of HDPE, and capped, and then stored in a constant temperature and humidity chamber at a temperature of 40 ° C. and a relative humidity of 75%, and the degree of generation of impurities was compared for 4 weeks. Impurities were each dissolved in 30% acetonitrile and solubilized sufficiently by sonication, and then filtered through a 0.45 um membrane filter and tested according to the liquid chromatograph method.
[Experimental Example 2]
The tablets of Example 2 were PTP-packed using PVDC and aluminum to obtain the same packaging state as Beshcare tablet, a commercial drug. Example 2 and Betsy care tablets were stored in a PTP packaging in a constant temperature and humidity chamber at a temperature of 40 ° C. and a relative humidity of 75%, and the degree of generation of impurities was compared for 2 months. Impurities were each dissolved in 30% acetonitrile and solubilized sufficiently by sonication, and then filtered through a 0.45 um membrane filter and tested according to the liquid chromatograph method.
Claims (4)
The granule is a method for producing a stable solifenacin-containing pharmaceutical composition, characterized in that 60% or more of the total granules have a particle size of 30 to 100 mesh.
The granules are excipients that do not affect the stability as a excipient, lactose, starch, hydroxypropyl methyl cellulose, low-substituted hydroxypropyl cellulose or a mixture thereof, the method for producing a stable solifenacin-containing pharmaceutical composition.
The granules contain 0.1 to 5.0% by weight (w / w) of stearic acid, talc, silicon dioxide, sodium stearyl fumarate, polyethylene glycol, or a mixture thereof as a lubricant without affecting stability, and magnesium stearate A method for producing a stable solifenacin-containing pharmaceutical composition, characterized in that it does not contain silver.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| KR1020110076452A KR20130014787A (en) | 2011-08-01 | 2011-08-01 | A manufacturing process of composition comprising solifenacin |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| KR1020110076452A KR20130014787A (en) | 2011-08-01 | 2011-08-01 | A manufacturing process of composition comprising solifenacin |
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| KR20130014787A true KR20130014787A (en) | 2013-02-12 |
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| Application Number | Title | Priority Date | Filing Date |
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| KR1020110076452A KR20130014787A (en) | 2011-08-01 | 2011-08-01 | A manufacturing process of composition comprising solifenacin |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| KR20180050639A (en) * | 2018-05-08 | 2018-05-15 | 씨제이헬스케어 주식회사 | Stable pharmaceutical composition comprising solifenacin, and method for preparing the same |
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2011
- 2011-08-01 KR KR1020110076452A patent/KR20130014787A/en not_active Application Discontinuation
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| KR20180050639A (en) * | 2018-05-08 | 2018-05-15 | 씨제이헬스케어 주식회사 | Stable pharmaceutical composition comprising solifenacin, and method for preparing the same |
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