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
  • A61K31/33—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
  • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
  • A61K31/445—Non condensed piperidines, e.g. piperocaine
• • 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
  • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
  • A61K31/445—Non condensed piperidines, e.g. piperocaine
  • A61K31/4453—Non condensed piperidines, e.g. piperocaine only substituted in position 1, e.g. propipocaine, diperodon
• • 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
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/20—Pills, tablets, discs, rods
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/20—Pills, tablets, discs, rods
  • A61K9/2004—Excipients; Inactive ingredients
  • A61K9/2022—Organic macromolecular compounds
  • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
• • 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
  • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate

Definitions

• the present invention relates to a pharmaceutical composition showing an improved stability comprising eperisone or a pharmaceutically acceptable salt thereof and a particular acidifying agent, a pharmaceutical formulation prepared from the composition and a method for preparing the formulation.
• Eperisone is a skeletal muscle relaxant widely used for the treatment of spastic paralysis induced by neurological disorders such as dolorific spasm, cerebrovascular disorders, spastic spinal paralysis, cervical spondylosis, etc. which are often accompanied by musculoskeletal disorders such as cervico-omo-brachial syndrome, adhesive capsulitis, lumbodynia and the like.
• Eperisone not only acts on r-motor nerve in the spinal cord to result in muscle relaxation effects but also acts as an analgesic by suppressing the pain reflex via inhibition of the spinal reflex and antagonizing the effect of substance P, a central peptide neurotransmitter which is released in response to nociceptive stimuli.
• eperisone functions as a calcium antagonist and an anti-sympathomimetic agent by reducing vascular smooth muscle contraction, thereby helping blood circulation with low adverse side effects, because it acts directly on motor neurons.
• Eperisone was developed in Japan in the form of eperisone hydrochloride having the structure of formula (I) below, and is commercially available in Japan, India and across East Asia.
• many products including Mulex Tab. have been approved as skeletal muscle relaxants and are sold in Korea.
• the stability of products containing eperisone is affected by temperature, light, humidity, oxygen and the like during a long-term storage, and such factors may break down the active ingredient and increase related substances (i.e., impurities such as starting materials, intermediates, byproducts and decomposition products).
• related substances i.e., impurities such as starting materials, intermediates, byproducts and decomposition products.
• the therapeutic effect deteriorates due to quality problems including decrease in drug potency.
• Li Ding, et al. reported that a significant amount of a decomposed material of formula (II) was produced from an oral pharmaceutical composition containing eperisone hydrochloride in the form of a solid formulation under high temperature and basic conditions (see Li Ding, et al, Journal of Pharmaceutical and Biomedical Analysis, 46, 2008, 282-287).
• the inventors of the present invention discovered that products containing eperisone hydrochloride produced related substances and the amount thereof increased under severe conditions (60°C) and accelerated conditions (40°C, 75% relative humidity). It was also confirmed that related substances were produced and the amount of the active ingredient reduced when eperisone hydrochloride was exposed to solvents such as water and ethanol used in a wet granulation process, thereby adversely affecting the stability of the product.
• the inventors of the present invention have found that the stability of a product containing eperisone hydrochloride is significantly improved when a particular acidifying agent is employed as a stabilizer. Further, the types and ratios of the acidifying agent are chosen to satisfy the stability criteria required under the International Conference on Harmonization (ICH) guideline by minimizing the production of related substances. Thus, a pharmaceutical composition with an improved stability having reduced sticking property has been obtained.
• ICH International Conference on Harmonization
• a pharmaceutical composition of the present invention contains eperisone or a pharmaceutically acceptable salt thereof as an active ingredient, an acidifying agent and a pharmaceutically acceptable excipient.
• a pharmaceutical formulation of the present invention is prepared by using the above pharmaceutical composition.
• a pharmaceutical composition in accordance with the present invention employs a particular acidifying agent, inhibiting the production of related substances derived from eperisone hydrochloride, thereby preventing undesirable side effects.
• Such pharmaceutical composition can be safely used for the treatment of cervico-omo- brachial syndrome, lumbodynia and the like because the content of the active ingredient can be maintained and its therapeutic effect is preserved. Also, problems associated with the addition of the acidifying agent during the manufacturing process, e.g., sticking, have been improved, and hence, it can be useful in the pharmaceutical industry.
• Fig. 1 is a graph showing production rates of related substances as a result of a forced degradation testing.
• Fig. 2 is a result of stability test of Examples 1 to 5 and Comparative Example 1 under severe conditions.
• Fig. 3 is a result of stability test of Example 6 and Comparative Example 2 under severe conditions.
• Fig. 4 is a result of stability test of Examples 1, 7 and 9 and Comparative
• Fig. 5 is a result of stability test of Examples 2 and 10 to 12 and Comparative Example 1 under severe conditions.
• Fig. 6 is a result of stability test of Examples 1 and 2 and Comparative Example 1 under accelerated conditions.
• the present invention provides a pharmaceutical composition
• a pharmaceutical composition comprising eperisone or a pharmaceutically acceptable salt thereof as a pharmaceutically active ingredient, an acidifying agent and a pharmaceutically acceptable excipient.
• An active ingredient employed in the pharmaceutical composition of the present invention is eperisone, which is widely used as a skeletal muscle relaxant, or a pharmaceutically acceptable salt thereof.
• the pharmaceutically acceptable salt is any pharmaceutically acceptable salt conventionally available, preferably eperisone hydrochloride, but not limited thereto.
• the active ingredient may be employed in an amount conventionally acceptable to give pharmacological activity, preferably in an amount ranging from 25 mg to 150 mg.
• eperisone or a pharmaceutically acceptable salt thereof may be employed in an amount ranging from 10 to 60% by weight, preferably 20 to 60% by weight, based on the total weight of the pharmaceutical composition, but not limited thereto.
• the pharmaceutical composition of the present invention comprises a particular acidifying agent. Only certain acidifying agents can act as a stabilizing agent in the present invention, which effectively inhibits the production of related substances derived from eperisone hydrochloride, to improve stability of the pharmaceutical composition.
• the acidifying agent has a property of increasing the concentration of hydrogen ion more than hydroxide ion when in aqueous solution, and thus, represents an excipient that lowers pH of a substance or a solution by increasing acidity thereof.
• an acidifying agent in the present invention may be an excipient which has acidifying effect or increases its acidity, resulting in a pH value of 7 or lower in an aqueous solution or dispersion.
• the acidifying agent in accordance with the present invention may have a pH value less than 7 when dissolved in water or dispersed, which may be selected from the group consisting of an organic acid such as alginic acid; a mineral acid such as phosphoric acid, sulfuric acid, hydrochloric acid, boric acid, hydrobromic acid and a mixture thereof; and a mixture thereof, preferably phosphoric acid, alginic acid or a mixture thereof, more preferably phosphoric acid, but not limited thereto.
• an organic acid such as alginic acid
• a mineral acid such as phosphoric acid, sulfuric acid, hydrochloric acid, boric acid, hydrobromic acid and a mixture thereof
• a mixture thereof preferably phosphoric acid, alginic acid or a mixture thereof, more preferably phosphoric acid, but not limited thereto.
• a pharmaceutical composition of the present invention may contain an acidifying agent in an amount within the range of acceptable daily intake for humans, 0.01 to 1 parts by weight, based on 1 part by weight of eperisone or a pharmaceutically acceptable salt thereof (i.e., 0.1 to 60% by weight based on the total weight of the pharmaceutical composition), preferably 0.02 to 0.4 parts by weight, more preferably 0.04 o 0.2 parts by weight.
• a sticking phenomenon may occur (a condition where a composition sticks with a tablet machine) during the manufacturing process of tablets containing an acidifying agent.
• a pharmaceutical composition in accordance with the present invention preferably contains an acidifying agent in an amount ranging from 0.05 to 0.1 parts by weight, based on 1 part by weight of eperisone or a pharmaceutically acceptable salt thereof.
• a pharmaceutical composition in accordance with the present invention may contain a pharmaceutically acceptable excipient.
• the pharmaceutically acceptable excipient may be any conventional excipient commonly used in the pharmaceutical industry, which may be selected from the group consisting of a dispersing agent, a disintegrating agent, a lubricating agent, a binding agent, other acidifying agent(s) and a mixture thereof.
• Examples of the dispersing agent in the present invention may be selected from the group consisting of lactose, microcrystalline cellulose, mannitol and a mixture thereof, but not limited thereto.
• the amount of dispersing agent employed may be, based on the total weight of composition, 15 to 70% by weight, preferably 25 to 50% by weight.
• disintegrating agent in the present invention may be selected from the group consisting of corn starch, crospovidone, croscarmellose sodium, sodium starch glycolate, low-substituted hydroxypropyl cellulose and a mixture thereof, but not limited thereto.
• the amount of disintegrating agent employed may be, based on the total weight of composition, 3 to 20% by weight, preferably 5 to 10% by weight.
• binding agent in the present invention may be selected from the group consisting of povidone, hydroxypropyl cellulose, hydroxypropyl methylcellulose and a mixture thereof, but not limited thereto.
• the amount of binding agent employed may be, based on the total weight of composition, 1 to 10% by weight, preferably 3 to 7% by weight.
• Examples of the lubricating agent in the present invention may be selected from the group consisting of talc, stearic acid, magnesium stearate and a mixture thereof, but not limited thereto.
• the amount of lubricating agent employed may be, based on the total weight of the composition, 0.5 to 5% by weight, preferably 2 to 4% by weight.
• the pharmaceutical composition of the present invention has a pH value of 1 to 5, e.g., when dissolved or dispersed in 10 to 20 niL of water.
• the present invention provides a pharmaceutical formulation prepared by using the above pharmaceutical composition.
• the pharmaceutical formulation in accordance with the present invention is in the form of an oral solid pharmaceutical formulation selected from the group consisting of a powder, a granule, a pellet, a tablet and a capsule, preferably in the form of a tablet.
• the present invention provides a method for manufacturing a pharmaceutical formulation comprising the steps of:
• step (ii) mixing the granules obtained from step (i) with a pharmaceutically acceptable excipient.
• granules may be prepared by mixing eperisone or a pharmaceutically acceptable salt thereof, an acidifying agent, and a pharmaceutically acceptable excipient. The ingredients were sifted through a 30 to 80 mesh sieve to allow a homogeneous mixture.
• the process for the preparation of granules may be accomplished by a dry granulation process or a wet granulation process.
• the dry granulation process in accordance with the present invention comprises the steps of:
• eperisone or a pharmaceutically acceptable salt thereof with an acidifying agent and a pharmaceutically acceptable excipient (e.g., a dispersing agent, a disintegrating agent and a binding agent);
• a pharmaceutically acceptable excipient e.g., a dispersing agent, a disintegrating agent and a binding agent
• the compression of the mixture may be accomplished by using a roller compactor, and the pulverization of the compressed agglomerates may be done by using an oscillator and a Fitz mill, or any conventional device used for a granulation process in the pharmaceutical industry.
• the wet granulation process in accordance with the present invention comprises the steps of:
• the combining of the mixed binding solution may be accomplished by using a high speed mixer or a fluid bed granulator, and the pulverizing of the combined material may be accomplished by using an oscillator and a Fitz mill, or any conventional device used for a granulation process in the pharmaceutical industry.
• the acidifying agent may be used in the step (i) of the granulation process so as to increase the specific surface area in contact with eperisone or a pharmaceutically acceptable salt thereof.
• the acidifying agent may be mixed with an active ingredient and a pharmaceutically acceptable excipient, sifted through a 30 to 80 mesh sieve, and the resulting mixture may be used for a dry or wet granulation process.
• the acidifying agent may be dissolved or dispersed in a binding solution to obtain a mixed binding solution, followed by combining with an active ingredient and a pharmaceutically acceptable excipient.
• the resulting combined material may be used for a wet granulation process.
• a pharmaceutically acceptable excipient may be added to the granules prepared in step (i), wherein the pharmaceutically acceptable excipient is as defined above (e.g., a dispersing agent, a disintegrating agent and a lubricating agent).
• the pharmaceutically acceptable excipient is as defined above (e.g., a dispersing agent, a disintegrating agent and a lubricating agent).
• the method may further comprise an additional step of formulating the mixture obtained in step (ii) into an oral solid pharmaceutical formulation in the form selected from the group consisting of a powder, a granule, a pellet, a tablet and a capsule.
• the final mixture obtained in step (ii) may be prepared into an oral solid pharmaceutical formulation using any conventional method commonly used in the pharmaceutical industry.
• the final mixture obtained in step (ii) may be compressed into a tablet using a tableting machine.
• the inventors of the present invention have discovered that a number of acidifying agents (e.g., phosphoric acid and alginic acid) can effectively inhibit the degradation of eperisone hydrochloride induced by an external environment such as temperature, moisture, oxygen, light and the like as compared to other conventional stabilizing agents, thereby preventing reduction in drug efficacy as well as lowering adverse side effects associated with related substances. It was observed that particular acidifying agents such as phosphoric acid and alginic acid have inhibitory activity on the production of related substances derived from eperisone hydrochloride. In addition, the pharmaceutical composition satisfied the requirement set forth in the ICH guideline for eperisone hydrochloride, and hence the inhibitory activity on the production of related substances was confirmed.
• acidifying agents e.g., phosphoric acid and alginic acid
• a tablet containing eperisone was prepared. Specifically, eperisone hydrochloride (Dongbang FTL, Korea) was mixed with lactose, microcrystalline cellulose and corn starch. To allow a homogeneous mixture, the ingredients were sifted through a 30 mesh sieve before the mixing. Povidone was added to distilled water in a separate container, and stirred to yield a solution. Phosphoric acid was added thereto, followed by stirring to yield a binding solution. The mixture prepared comprising eperisone hydrochloride was added to the binding solution, followed by combining to obtain combined material. The combined material obtained was dried at 60°C to eliminate moisture, and then pulverized through a 30 mesh sieve. Microcrystalline cellulose and corn starch was added to the pulverized material, followed by adding talc and magnesium stearate for final mixing. The final mixture was compressed into a tablet using a tableting machine (GRC-18, Sejong Pharmatech).
• tablets containing eperisone were prepared.
• the procedure of Example 1 was repeated except for using alginic acid, fumaric acid, ascorbic acid and erythorbic acid, instead of phosphoric acid, to prepare a tablet.
• Example 1 a tablet containing eperisone was prepared. The procedure of Example 1 was repeated to prepare a tablet except that no phosphoric acid was employed.
• eperisone hydrochloride (Dongbang FTL, Korea) was mixed with alginic acid, lactose, microcrystalline cellulose and corn starch. The ingredients were sifted through a 30 mesh sieve to allow a homogeneous mixture. The mixture was formed into a compressed material having a ribbon shape in uniform size by using a roller compactor (Freund), followed by pulverizing or dividing the prepared compressed materials to obtain dry granules with irregular shape by using oscillator (Freund).
• Example 2 In accordance with the ingredients listed in Table 2, a tablet containing eperisone was prepared. The procedure of Example 6 was repeated to prepare a tablet except that no alginic acid was employed. Table 2
• eperisone hydrochloride (Dongbang FTL, Korea) was mixed with lactose, microcrystalline cellulose and corn starch. These ingredients were sifted through a 30 mesh sieve to allow a homogenous mixture. Povidone was added to distilled water in a separate container, and stirred to yield a solution. Phosphoric acid was added thereto, followed by stirring to yield a binding solution. The mixture prepared containing eperisone hydrochloride was added to the binding solution, followed by combining to obtain a combined material.
• the combined material obtained was dried at 60°C to eliminate moisture, and then pulverized through a 30 mesh sieve to prepare wet granules.
• Microcrystalline cellulose and corn starch were additionally mixed, followed by adding talc and magnesium stearate for final mixing.
• the final mixture was compressed into a tablet using a tableting machine (GRC-18, Sejong Pharmatech).
• tablets containing eperisone were prepared.
• the procedure of Example 7 was repeated to prepare a tablet except that different amounts of phosphoric acid added to the binding solution were used.
• tablets containing eperisone were prepared. Specifically, eperisone hydrochloride (Dongbang FTL, Korea) was mixed with lactose, microcrystalline cellulose and corn starch. The said ingredients were sifted through a 30 mesh sieve to allow a homogeneous mixture. Povidone was added to distilled water in a separate container, and stirred to yield a solution. Alginic acid was added thereto, followed by stirring to yield a binding solution. The mixture prepared containing eperisone hydrochloride was added to the binding solution, followed by combining to obtain a combined material.
• the combined material obtained was dried at 60°C to eliminate moisture, and then pulverized through a 30 mesh sieve to prepare wet granules.
• Microcrystalline cellulose and corn starch were additionally mixed, followed by adding talc and magnesium stearate for final mixing.
• the final mixture was compressed into a tablet using a tableting machine (GRC-18, Sejong Pharmatech).
• Example 10 In accordance with the ingredients listed in Table 4, tablets containing eperisone were prepared. The procedure of Example 10 was repeated to prepare a tablet except that different amounts of alginic acid added to the binding solution were used.
• a forced degradation test of eperisone hydrochloride was performed to compare the production rate of related substances according to acidifying agents of the pharmaceutical composition. The test conditions are described hereinafter.
• eperisone hydrochloride Specifically, eperisone hydrochloride was dissolved in acetonitrile and the solution was stored under four different degradation conditions mentioned above for 2 hours each so as to determine under which condition degradation of eperisone hydrochloride is accelerated. Thereafter, an eperisone hydrochloride solution was prepared to have a final concentration of 1000 ⁇ g/mL, and the resulting solution was analyzed for related substances under the following conditions using a liquid chromatography. The results are shown in Fig. 1. ⁇ Analysis Conditions>
• UV-absorption detector (absorbance at 254 nm)
• Example 6 containing alginic acid resulted in less related substances than Comparative Example 2 which does not contain alginic acid when stored under severe conditions for 4 weeks. Therefore, it was confirmed that a particular acidifying agent can effectively inhibit the production of related substances in a formulation containing eperisone hydrochloride prepared by a dry granulation process as well. Table 6

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• 2012
  • 2012-01-13 KR KR1020120004432A patent/KR101832842B1/ko not_active Expired - Fee Related
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