JP2019112373A - Pharmaceutical preparation - Google Patents

Abstract

To provide a pharmaceutical preparation that avoids the trouble of e.g. malodor and expansion or cracking while having loxoprofen and methocarbamol.SOLUTION: A pharmaceutical containing preparation is characterized in that: a pharmaceutical composition containing loxoprofen or a pharmaceutically acceptable salt thereof and methocarbamol, is included in a pharmaceutical container together with an adsorbent selected from silicate or aluminosilicate or a mixture of them and activated carbon.SELECTED DRAWING: None

Description

  The present invention relates to a pharmaceutical preparation, and more particularly, as an OTC medicine (general-use medicine) etc., the anti-inflammatory action, the analgesic action and the antipyretic action are further improved as compared with conventional ones and handling is easy. A pharmaceutical composition containing loxoprofen as a main component, which is suitable for self-medication, is easy to use for alleviation of symptoms of light illness, etc., is easy to handle even at the time of distribution, and is excellent in safety and stability. About.

  Loxoprofen is a non-steroidal antipyretic analgesic / antiinflammatory agent based on propionic acid, which has excellent anti-inflammatory, analgesic and antipyretic effects by suppressing the biosynthesis of prostaglandins that cause fever and inflammation. It is widely used as a medicine.

  By the way, it is known that the medicinal effects of pharmaceuticals may be improved by the combination with other drugs, and the effect of such a combination is also reported for loxoprofen (Patent Documents 1 to 8 and the like).

  From this point of view, the present inventors have also searched for pharmaceuticals that can obtain new effects by combining with loxoprofen. Metocarbamol having skeletal muscle relaxing action and weak analgesic action is analgesia of loxoprofen I found it to improve the effect.

  However, when the preparation combining this loxoprofen and methocarbamol is examined in more detail, although there is no problem at the initial stage of production, when stored for a certain period of time, an offensive odor is generated, and when it is made into tablets, the swelling and cracking There are problems such as the occurrence of, and I learned that it would greatly reduce the commercial value.

  Therefore, in order to incorporate methocarbamol into loxoprofen, it is necessary to solve the above-mentioned problems.

Patent No. 5525323 Patent No. 5525324 Patent No. 5624367 Patent No. 5798800 Patent No. 5896645 JP 2010-215611 A JP, 2011-6407, A JP 2012-46445

  Therefore, an object of the present invention is to provide a pharmaceutical preparation which has loxoprofen and methocarbamol but does not have problems such as odor and swelling and cracking.

  The present inventors have intensively studied to solve the above-mentioned problems, and in a pharmaceutical composition in which loxoprofen or a pharmaceutically acceptable salt thereof and methocarbamol are combined in a container filled with the pharmaceutical composition. It has been found that by arranging a specific adsorbent in the present invention, problems such as malodor and swelling and cracking when made into tablets can be prevented, and the present invention has been completed.

  That is, the present invention relates to a pharmaceutical composition containing loxoprofen or a pharmaceutically acceptable salt thereof and methocarbamol together with an adsorbent selected from silicates or aluminosilicates or mixtures thereof with activated carbon in a pharmaceutical container. It is a pharmaceutical preparation comprising.

  The present invention is also the above-mentioned pharmaceutical preparation, wherein the above-mentioned pharmaceutical composition is obtained by granulating loxoprofen or a pharmaceutically acceptable salt thereof and methocarbamol, and formulating this into a pharmaceutical composition.

  Furthermore, the present invention relates to a method for preserving a pharmaceutical composition comprising loxoprofen or a pharmaceutically acceptable salt thereof and methocarbamol, which comprises a silicate or aluminosilicate or a mixture thereof with activated carbon in a pharmaceutical container. Storage with an adsorbent selected from

  The pharmaceutical composition of the present invention is a combination of loxoprofen or a pharmaceutically acceptable salt thereof and methocarbamol to enhance the anti-inflammatory analgesic effect, particularly in the area of orthopedics.

  And, this pharmaceutical composition is made into a pharmaceutical preparation filled with a specific adsorbent in a pharmaceutical container, whereby malodor problems that are considered to be due to the interaction between loxoprofen and methocarbamol, and tablets are made. It can prevent the problem of swelling and cracking, and can be made highly commercial.

  In addition, the problem when mixing loxoprofen and another pharmaceutical ingredient is described also in the patent documents mentioned by the said prior art document. However, the problems in these patent documents are problems of discoloration, solidification, wetting, etc. which are considered to be due to the influence of water vapor in the air, and the solution means is also the arrangement of a hygroscopic agent, so the problems that occur with the present invention. Also, the solution is different.

  The pharmaceutical composition used in the pharmaceutical preparation of the present invention is a combination of loxoprofen or a pharmaceutically acceptable salt thereof and methocarbamol.

Loxoprofen used in this pharmaceutical composition has a chemical name of (RS) -2- [4-[(2-oxocyclopentyl) methyl] phenyl] propanoic acid ((RS) -2- [4-[(2 -oxocyclic pentyl) methyl] phenyl] propanoic acid), and the dihydrate of its sodium salt is widely used as a medicine (molecular formula (Na salt): C ₁₅ H ₁₇ O ₃ Na · H ₂ O, molecular weight (Na salt): 304.31). Loxoprofen is an anti-inflammatory analgesic already known as a non-steroidal anti-inflammatory analgesic based on propionic acid, and includes rheumatoid arthritis, osteoarthritis, gout attack, ankylosing spondylitis, lumbago, shoulder and shoulder joint syndrome, cervical shoulder arm syndrome , Tendonitis, dysmenorrhea, anti-inflammation of herpes zoster diseases, analgesia, fever reduction, post-traumatic and post-operative anti-inflammatory, analgesia, tooth extraction in dental and oral surgery area, post-surgery anti-inflammatory, analgesia etc. It is widely used.

  Examples of pharmaceutically acceptable salts of loxoprofen include sodium salts, potassium salts, ammonium salts, meglumin salts, tris salts, salts of basic amino acids and the like.

  The compounding amount of loxoprofen or a pharmaceutically acceptable salt (hereinafter, also simply referred to as "loxoprofen") in the pharmaceutical composition of the present invention may be appropriately determined depending on the sex, age, symptoms and the like of the recipient. For example, for efficacy and safety as an OTC drug, it is preferable to incorporate in the pharmaceutical composition of the present invention such that the dose per adult is usually about 30 to 120 mg, preferably 60 to 70 mg. . In addition, the content of loxoprofen relative to the total mass of the pharmaceutical composition of the present invention is, for example, preferably 1 to 30% by mass (hereinafter referred to as "%"), and more preferably 3 to 15%.

On the other hand, in the pharmaceutical composition of the present invention, methocarbamol is blended in addition to the above loxoprofen. This methocarbamol is its chemical name (nomenclature) 3- (o-methoxyphenoxy) -2-hydroxypropyl-1-carbamate (3- (o-Methoxyphenoxy) -2-hydroxypropyl-1-carbamate), The molecular formula is C ₁₁ H ₁₅ NO ₅ and the molecular weight is 241.24. Metocarbamol is one of the central skeletal muscle relaxants used to relieve skeletal muscle spasm and tension, and is already marketed as a central nervous system depressant with skeletal muscle relaxation and weak sedation. It is.

  The compounding amount of methocarbamol described above is about 0.3 to 4.5 g, preferably about 0.5 to 1.5 g, in the pharmaceutical composition of the present invention as a daily dose for adults. Is preferred.

  In the pharmaceutical composition of the present invention, the compounding ratio of loxoprofen to methocarbamol is preferably 2 to 20 parts by weight, more preferably 5 to 12 parts by weight of methocarbamol to 1 part by weight of loxoprofen. .

  In addition to loxoprofen and methocarbamol described above, the pharmaceutical composition of the present invention may be formulated, if necessary, with formulation components to be described later, and other pharmaceutical components (except those described above), according to a conventional method. It is prepared by The solid preparation referred to herein includes internal preparations such as fine granules, granules, powders, tablets, caplets, hard capsules, orally disintegrating tablets, chewable tablets, troches, effervescent tablets, dry syrups and the like.

  As an example of the manufacturing method of the above-mentioned pharmaceutical composition, a method of mixing the above-mentioned pharmaceutical component, necessary formulation component and other pharmaceutical component to make it into powder, fine granules, granules and the like, and powder obtained And the method of further filling granules and the like in hard capsules to make capsules, and the method of making the obtained powder, granules and the like into tablets by further known tableting methods.

  As an example of the preparation method of a more preferable pharmaceutical composition, in order to prevent that loxoprofen and methocarbamol cause an unnecessary interaction in the formed pharmaceutical composition, each is separately formulated as a formulation component, A two-layered or multi-layered tablet, or a nucleated tablet, formulated as a capsule granulated with other pharmaceutically active ingredients and filled as it is in granules or hard capsules, or formulated without mixing the granules internally The method of setting it as a tablet is mentioned.

  For each formulation described above, for example, Yusuke Tsuda and Hisashi Ueno, “Pharmaceutical development basic course XI Pharmaceutical manufacturing method (upper) (bottom)”, Jijin Shokan, 1971 published; Nakai Yusen, “Formulation Engineering handbook, published by 1983, Yuki Nakai, "Development of pharmaceutical products 11. Unit operation and machine of pharmaceutical preparation", Kamogawa Shoten, published in 1989; Mitsuru Hashida, "design and evaluation of orally administered pharmaceutical preparation" Y. Shiyaku Shikkan, published in 1995; Hashida, Mitsuru, "Prescription design of orally administered preparation", K. Shiyaku Shiksha, published in 1995, etc., can adopt a commonly used method.

  In the pharmaceutical preparation of the present invention, an adsorbent selected from a silicate or an aluminosilicate or a mixture of these and activated carbon is disposed and used in a container together with the above-mentioned pharmaceutical composition, which is used in the container It is not particularly limited as long as it can adsorb the offensive odor component to be generated and other volatile components, and one or more of them can be used.

  Examples of the adsorbent include silica gel as a silicate and silica alumina gel as aluminosilicate, natural or synthetic zeolite, montmorillonite and the like. Moreover, mixing of these and activated carbon can be performed by a conventional method.

  Among these adsorbents, commercially available products include Dryan tablet PW or DO type, dry silica gel such as dry solid packaged products (all manufactured by Yamanin Pharmaceutical Co., Ltd.), Allophane (manufactured by Fuji Gel Sangyo Co., Ltd.), etc. Natural or synthetic zeolites such as silica-alumina gel, molecular sieve (manufactured by Fuji Gel Industries Co., Ltd.), MS-tablet, MS-CERAM-W (all manufactured by Tokai Chemical Industry Co., Ltd.), NaturaSorb FN (Fuji) Bentonite clay (Montmorillonite) such as Gel Industry Co., Ltd. can be mentioned as a specific example.

  Further, the shape of these adsorbents in the container is not particularly limited as long as it is a shape capable of sufficiently adsorbing offensive odor components and volatile components in the container, and bag-like, plate-like, sheet-type, tablet-type, etc. may be mentioned. be able to.

  The compounding amount of the adsorbent in the pharmaceutical preparation of the present invention varies depending on the size of the container and the shape of the pharmaceutical composition, but generally 0.1 to 10 parts by mass with respect to 1 part by mass of loxoprofen in the pharmaceutical composition Preferably, it is 0.4-5 mass parts.

  In the pharmaceutical composition of the present invention, the pharmaceutical ingredients that can be optionally formulated include anti-inflammatory, antipyretic, analgesic agents other than loxoprofen, central nervous system excitatory agents, sedative agents, gastric mucosal protective agents, antispasmodic agents, muscles other than methocarbamol There may be mentioned relaxants, migraine drugs, herbal medicines, vitamins, mucopolysaccharides and the like.

  Among them, as anti-inflammatory, antipyretic and analgesic agents, for example, acetaminophen, lactylphenetidine, aspirin, aspirin aluminum, ethensamide, sazapyrin, salicylamide, sodium salicylate, isopropylantipyrin, ibuprofen, aluminoprofen, loxoprofen, tranexam An acid etc. are mentioned.

  Moreover, as central nervous system excitotoxic agents, for example, sodium caffeine benzoate, caffeine, anhydrous caffeine and the like can be mentioned. Among these, caffeine and anhydrous caffeine are preferred.

  Further, as the sedative agent, for example, allylisopropylacetylurea, bromovalerylurea and the like can be mentioned, and as the gastric mucosa protective agent, for example, teprenone, aldioxa, sucralfate, cetraxate, azulene, rebamipide and the like can be mentioned.

  Furthermore, as the spasmolytic agent used in the pharmaceutical composition of the present invention, for example, butylscopolamine or a salt thereof, thymepidium bromide, papaverine hydrochloride, ethyl aminobenzoate, roto extract and the like can be mentioned. For example, tolperisone, chlorzoxazone, pridinol mesylate, chlorphenesin carbamate, eperisone hydrochloride, afloquaron, tizanidine, baclofen and the like can be mentioned.

  Still further, examples of migraine drugs used in the pharmaceutical composition of the present invention include zolmitriptan, sumatriptan, naratriptan, rizatriptan, eletriptan, lomerizine hydrochloride, dimethothiazine mesilate, dihydroergotamine and the like. Examples of the herbal medicine include earthworm, licorice, caulis, peony, bokinpi, kanokosou, sanshu, shokyo, chimpi and the like.

Furthermore, as vitamins, for example, vitamin B ₁ , vitamin B ₂ , vitamin C, hesperidin and the like can be mentioned, and these vitamins may be derivatives or salts thereof. Specifically, as vitamin B ₁ and derivatives thereof and salts thereof, thiamine, thiamine chloride hydrochloride, thiamine nitrate, thiamine disulphide nitrate, thiamine disulphide, thiamine dicetyl sulfate, disetiamine hydrochloride hydrate, There may be mentioned flusultiamine hydrochloride, flusultiamine, octothiamine, sicochiamine, bisbutchiamine, bisbenchamine, prosulthiamine, benfotiamine, cocarboxylase, dibenzoyl thiamine and the like. In addition, as vitamin B ₂ and derivatives thereof and salts thereof, riboflavin, riboflavin butyrate ester, riboflavin sodium phosphate, flavin adenine dinucleotide and the like can be mentioned. Further, as vitamin C and derivatives thereof and salts thereof, ascorbic acid, metal salts of ascorbic acid (sodium ascorbate, potassium ascorbate, calcium ascorbate, magnesium ascorbate, aluminum ascorbate and the like) and the like can be mentioned. Furthermore, hesperidin and its derivatives and salts thereof include hesperidin, αG hesperidin and the like.

  Examples of the mucopolysaccharides include glucosamine, chondroitin and the like. These mucopolysaccharides can be used alone or in combination of two or more.

  On the other hand, examples of formulation additives preferably used in the pharmaceutical composition of the present invention include known excipients, binders, disintegrants, lubricants, various carriers, stabilizing agents, surfactants. , Plasticizers, lubricants, solubilizers, reducing agents, buffers, sweeteners, bases, adsorbents, flavoring agents, suspending agents, antioxidants, brighteners, coatings Agents, coats, wetting agents, wetting control agents, fillers, antifoaming agents, refreshing agents, coloring agents, coloring agents, flavoring agents, flavoring agents, coating agents, tonicity agents, softeners, emulsifiers, thickening agents, Thickeners, foaming agents, pH adjusters, diluents, dispersants, disintegrants, disintegrants, disintegrators, fragrances, moisture proofs, preservatives, preservatives, solubilizers, solubilizers, solvents, fluidizers, Examples include formulation additives such as antistatic agents, extenders, moisturizers and moisturizers. Specific examples of these additives are Medicinal Food 1204 No. 1 (Pharmaceutical Affairs Administrative Act), Pharmaceutical Additives Act 2016 (Edited by the Japan Pharmaceutical Additives Association, Pharmaceutical Daily News Agency) and 8th Edition Food Additives Official Declaration (Japan Food Additives Association).

  The container in which the pharmaceutical composition of the present invention is contained together with the adsorbent is not particularly limited as long as it prevents free passage of air, but closed containers such as glass bottles, plastic bottles, PTP packaging, aluminum heat seal packaging etc. Can be used. In addition, the position of the adsorbent is not particularly limited, and can be disposed at an appropriate portion such as the bottom of the container, the back of the cap, or the enclosed in the container.

  The pharmaceutical composition of the present invention thus obtained is preferably divided into two or three daily doses in the daily dose range of loxoprofen and methocarbamol.

  Hereinafter, the present invention will be specifically described with reference to Test Examples, Examples, and Formulation Examples, but the present invention is not limited thereto.

Example 1
(1) A tablet containing loxoprofen and methocarbamol in a mixed state was manufactured according to the composition and manufacturing method shown below.

[Composition]
Blended component content (mg)
<Granulation end>
Loxoprofen Na hydrate 34.05
Methocarbamol 250.00
Binding solution ^{* 1} 78.50
<Tablet Additives>
Low substitution degree hydroxypropyl
Cellulose (LH-11) 52.125
Magnesium stearate 3.475
<Total> 347.50
* 1 Eudragit RS (ethyl acrylate, methyl methacrylate ·
Methacrylated trimethylammoniumethyl copolymer)
Dissolved in 95% ethanol solution at 10% concentration.

[Method]
Loxoprofen sodium hydrate (Daiwa Pharmaceutical Co., Ltd .: trade name Japan Pharmacopoeia Loxoprofen sodium hydrate) 340.5 g, methocarbamol (CCSB product: trade name methocarbamol) 2500 g high speed stirring granulator (Powrex VG) Mixed with water and then dissolved in 706.5 g of 95% ethanol with 78.5 g of ethyl acrylate, methyl methacrylate, methacrylated trimethylammoniumethyl copolymer (manufactured by Evonik: trade name Eudragit RS) The combined solution 785 g was added and kneaded to obtain a granulated product.

  The granulated product was allowed to stand and dried in a box-type drier (PH-202 type manufactured by ESPEC), and then sized using a granulator (QC-U10 type manufactured by Powrex). 2919 g of this sized product and 521.25 g of low substitution degree hydroxypropyl cellulose (manufactured by Shin-Etsu Chemical Co., Ltd .: trade name LH-11), magnesium stearate (manufactured by Taihei Kagaku Kogyo Co., Ltd .: trade name magnesium stearate (vegetable)) 34 After charging .75g into a mixer (V-10 type manufactured by Tokusyu Seisakusho Co., Ltd.) and mixing, it is tableted using a tableting machine (Model VIRG manufactured by Kikusui Seisakusho Co., Ltd.) equipped with a 9.5 mm diameter punch and 1 tablet 10000 tablets having a mass of 347.5 mg and an average thickness of 5.1 mm.

  (2) A PS-5K standard glass bottle (about 50 ml volume) was filled with adsorbents of the type and amount shown in Table 1 and 40 each of the above tablets, and sealed with a metal cap. The glass bottle sealed with the metal cap was stored at a temperature of 60 ° C., and after 10 days and 21 days, the odor in the glass bottle and the thickness of the tablet were examined and evaluated according to the following criteria. The results are also shown in Table 1.

[ Evaluation criteria ]
After a predetermined period of time, the lid of the glass bottle was opened, and the odor and the thickness of the tablet at that time were evaluated. The stages of evaluation are as follows. In addition, the tablet thickness was shown by the average numerical value measured by the tablet thickness measuring device (SMD-540 type; made by Techlock), and the result of having evaluated this with the following reference | standard.

(Smells)
Stage: Contents +++: Awful smell ++: No smell +: Somewhat smell-: Almost no smell

(Lock thickness)
Stage: Content +++: Increase of 0.15 mm or more ++: Increase of 0.10 to 0.14 mm or less +: Increase of 0.05 to 0.09 mm or less-: Increase of 0.04 mm or less

  From the results shown in Table 1, when tablets containing loxoprofen and methocarbamol are stored in a closed container, they are stored by adding an adsorbent selected from silicates or aluminosilicates or a mixture of these with activated carbon into the container. It has been found that it is possible to clearly prevent the odor and the swelling of the tablets over time.

  The pharmaceutical preparation of the present invention adsorbs the problem of odor of a pharmaceutical composition containing both of them caused by the interaction of loxoprofen and methocarbamol, and the problem of tablet swelling which may lead to cracking or chipping of the preparation. Since it can prevent by the simple means of use of the container which enclosed the agent, it contributes to the improvement of the antipyretic analgesic anti-inflammatory effect of loxoprofen, and can also improve the commercial property as a pharmaceutical.

Therefore, the pharmaceutical preparation of the present invention can be advantageously used as a medical preparation and as a preparation for OTC.

Claims (6)

  A pharmaceutical formulation comprising a pharmaceutical composition containing loxoprofen or a pharmaceutically acceptable salt thereof and methocarbamol together with an adsorbent selected from silicates or aluminosilicates or mixtures thereof with activated carbon in a pharmaceutical container .   The pharmaceutical preparation according to claim 1, wherein the pharmaceutical container is a closed container selected from a glass bottle, a plastic bottle, a PTP package and an aluminum heat seal package.   The pharmaceutical preparation according to claim 1 or 2, wherein the shape of the adsorbent is bag-like, plate-like, sheet-like or tablet-like.   4. The method according to any one of claims 1 to 3, wherein the pharmaceutical composition is obtained by granulating loxoprofen or a pharmaceutically acceptable salt thereof and methocarbamol and formulating the same into a pharmaceutical composition. Pharmaceutical formulation.   The pharmaceutical preparation according to any one of claims 1 to 4, wherein the pharmaceutical composition is a solid pharmaceutical composition. A method for preserving a pharmaceutical composition comprising loxoprofen or a pharmaceutically acceptable salt thereof and methocarbamol, which is an adsorbent selected from silicates or aluminosilicates or mixtures thereof with activated carbon in a pharmaceutical container Storing the above method.