JP2012106936A - Oral agent - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide an oral agent which is stable over a long period at room temperature and lies in a solid state at ordinary temperature while having superior taking properties.SOLUTION: The oral agent comprising an ethylene oxide polymer, lying in a solid state at ordinary temperature and not deformed even if being left at 40°C has high preservability, and is usable as an oral agent with a chocolate-like or candy-like taste.

Description

The present invention relates to an oral preparation which can be stored without water and can be stored at room temperature with improved palatability.

In recent years, various preparations have been attempted for patients who have difficulty in swallowing ordinary solid preparations, and some of them have been used commercially or clinically. For example, an orally rapidly disintegrating tablet whose shape quickly collapses in the mouth, a jelly-like preparation that exhibits a semi-solid or liquid form, and a form that is dissolved in hot water or water at the time of taking it while being a conventional tablet or granule There are preparations that can be dissolved when used. In addition, chewable tablets, which are not such novel dosage forms but are tasted by being bitten in the mouth, are increasing as items of pharmaceutical preparations.

The common feature of intraoral quick disintegrating tablets, jelly-like preparations and chewable tablets is that they do not necessarily require water at the time of taking them, and thus have the advantage that they can be taken whenever necessary. Further, as a common point to the above-mentioned preparations for dissolution, it is characteristic that any preparation can be taken deliciously, and therefore it can be said that the preparation is easy to take. For patients who have been overlooked while being said to be `` suffering from a good drug mouth '' and have difficulty in swallowing solid preparations, it is possible to relieve the pain as much as possible (improve the dosage) and improve compliance It can be said that it is one of the trends of recent pharmacotherapy and pharmaceutics that tries to improve.

Chocolate has a high palatability and can be chewed or melted in the mouth, and when used as a base for oral preparations, it has the advantage that it can be taken easily without masking the bitterness of medicinal ingredients and without water. The manufacture of a medicine using chocolate has been attempted (see Patent Documents 1 to 3). These are based on the chocolate itself and the cacao component used in chocolate, and a temperature adjustment process (tempering) at the time of manufacture is required to give the same flavor and texture as food. Temperature control (at least the product temperature does not exceed 34 ° C.) when transporting and storing the product is also important. In addition, even if thorough manufacturing, distribution, and sales of such temperature management is done, it is unclear whether consumers who purchased it can manage it in the same way (especially in the summer in Japan and the tropical and subtropical regions) If). In fact, in order to obtain approval as a drug, an accelerated test at 40 ° C. is required, and those that cannot be kept in shape when left at 40 ° C. are not approved as drugs that can be stored at room temperature and are refrigerated. It becomes the medicine only for preservation. In addition, the expiration date of food chocolate is generally about one year. In addition to the deterioration of its components, fat blooming that gradually progresses even if the above-mentioned temperature control is applied for several years. It is also related to the fact that it is virtually impossible to suppress. A formulation with fat blooming causes a decrease in flavor and cannot be taken at least deliciously.

On the other hand, ethylene oxide polymers such as polyethylene glycol and polyoxyethylene hydrogenated castor oil are used as a base for dissolving or dispersing drugs, and are often used as a base for external preparations such as ointments. Patent Documents 4 to 6 disclose oral preparations containing an ethylene oxide polymer such as polyethylene glycol. Since these are liquid or the contents of tube fillings and capsules, they are not solid at room temperature.

JP 59-27819 A JP 2001-114668 A Special table 2004-536792 gazette Japanese translation of PCT publication No. 2002-516849 JP 2005-538191 A JP-A-2005-75804

As mentioned above, oral preparations that utilize the flavor and texture of chocolate have advantages, but there are problems with temperature management during manufacturing, temperature management during transportation and storage, and consumer preservation after purchase. is there. An object of the present invention is to provide a solid oral preparation that can be stored at room temperature for a long period of time and is excellent in palatability and ingestibility.

The present invention solves the above-mentioned problems by a completely different approach. That is, the present invention is an oral preparation containing an ethylene oxide polymer, which is solid at ordinary temperature (25 ° C.) and does not deform even when left at 40 ° C. It is based on the knowledge that it can be used. The present invention includes the following items.
(1) An oral preparation that contains an ethylene oxide polymer, is solid at normal temperature, and does not deform when left at 40 ° C.
(2) The oral preparation according to (1), which has a freezing point of 34 to 64 ° C.
(3) The oral preparation according to (1) or (2), wherein the content of the ethylene oxide polymer is 30 to 99.9% by weight of the oral preparation dough.
(4) The oral preparation according to any one of (1) to (3), wherein the content of the ethylene oxide polymer is 35 to 80% by weight.
(5) The oral preparation according to any one of (1) to (4), wherein the ethylene oxide polymer is an orally administrable pharmaceutical additive.
(6) The ethylene oxide polymer is one or more selected from polyoxyl stearate, polyoxyethylene hydrogenated castor oil, polyoxyethylene polyoxypropylene glycol, macrogol, and polyethylene glycol fatty acid ester (1) The oral preparation in any one of-(5).
(7) The oral preparation according to any one of (1) to (6), comprising a polyglycerin condensed ricinoleic acid ester.
(8) A method for producing an oral preparation comprising a step of melting an ethylene oxide polymer, a step of preparing an oral preparation dough by mixing the melted ethylene oxide polymer and a powder raw material, and a step of forming an oral preparation dough.
(9) The method for producing an oral preparation according to (8), wherein the step of forming the oral preparation dough is any one of molding, extrusion molding, pan coating, enrobing, drop molding, sheet molding, and roll molding.
(10) The method for producing an oral preparation according to (8) or (9), wherein polyglycerin condensed ricinoleic acid ester is added.

According to the present invention, it is possible to provide a completely new oral preparation that can be stored at room temperature while exhibiting a preferable texture, and can contribute to the improvement of drug administration.

The oral preparation of the present invention contains an ethylene oxide polymer, does not deform even when left in an atmosphere of 40 ° C., and can be ingested or chewed in the mouth. Moreover, since the oral preparation of this invention does not deform | transform even if left still in the atmosphere of 40 degreeC, naturally it is solid at normal temperature. In the present invention, room temperature indicates 25 ° C. In the present invention, the ethylene oxide polymer includes a molecular structure in which ethylene oxide (ethylene oxide) is polymerized in the molecule. As the ethylene oxide polymer, those that can be administered orally as pharmaceutical additives can be used, among which polyoxyl stearate, polyoxyethylene hydrogenated castor oil, polyoxyethylene polyoxypropylene glycol, macrogol, polyethylene glycol fatty acid ester are used. Is preferred.

Polyoxyl stearate is a monostearic acid ester of an addition polymer of ethylene oxide, and is a nonionic surfactant represented by H (OCH ₂ CH ₂ ) _n OOCC ₁₇ H ₃₅ . In the present invention, polyoxyl 40 stearate having n of about 40 is preferable because it can be administered orally.

Polyoxyethylene hydrogenated castor oil is a nonionic surfactant obtained by addition polymerization of ethylene oxide to hydrogenated oil obtained by adding hydrogen to castor oil. In the present invention, polyoxyethylene hydrogenated castor oil 60 having an average added mole number of ethylene oxide of about 60 is preferable because of its large oral dose.

Polyoxyethylene polyoxypropylene glycol is obtained by addition-polymerizing ethylene oxide to polypropylene glycol obtained by polymerizing propylene oxide. In the present invention, polyoxyethylene (160) polyoxypropylene (30) glycol having an average degree of addition polymerization of propylene oxide and ethylene oxide of about 30 and about 160, respectively, and polyoxyethylene (105) of about 5 and about 105, respectively. ) Polyoxypropylene (5) glycol is preferred because it can be administered orally.

Macrogol, also called polyethylene glycol, is an addition polymer of ethylene oxide and water, and is represented by HOCH ₂ (CH ₂ OCH ₂ ) _n CH ₂ OH. In the present invention, macrogol 1500 (freezing point 37-41 ° C.) in which n is an equal mixture of 5-6 and 28-36, macrogol 4000 (freezing point 53-57 ° C.) in which n is 59-84, n Is preferable, since macrogol 6000 (freezing point 56-61 ° C.) having a 165 to 210-210 and macrogol 20000 (freezing point 56-64 ° C.) having an n of 340-570 can be orally administered.

The polyethylene glycol fatty acid ester is obtained by adding a fatty acid to polyethylene glycol, and a saturated polyglycolized glyceride can be used as a pharmaceutical additive. Saturated polyglycolized glycerides are the product of hydrogenated palm oil and macrogol 1500, which, as polyethylene glycol fatty acid esters, contains about 43% diester, about 29% monoester, and about 7% free polyethylene glycol. % Is included.

The oral preparation has a freezing point of 34 to 64 ° C., desirably 34 to 54 ° C., so that it does not deform at 40 ° C. and can be chewed or licked and dissolved in the mouth. Even if the freezing point is lower than 40 ° C., it does not deform if it is in a stationary state, but it deforms when it is pressed with a finger and a force is applied. A freezing point of 40 ° C. or higher is preferable because it does not easily deform even when a force is applied. Further, the total content of the ethylene oxide polymer-containing materials having a freezing point of 42 ° C. or lower, such as polyoxyethylene hydrogenated castor oil 60, polyoxyl stearate 40, saturated polyglycolized glyceride, etc. is preferably 7% by weight or more, preferably 10% by weight. When it is at least%, a chocolate-like snapping texture that can be chewed in the mouth is preferred. When the total content of the ethylene oxide polymer-containing material having a freezing point of 42 ° C. or lower is less than 7% by weight, it becomes hard and difficult to chew, but dissolves in saliva to give a candy-like texture.

The oral preparation of the present invention can be produced by the following method. First, the ethylene oxide polymer is melted preferably by heating to about 50 to 80 ° C., and powdered raw materials such as powdered medicinal ingredients and powdered pharmaceutical additives are added to and mixed with the melted ethylene oxide polymer. Prepare the dough. If there are raw materials that become liquid at room temperature or liquid when heated, such as liquid medicinal ingredients, oils and fats, emulsifiers, etc., if the liquid raw material is small, it is mixed with the powder raw material and added to the molten ethylene oxide polymer. Alternatively, the ethylene oxide polymer and the liquid raw material may be mixed first, and then the powder raw material may be added and mixed. Oral dough may be used in the molding process as it is, but may be pulverized using a refiner, a ball mill or the like to reduce the particle size. Further, the viscosity may be adjusted by performing conching after pulverization or by adding an ethylene oxide polymer. In the present invention, the oral dough refers to a raw material mixture that contains medicinal ingredients and various pharmaceutical additives and can be formed into an oral preparation by molding. In addition, conching refers to a process of kneading and liquefying raw materials that have been pulverized and refined by a refiner or the like in a chocolate manufacturing process. The process of kneading and liquefying.

When polyglycerin condensed ricinoleate is added to an oral dough, the viscosity of the dough can be reduced. By adding 0.6% by weight of the polyglycerin condensed ricinoleic acid ester, the viscosity becomes substantially equal even if the blending amount of the ethylene oxide polymer is reduced by about 10% by weight. The use of polyglycerin condensed ricinoleic acid ester is advantageous in that many relatively inexpensive raw materials such as sugar can be blended, resulting in cost reduction and improved processability in the molding process.

The obtained oral dough can be molded by cooling and solidifying, and can be molded using a method of molding chocolate. For example, preparing a mold for molding, pouring molten oral dough into the mold, cooling and solidifying (molding), extruding oral dough using an extruder and cooling and solidifying (extrusion molding) ), Using a rotating kettle to hang an edible dough on a edible center such as a tablet, and coat it while cooling (pan coating). The method of coating the oral dough by passing through and cooling and solidifying (enrobing), dropping the oral dough on the conveyor, etc., cooling and solidifying as it is to form into granules (drop molding), weir A large amount of oral dough is poured on a conveyor, etc. provided, cooled and solidified to a certain thickness, and cut into a sheet-like oral dough (sheet molding). It can be formed by a method (roll molding) or the like in which an oral dough is poured between two dug-out rotating rolls, and the dough enters the gap formed when the two rotating roll molds are fitted, cooled and solidified. . In addition, the oral dough thus formed may be further subjected to processing such as shellac hanging and sugar coating.

The content of the ethylene oxide polymer is preferably 30 to 99.9% by weight of the oral dosage form. If the ethylene oxide polymer is less than 30% by weight, it is difficult to mold. On the other hand, molding is possible even if the entire amount is made of an ethylene oxide polymer, but since a medicinal component is essential for a pharmaceutical product, the entire amount (for example, 99.9% by weight) other than the medicinal component is made an ethylene oxide polymer. You can also. When the content of the ethylene oxide polymer is 38% by weight or more of the oral preparation dough, it can be molded by any molding method.

When considering the balance between food texture and palatability, the oral preparation of the present invention contains 35 to 80% by weight of an ethylene oxide polymer, additives and medicinal components other than the ethylene oxide polymer such as sweeteners, flavoring agents, and fragrances. By making the total amount of about 20 to 65% by weight, a smooth texture can be obtained and a preferable flavor can be obtained.

The oral preparation of the present invention can contain an orally administrable medicinal component, such as cold medicine, antipyretic analgesic, hypnotic sedative, sleepiness preventive, antipruritic, pediatric sedative, histamine H ₂ receptor antagonist Contained drugs, antacids, stomachic drugs, intestinal drugs, digestives, gastrointestinal analgesics, antipruritics, laxatives, enemas, anthelmintics, cardiotonic drugs, arteriosclerotic drugs, anemia drugs, antitussive Expectorant, expectorant, anti-hypermedication, vitamin active ingredient, vitamin-containing health care, calcium active ingredient, protein / amino acid active ingredient, herbal active ingredient, gynecology, contraceptive, antihistamine active ingredient, oral throat It can be used as a medicine for stomatitis, toothache, alveolar purulent medicine, etc.

In addition to medicinal ingredients and ethylene oxide polymers, stabilizers, antioxidants, colorants, dispersants, plasticizers, emulsifiers, solubilizers, reducing agents, sweeteners, preservatives, cooling agents as pharmaceutical additives Agents, food intake accelerators, flavoring agents, chewing agents, excipients, fragrances, enhancers and the like can be used. Specifically, powdered sugar, sucrose, brown sugar, glucose, fructose, lactose hydrate, maltose hydrate, sorbitol, xylitol, maltitol, erythritol, saccharin, aspartame, sucralose, stevia extract, amino acid, casein, defatted Powdered milk, cacao powder, cacao butter, taurine, licorice powder, dried chlorella, dried yeast, fennel, orange, caramel, lemon powder, green tea powder, citric acid, acetic acid, lactic acid, malic acid, tartaric acid, red pepper, royal jelly, spearmint oil, Vanillin, peppermint oil, lemon oil, peppermint powder, methylcellulose, sodium chloride, dextrin, starch, crystalline cellulose, xanthan gum, guar gum, alginic acid, ascorbic acid, tocopherol, soy lecithin, glycerin fatty acid ester Sugar fatty acid esters, sorbitan fatty acid esters, gelatin, talc, saffron, silicon dioxide or the like may be used. Other than these, there is no limitation on the use as long as it is a powdery raw material that can be administered orally, but there is a problem in moldability and deformability at 40 ° C. even if it is a liquid or paste such as oil or fat. It can be used as long as there is no.

Test example 1
Various ethylene oxide polymers were heated and melted at 70 to 80 ° C. to form a liquid. The basic raw material shown in Table 1 was added to the liquefied ethylene oxide polymer, and the mixture was stirred and mixed while maintaining the temperature to prepare an oral preparation. In addition, the numerical value which concerns on the raw material mixing | blending in the following table | surface shows weight% unless there is particular designation | designated.

Oral dough was filled in a circular mold having a diameter of 15 mm on the bottom, cooled and solidified at 10 ° C. for 30 to 40 minutes, and peeled from the mold to produce an oral preparation having a weight of 1.5 g. The obtained oral preparation was solid at room temperature.
The obtained oral preparation was allowed to stand in an atmosphere of 40 ° C. for 2 hours and examined for deformability. Moreover, the freezing point was measured by the Japanese Pharmacopoeia general test method. Furthermore, the texture when ingested was examined. The results are shown in Tables 2 and 3.
In the table, UNIOX HC-60 is Nippon Oil & Fats 'polyoxyethylene hydrogenated castor oil 60, Macrogol 4000 and Macrogol 6000 are made by Nippon Oil & Fats, and Pronon 188P is Nippon Oil &Fats' polyoxyethylene (160 ) Polyoxypropylene (30) glycol, PEP-101 is Freund Sangyo's polyoxyethylene (105) Polyoxypropylene (5) glycol, MYS-40MV is Nikko Chemicals polyoxyl stearate 40, Gelucire 50/13 is CBC The company's saturated polyglycolized glyceride, DK ester F-160, represents Daiichi Kogyo Seiyaku's hydrophilic (HLB16) sucrose fatty acid ester.

A powdery raw material dispersed in an ethylene oxide polymer had a chocolate-like or candy-like texture. Moreover, when the freezing point was 34 ° C. or higher, it did not deform even when it was left at 40 ° C. On the other hand, we tried to disperse powder raw material in sucrose fatty acid ester, but it was very sticky, it was not fluid and it was difficult to fill the mold, so it could not be molded, freezing point, deformation at 40 ° C Sex and texture could not be examined (Comparative Example 3).

Example 12
11 parts by weight of sucrose and 0.6 parts by weight of a polyglycerin condensed ricinoleic acid ester (trade name: Sunsoft No. 818R manufactured by Taiyo Kagaku) were added to 100 parts by weight of the oral dough of the formulation of Example 8 and mixed well. The obtained oral dough showed almost the same viscous fluidity as the oral dough of the formulation of Example 8. In addition, an oral preparation having a weight of 1.5 g was produced in the same manner as in Test Example 1 using the oral preparation dough. The obtained oral preparation showed a chocolate-like texture and did not deform even when left in a 40 ° C. atmosphere for 2 hours.

Test example 2
43 parts by weight of UNIOX HC-60, 29 parts by weight of MACROGOL 4000, 16 parts by weight of PRONONE 188P and 12 parts by weight of PEP101 were mixed and heated to melt to obtain an ethylene oxide polymer mixture. The ethylene oxide polymer mixture and the basic raw materials shown in Table 1 were mixed at various ratios to prepare an oral preparation. It was evaluated whether or not molding was possible when various moldings were performed using the oral drug dough. The results are shown in Table 4.

Claims (10)

An oral preparation containing an ethylene oxide polymer, which is solid at normal temperature and does not deform when left at 40 ° C. The oral preparation according to claim 1, having a freezing point of 34 to 64 ° C. The oral preparation according to claim 1 or 2, wherein the content of the ethylene oxide polymer is 30 to 99.9% by weight of the oral preparation dough. The oral preparation according to any one of claims 1 to 3, wherein the content of the ethylene oxide polymer is 35 to 80% by weight. The oral preparation according to any one of claims 1 to 4, wherein the ethylene oxide polymer is an orally administrable pharmaceutical additive. The ethylene oxide polymer is one or more selected from polyoxyl stearate, polyoxyethylene hydrogenated castor oil, polyoxyethylene polyoxypropylene glycol, macrogol, and polyethylene glycol fatty acid ester. The oral preparation according to any one of the above. The oral preparation according to any one of claims 1 to 6, comprising a polyglycerin condensed ricinoleic acid ester. A method for producing an oral preparation comprising: a step of melting an ethylene oxide polymer; a step of preparing an oral preparation dough by mixing the melted ethylene oxide polymer and a powder raw material; and a step of solidifying and forming the oral preparation dough. 9. The step of solidifying and molding an oral dough is any one of molding, extrusion molding, pan coating, enrobing, drop molding, sheet molding, and roll molding.
The manufacturing method of the oral preparation as described in any one of. The method for producing an oral preparation according to claim 8 or 9, wherein polyglycerin condensed ricinoleic acid ester is added.