JPH051243B2 - - Google Patents

Description

[Detailed description of the invention] FIELD OF THE INVENTION The present invention relates to soft oral preparations.

Conventionally, troches (oral tablets), sublingual tablets, buccal (oral tablets), pastes, and the like have been known as preparations intended for intraoral application. However, these preparations suffer from various disadvantages, such as poor usability and retention in the mouth, low drug absorption and bioavailability, and low persistence of drug efficacy. It has the following disadvantages. For example, these preparations cause an unpleasant sensation in the mouth when used, are difficult to keep in the mouth for long periods of time because they can be chewed, swallowed, or spit out, and disintegrate quickly. Because the application time in the oral cavity is short, sufficient medicinal efficacy cannot be expected to last. Furthermore, in terms of bioavailability of the drug, no preparation has yet been obtained that is satisfactory in terms of absorption through the oral mucosa compared to oral administration. Therefore, there has been a desire for an oral preparation that does not have such conventional problems.

As a result of repeated studies to obtain a new oral preparation that improves the above-mentioned problems, the present inventors have developed an oral preparation that is soft to the touch and comfortable to use by incorporating water-soluble protein as a base component. (Hereinafter, an oral preparation having such characteristics may be abbreviated as a soft bulge), and the present invention has been completed. That is, the soft capsule provided by the present invention is a soft oral preparation that contains a drug for absorption through the oral mucosa and a water-soluble protein that exhibits an absorption-promoting effect, and that conforms to the shape of the oral cavity and is retained. It is. It is an object of the present invention to provide such a soft backbone.

Any drug suitable for mucosal absorption may be used as a drug to be incorporated into the soft capsule of the present invention. These drugs are selected from drugs that act on the oral cavity, which is the application site, and on organs and tissues other than the oral cavity. Examples of such drugs are shown below.

Central nervous system drugs (hypnotic sedatives such as diazepam and estazolam, anticonvulsants such as phenytoin, meprobamate, and nitrazepam; acetaminophenone, ethenzamide, salicylamide, pentazocine, clofezone, indomethacin, ketobrofen, flupiprofen, diclofenac, clidanac, alc) Antipyretic, analgesic and anti-inflammatory agents such as Rofuenac, flufenamic acid, mefenamic acid, sulindac, piroxycar, menthol, camphor, D-penicillamine, and corticosteroids; Neuropsychiatric agents such as chlorbromazine; Isoprenaline, petahistine mesylate, and scopolamine Anti-vertigo drugs such as;
drugs for peripheral nerves (local anesthetics such as procaine and lidocaine; muscle relaxants such as triperisone hydrochloride, baclofen, dantrolene sodium, and cyclobenzapyrine hydrochloride; drugs for autonomic nerves such as atropine and levodopa; antispasmodics, etc.) ), allergy drugs or antihistamines (diphenhydramine, periactin, etc.), cardiovascular drugs (cardiac drugs such as digitalis, iupidecarenone; β-protrusions or arrhythmia therapeutics such as pindolol, propranol hydrochloride; theophylline, trichlor) Diuretics such as methiazine, spironolactone, methyclothiazide, metolazone, tripamide, furosemide, penfluzide; antihypertensive agents such as reserpine, clonidine hydrochloride, methyldopa, hydralazine, syrosingopine, recinamine, cinnarizine, prazosin hydrochloride; vascular reinforcement such as rutin, carbazochrome Agent; dihydroergotamine mesylate,
Vasoconstrictors such as dihydroergotoxin mesylate; coronary vasodilators such as nitroglycerin, isosorbitol nitrate, dilazeb hydrochloride, nifedipine, diltiazem hydrochloride, trimetazidine hydrochloride, trapidil, dipyridamole; peripheral vasodilators such as inositol hexanicotinate ; agents for osmotic stiffness such as clofibrate; pentoxifylline, cytochrome C, sodium dextran sulfate, pyrithioxine, citicoline, nicardipine hydrochloride, dopamine hydrochloride, doptamine hydrochloride, alprostadil, ifenprodil tartrate, etc.), agents for respiratory organs (antitussive expectorants such as efuedrine, codeine, bromhexine; isoproterenol, dextromethorphan, orciprenaline, ibratrobium bromide, cromoglycic acid, etc.), digestive system drugs (allantoin, aldioxa, alcloxa, pirenzepine hydrochloride, secretin) , urogastrone, cetraxate, cimetidine, ranitidine, and other peptic ulcer treatments;
cholerotic agents such as bile acids), forman drugs or antihormonal agents (human growth hormone, corticothrobin, oxytocin, vasopressin, pituitary hormones such as protirelin tartrate; male hormones such as testosterone; progesterone, estradiol, etc.) female hormones; salivary gland hormones, thyroid and parathyroid hormones, anabolic steroids, adrenal hormones, kallikrein, isosyurin, chlorazinon acetate, desmopressin acetate, etc.), drugs for the urogenital system (dinoprost, etc.), oxelodrone, etc. , uterotonic agents such as dinoprostone), metabolic medicines (vitamins such as alfalcasidol and mecobalamin; nutritional and tonic altering agents;
glutatin, ATP, aprotilin, gapexate mesylate, etc.), cell activating drugs, tumor drugs (krestin, ancitabine, cytarabine, picibanil, 5-fluorouracil derivatives including tegafur and carmofur, etc.), herbal medicines (licorice, aloe, etc.), antibiotics substances (ampicillin, amoxicillin,
erythromycin, dibekacin, gentamicin, amikacin, cefazolin, griseofulvin, tetracycline, nystatin, amphotecillin B, cycloserine, fosfomycin, peptide antibiotics), chemotherapeutic agents (clotrimazole, pyrrolnitrin, alaphosphalin, sulfur drugs, etc.), Enzymes (urokinase, bromelain, lysozyme, L-asparaginase, etc.).

Among these drugs, it is particularly effective to employ drugs that have a similar bioavailability in oral administration or drugs that require injection as the medicinal ingredient of the soft pill of the present invention. be.

In the present invention, the above-mentioned drug is used in an amount sufficient to achieve this medicinal effect, and in most cases, the amount of the drug blended is 0.05 to 60% by weight of the total amount of the soft capsule. Within this range, the amount of each drug to be used is appropriately increased or decreased depending on the type of drug and the purpose of treatment, and the amount of each drug to be used is determined, for example, depending on whether a small amount of administration is sufficient to achieve the drug effect or a larger amount is required.

Next, the water-soluble protein to be incorporated into the soft capsule of the present invention may be any water-soluble protein as long as it exhibits a respiratory promoting effect on the drug. These water-soluble proteins are natural or non-natural proteins, and natural proteins include animal and vegetable proteins.
Also, examples of non-natural peptides include artificially obtained peptides. Although there are technical fields in which peptides are distinguished from proteins, in the present invention they are included in proteins from the viewpoint of their effects. Natural proteins used in the present invention include gelatin, solubilized collagen, casein, glue, and hydrolysates thereof, among which animal proteins such as gelatin and solubilized collagen are preferred. The gelatin used here has a molecular weight of about tens of thousands to hundreds of thousands, and is
It contains acid gelatin obtained by hydrolyzing proteins contained in tendons etc. with acid, and alkaline gelatin obtained by hydrolyzing with alkali, and the solubilized collagen used also contains insoluble collagen. Examples include those obtained by solubilization through partial hydrolysis or chemical modifications such as maleation, succinylation, and phthalation, and their molecular weights are comparable to gelatin. Furthermore, the above-mentioned peptides used in the present invention include peptides obtained by combining the same or different amino acids by synthetic or semi-synthetic means. Such peptides include polyalanine, a conjugate of homologous amino acids,
Examples include polylysine, polyglutamine, etc., and peptides in which various neutral, basic, or acidic amino acids are linked in a desired sequence as conjugates of different amino acids, and these have a molecular weight smaller than that of the above-mentioned natural proteins. There are many cases in the hundreds or thousands. In the present invention, one or a mixture of the water-soluble proteins listed above is used.

The amount of the water-soluble protein added to the soft capsule may be any amount sufficient to promote drug absorption from the oral mucosa. In general, the same amount as the drug is required, but depending on the drug and the desired absorption rate, a lower or appropriate amount may be used, so it cannot be absolutely limited, but usually 1 part water-soluble protein
It is blended in an amount of 0.5 to 150 parts, preferably about 1 to 100 parts. Here, if the amount of drug used in the soft vaccine is large, 0.5 to 0.5 to 1 part of water-soluble protein should be added to 1 part of drug.
About 10 parts are used, and when the amount of drug used is small, about 10 to 150 parts of water-soluble protein is used for 1 part of drug. Furthermore, the amount of water-soluble protein blended can be reduced by adding one or more of the additives described below to fill the remainder of the formulation.

Furthermore, in order to efficiently achieve the purpose of the present invention, in addition to the above-mentioned drugs and water-soluble proteins, additives having the function of adjusting and maintaining the softness of the soft capsule or the rate of dissolution or disintegration may be added. Good to use. Pharmaceutically acceptable additives are selected, such as polyhydric alcohols (glycerin, ethylene glycol, propylene glycol, butylene glycol, polyethylene glycol, polyvinyl alcohol, etc.), vinyl polymers (carboxyvinyl polymer, polyvinylpyrrolidone, allylic acid polymer, etc.), celluloses (hydroxyethyl cellulose, hydroxypropyl cellulose,
(alkyl celluloses, etc.), fatty acid esters (intermediate to higher fatty acid alkyl esters, sucrose fatty acid esters, phthalate esters, fatty acid glycerin esters, etc.). In the present invention, non-volatile additives are preferred among these additives, and among them, those having plasticity such as polyhydric alcohols are often preferred. The amount of these additives added to the soft envelope varies depending on the type and amount of water-soluble protein, but generally correlates to the amount of water-soluble protein added. That is, in general, the above additives are added to 1 part of water-soluble protein.
It is good to use about 0.01 to 3 parts, preferably about 0.03 to 2 parts.

In addition to the above-mentioned additives, in order to express more of the characteristics of the soft capsule of the present invention, drug additives may be added for the purpose of improving the processing/forming properties and quality of the preparation, and improving the dispersibility and stability of the drug. It is possible to further include chemically acceptable additives selected depending on the purpose. Examples of such additives include the following.

Emulsifiers or dispersants (nonionic surfactants, higher alcohols, higher fatty acids, etc.), binders or binders (ester gum, glutenin, carboxymethylated starch, sodium polyacrylate, hydroxypropyl starch, etc.)
(sodium alginate, gum arabic powder, etc.), flavoring agents or flavoring agents (mannitol, saccharin sodium, glycyrrhizin, starch syrup, citric acid, tartaric acid, menthol, sweet flavoring,
salt, etc.), stabilizers or preservatives (paraoxybenzoic acid alkyl esters, antioxidants, etc.), colorants (water-soluble tar pigments, natural pigments, titanium oxide, etc.), excipients or disintegration regulators (carboxyalkylcellulose, etc.) or its sodium salt, magnesium silicate, light anhydrous silicic acid, crystalline cellulose, synthetic aluminum silicate, white sugar, precipitated calcium carbonate, dextrin, starch, lactose, D
-Sorbitol, D-mannite, magnesium aluminate metasilicate, calcium hydrogen phosphate, etc.), fats and oils (vegetable oils, animal oils, waxes, etc.), water-soluble polymers other than water-soluble proteins (mannan, dextran, etc.) natural polymers, synthetic polymers, etc.), and others (known ones such as stearic acid, calcium stearate, magnesium stearate, talc, palmitic acid, sodium lauryl sulfate, etc.).

Typical examples of the use of the above additives include emulsifiers or dispersants for uniformly dispersing drugs and water-soluble proteins, flavoring agents or flavoring agents for adding flavor to soft capsules, and pharmaceutical stabilization of soft capsules. Stabilizers or preservatives may be used to improve properties, binders or excipients may be used to maintain the shape of soft capsules, but they are not necessarily used for a single purpose. Not necessarily.

The shape of the soft buttock of the present invention may be any shape that fits and is held in the shape of the oral cavity.
Therefore, it is given a size and shape that is easy to apply within the oral cavity. Preferably, plate-like, strip-like, disc-like, note-like, cylindrical or spindle-like forms are selected as such forms, but in most cases plate-like forms (e.g. vertical, vertical, etc.) are selected.
0.5-3 cm x width 1-10 cm x thickness 0.1-0.5 cm) is suitable.

Along with such a form, the soft buttock of the present invention is generally soft, but those having flexibility in the oral cavity are included in the concept of soft in the present invention.
Specifically, it has flexibility and viscoelasticity, as evidenced by its softness that allows it to be slightly deformed without damage to its shape. For example, it can be easily bent at an angle of about 90°, and can be easily expanded, contracted, or dented by applying some external force. When using the soft buckle of the present invention, such modifications may be made, or it may be cut and used.

It is generally desirable for the soft capsule of the present invention to contain water for the purpose of maintaining formulation properties such as softness, solubility or disintegration, and drug absorption. The water content is about 3 to 30% by weight, preferably 5 to 20% by weight of the entire soft envelope.

There are various methods for producing the soft envelope of the present invention. Conventionally existing means used in the production of tablets and suppositories, chewing gum, confectionery or noodles, etc. can be used with the necessary modifications in the production of the soft capsules of the present invention. can. This modification is a modification to provide flexibility and improve drug absorption, which is the object of the present invention. A typical manufacturing method is to use the above-mentioned drug and water-soluble protein together with the above-mentioned additives as necessary.The first method is to add a small amount of water to the mixture and knead it uniformly. Examples include the steps of compressing and spreading the mixture while warm, cutting it to form it after cooling, or molding it by injecting it into a mold after kneading. The second method involves pulverizing the mixture of the above ingredients without adding water, and then molding the mixture by compression.The third method involves uniformly dispersing the mixture of the above ingredients in water. Examples include a step of melting or melting, then molding at a warm temperature, and then drying. Further, the steps in these manufacturing methods may be combined as appropriate. In the production of the soft capsule of the present invention, the amounts of drug, water-soluble protein, and additives specified above are used. Furthermore, in the above-mentioned molding process, by adjusting the molding frame to an appropriate shape during compression molding, or by cutting into an appropriate shape after pouring or spreading into a molding machine, plate-like, band-like, A soft backbone having a desired shape such as a disk shape, a columnar shape, a cylindrical shape, a spindle shape, etc. can be obtained. Since this manufacturing method consists of simple and convenient operations and steps, it is advantageous as a manufacturing method on an industrial scale, and it is possible to obtain soft bags in various forms depending on the operational purpose. By providing a dispersion step, it is possible to incorporate liquid or low-melting point drugs, which have conventionally been difficult to incorporate into solid preparations.

The application site of the soft buttock of the present invention is on the mucous membrane in the oral cavity, specifically, it is applied mainly by holding it between the cheeks or lips on the outside of the gums, and in some cases on the inside of the gums and the tongue. It may also be applied sublingually or on the maxillary mucosa. Since the soft bulge of the present invention is soft, it feels soft in the oral cavity and can be applied without any discomfort.Furthermore, after application, it swells due to the action of saliva and secretions in the mouth, and spreads to the oral mucosa. It shows good adhesion and has good retention in the mouth, and is retained in the oral cavity for a long time without falling off. Therefore, activities in daily life (conversation, eating, drinking, smoking, exercise, learning, etc.) are not restricted while the application is applied. The soft capsule of the present invention can be manufactured in such a way that it takes, for example, 10 minutes or more to dissolve or disintegrate in the mouth, so it can be used as a sustained-release preparation in which the medicinal ingredients contained therein are continuously and gradually released. It has the desirable properties of

In addition to such sustained release properties, the soft capsule of the present invention is an intraoral preparation that significantly improves mucosal absorption of the drug. In other words, the released drug is efficiently absorbed through the oral mucosa and esophageal mucosa, improving the bioavailability of the drug, allowing the expected pharmacological effect to be achieved with a smaller dose of the drug, and at the same time eliminating excess doses of the drug. By avoiding administration, side effects can be reduced and safety improved. In particular, drugs whose medicinal ingredients are orally administered and poorly absorbed in the gastrointestinal tract, or drugs that are easily metabolized quickly and lose their efficacy when absorbed in the gastrointestinal tract, and both are orally administered drugs with poor bioavailability The soft backbone of the present invention can also be used when administering drugs that are difficult or ineffective to administer orally because they are susceptible to decomposition in the gastrointestinal tract or first-pass effect in the liver, and must be administered by injection. The application facilitates the administration of these drugs and provides high bioavailability. For example, as detailed in the test examples below, the soft vacuole of the present invention has more than double the effectiveness of the medicinal ingredients due to rapid mucosal absorption compared to ordinary oral preparations or sublingual tablets of the same dosage. It was found that the concentration in the blood and its persistence over a long period of time were shown. Furthermore, it has been demonstrated that even medicinal ingredients that can only be absorbed and have medicinal effects in injections are well absorbed by the soft capsule of the present invention.

The various properties of the soft capsule of the present invention described above (good feeling of use, good retention in the mouth, sustained release, improved mucosal absorption and bioavailability of the drug, etc.) are due to the fact that it is water-soluble as a base component. This is mainly achieved by incorporating proteins.
Various examples of conventional uses of water-soluble proteins are known, but as the main base component of oral preparations,
No example has yet been found demonstrating its usefulness.

Next, the present invention will be explained in more detail by describing a more specific manufacturing method of the soft bag according to the present invention and various test results.

Example 1 Soft capsule containing riboflavin tetrabutyrate (a) 2.4 g of riboflavin tetrabutyrate was added to a homogeneous solution consisting of 30 g of purified water, 16 g of concentrated glycerin, and 0.8 g of sucrose fatty acid ester (S-770).
was added and stirred and dispersed to obtain a uniform suspension. To this, add a solution of 32g of gelatin (jelly strength: 150) dissolved in 50g of purified water at a temperature of 50°C.
Using a vacuum stirring device, while preventing water evaporation, the mixture was stirred until a homogeneous mixture was obtained, and at the same time, a defoaming treatment was performed. Then, it was poured into a molding machine (10 x 20 x 0.3 cm) while still warm (approximately 40°C) and spread uniformly. The plate-like drug substance obtained by cooling this was cut into a size corresponding to one dosage form using a cutter. This product contains 60 mg of riboflavin tetrabutyrate and weighs 3.28 g.
(Weight deviation: within ±0.5%) 1.5 x 6.3 x 0.3cm
It has a plate-like form (length x width x thickness). This was dried with ventilation at 25℃ for about 2.5 hours to form the final product of soft buttock (weight of 1 agent: 2.2
g).

(b) In the spreading process in method (a) above, the drug substance is spread thickly (approximately 0.7 cm), and after cooling, the obtained drug substance is punched into a cylindrical shape (0.7 cm in diameter x 7.3 cm in length). , and then dried to obtain a cylindrical soft bulge.

(c) 1.8 g of riboflavin tetrabutyrate, 4.5 g of concentrated glycerin, Uitetupzol (trade name,
1.5 g of Dynamite Nobel (manufactured by Dynamite Nobel) and 0.12 g of sucrose fatty acid ester (S-970) were added and mixed uniformly at a temperature of about 70°C. To this were added 16.2 g of gelatin, 1.2 g of sorbitol, 0.03 g of methylparaben, and 0.015 g of propylparaben, and further added 2.84 g of purified water and kneaded until the whole was homogeneous. Warm the mixture (approximately 70
℃) with a forming roll and spread uniformly. After cooling, the obtained drug substance was prepared into a size corresponding to a single dosage form. This product contains 60 mg of riboflavin tetrabutyrate, weighs approximately 900 mg (weight deviation: within ±2%), and has a plate-like shape (length x width x thickness: 1.0 x 4.0 x 0.2 cm). have

Example 2 Soft capsule containing allantoin (a) A mixture of 50 g of gelatin (jelly strength: 280), 70 g of concentrated glycerin and 74.15 g of purified water was
The solution was heated to 0.degree. C. and stirred to obtain a homogeneous solution, followed by defoaming treatment (required approximately 2 hours). To this was added 108.5 g of allantoin fine powder suspended in 30 ml of water, and the mixture was thoroughly mixed for about 10 minutes until the whole was homogeneous. Next, the operations consisting of molding, cooling and drying were performed in the same manner as in Example 1(a), and a plate shape (length x width x thickness of approximately 1.4 x 7.0 A soft backbone of 0.3 cm) was obtained.

(b) In the step of pouring into the molder in method (a) above, a molder is used to obtain a cylindrical shape.
x length 7.6 cm) and then dried to obtain a cylindrical soft buttock.

Example 3 Soft capsule containing pindolol (a) 1.08 g of pindolol was stirred and dispersed in 18.92 g of purified water, and after adding 6 g of concentrated glycerin and 10 g of gelatin (jelly strength 150),
The mixture was stirred for 3 hours while heating to 70°C while preventing moisture evaporation. Next, after degassing under reduced pressure, it was poured into a molding machine while still warm, and Example 1-
A plate-shaped soft capsule containing 30 mg of pindolol per drug was prepared in the same manner as in (a).

(b) 15 g of pindolol and 135 g of gelatin (jelly strength 180) were ground in a vibrating ball mill for 2 hours, and then 50 g of concentrated glycerin was added and mixed and ground. Next, it is an amount equivalent to one drug.
200 mg each was compressed and molded to obtain cylindrical soft capsules containing 15 mg of pindolol per drug.

Example 4 Soft capsule containing dipyridamole 50 g gelatin (jelly strength 150), 2.375 g dipyridamole, 40 g concentrated glycerin and 100 g purified water
A plate-shaped soft capsule containing 25 mg of dipyridamole per agent was prepared by carrying out the same operation as in Example 3-(a) using

Example 5 Soft capsule containing oxendrone (a) Oxendrone was made into fine crystals by dispersing a solution of oxendrone in a small amount of ethanol in water while stirring. After drying this, 5 g of it was weighed and dispersed in 45 ml of water, and 25 g of concentrated glycerin and 25 g of gelatin (jelly strength: 150) were added, and the mixture was heated to 70°C with stirring for 2.5 hours while preventing water evaporation. .
After the defoaming treatment, the same operation as in Example 1-(a) was carried out to prepare a plate-shaped soft capsule (1.6 x 1.6 x 0.3 cm) containing 50 mg of oxendrone per agent. Here, the weights (average) before drying and after drying were 1.015 g and 0.695 g, respectively.

(b) 2.5 g of oxendron and 22.5 g of gelatin (jelly strength: 180) were ground in a vibrating ball mill for 2 hours, and 10 g of concentrated glycerin was added and ground for about 6 hours. Next, compress and mold 350 mg each, which is the amount equivalent to one drug, and
A cylindrical soft buttock containing 25 mg of oxendrone was obtained.

(c) 1.5 g of oxendrone and 3.75 g of concentrated glycerin;
Add 1.2g of medium chain fatty acid triglyceride and 0.12g of sucrose fatty acid ester (S-970) to make approx.
The mixture was mixed uniformly at 70°C. This and gelatin 15
g, sorbitol 1.2g, methylparaben 0.03
g and 0.015 g of propylparaben, and further added 2.1 g of purified water and kneaded until the whole was homogeneous. This was compressed in a molding machine while heating (approximately 65°C), and after cooling, the plate-shaped drug substance was taken out from the molding machine and further prepared into a size corresponding to a single dosage form. . This product contains 50mg of oxendrone, and its weight is approximately 830mg.
(Weight deviation: within ±2%) 1.0 x 3.5 x 0.2 cm
It has a plate-like form (length x width x thickness).

(d) 2.5 g of concentrated glycerin to 1 g of oxendrone,
0.8 g of cacao butter and 0.08 g of sucrose fatty acid ester (S-770) were added and mixed uniformly at about 70°C. Add to this 9g of gelatin and sorbitol.
0.8g, methylparaben 0.02g and propylparaben 0.01g were added and kneaded. Separately, a solution was prepared in which 0.02 g of dipotassium glycyrrhizinate was dissolved in 1.57 g of purified water, and this was added to the above-mentioned kneaded mixture, stirred and kneaded so that the whole was homogeneous. This was compressed and spread uniformly using metal forming rolls while heating (approximately 70°C). After cooling, the obtained drug substance was prepared into a size corresponding to a single dosage form. One drug of this product contains 50 mg of oxendrone, weighs approximately 800 mg (weight deviation: within ±2.0%), and has a plate-like shape of 1.0 x 3.2 x 0.2 cm (length x width x thickness).

(e) 2.25 g of concentrated glycerin to 1 g of oxendrone,
0.72 g of Witepzol (H-15) and 0.072 g of sucrose fatty acid ester (S-770) were added and mixed uniformly at about 70°C. This and gelatin 9
g, sorbitol 0.9g, methylparaben 0.018
g and 0.010 g of propylparaben were added and kneaded. Separately dipotassium glycyrrhizinate 0.020
Prepare a solution in which g and 0.18 g of sodium chloride are dissolved in 1.4 g of purified water, add this to the above mixture, stir until the whole is homogeneous,
We practiced. This was compressed using a forming roll under heating (approximately 70°C) and spread uniformly. After cooling, the resulting bulk formulation was prepared into a size corresponding to the dosage form. One drug of this product contains 50 mg of oxendrone, and its weight is approximately 750 mg (weight deviation: within ±2.0%), 0.8 x 3 x 0.2 cm (length x width x
It has a plate-like form with a thickness (thickness).

Example 6 Soft capsule containing dihydroergotamine methanesulfonate (a) 1 g of dihydroergotamine methanesulfonate
Add 9g of concentrated glycerin and 50g of purified water to
A homogeneously dispersed suspension was obtained. Add 20g of gelatin (jelly strength: 150) to this and heat (70℃)
Then, after degassing using a vacuum stirrer to prevent water evaporation, dissolve at room temperature (approximately 50°C).
The mixture was poured into a molding machine and spread uniformly. The drug substance obtained by cooling was prepared into a size corresponding to one dosage form. This product contains 1 mg of dihydroergotamine methanesulfonate, and its weight is 80 mg.
(Weight deviation: within ±2%) 0.5 x 0.5 x 3 cm
It has a plate-like form (length x width x thickness). This was dried with ventilation at 2.5°C for about 10 hours to obtain the final product of soft buttock (1 agent weighs 35 mg).

(b) 1 g of dihydroergotamine methanesulfonate
and 9 g of gelatin (jelly strength: 150) were mixed and ground in a vibrating ball mill for 1 hour (no endothermic peak of dihydroergotamine methanesulfonate was observed in the mixed ground product by differential scanning calorimetry (DSC)). Next, 5 g of concentrated glycerin,
10 g of lactose and 30 g of powdered starch syrup were added and stirred and mixed for 10 minutes in an automatic mortar. Furthermore, 55 mg each, equivalent to one drug, was compressed and molded using a hydraulic pressure machine in a mold molding machine, and 0.8x containing 1 mg of dihydroergotamine methanesulfonate per drug.
1.0 x 0.2 cm (length x width x thickness) plate-shaped soft
I made Batukaru.

(c) The mixed pulverized product obtained in Example 6-(b) was pressure-molded using a rotary tablet machine to form a cylindrical shape (diameter 3.0 mm, thickness 1.5 mm; weight) containing 1 mg of dihydroergotamine methanesulfonate per tablet. 10mg) of soft buttucal was obtained.

Example 7 Soft capsule containing ubidecarenone (a) 0.5 g of ubidecarenone was dispersed in 54.5 g of purified water, 15 g of concentrated glycerin and 30 g of gelatin (jelly strength: 150) were added, and the mixture was heated to 70°C.
The mixture was stirred for 1 hour while preventing moisture evaporation. After degassing under reduced pressure, the mixture was poured into a mold while still warm. Containing 10 mg of ubidecarenone per drug was prepared using the same method as in Example 1-(a) below.
It has a plate-like form of 1.5 x 3.0 x 0.3 cm (length x width x thickness) and weighs 2 g (weight deviation: within ±1.0%).
I got a soft backbone. This is heated to about 4℃ at 25℃.
The final product was air-dried for several hours (weight of one drug)
1.2g).

(b) 10 g of ubidecarenone and 90 g of gelatin (jelly strength: 180) were mixed and ground in a vibrating ball mill for 1 hour to produce a mixture in which the endothermic peak of ubidecarenone disappeared by DSC. Add 25 g of concentrated glycerin and 25 g of lactose to this, mix well, and prepare a cylindrical tablet containing 10 mg of ubidecarenone per tablet (diameter: 7.5mm,
A soft buttock with a thickness of 2.5 mm and a weight of 150 mg was manufactured.

(c) 25 g of concentrated glycerin was added to 100 g of the mixed pulverized material obtained in Example 7-(b), and mixed uniformly in a mortar. Weigh out the amount equivalent to one drug (125 mg),
It was molded under pressure in a mold molding machine while being heated to 50°C.
Take out after cooling, 1.2 x 1.5 x 0.2 cm (length x width x thickness) containing 10 mg of ubidecarenone per drug.
A plate-shaped soft backbone was made.

Example 8 Soft capsule containing nifedipine (a) 10 g of concentrated glycerin and 34 g of purified water were added to 1.0 g of nifedipine, and 15 g of gelatin (jelly strength: 180) was added to the homogeneously stirred and dispersed suspension, and heated to 70°C. The mixture was dissolved under heating to form a homogeneous mixed solution. This was degassed while preventing moisture evaporation, and poured into a molding machine at a temperature of about 50°C. Example 1 below
- By the same method as in (a), each drug contains 10 mg of nifedipine and weighs 600 mg (weight deviation:
Within ±1.0%), a plate-shaped soft buttock measuring 1.0 x 1.5 x 0.3 cm (length x width x thickness) was obtained. this
The final product was dried with ventilation at 25°C for 8 hours (weight of 1 drug: 300 mg).

(b) 5 g of nifedipine and 45 g of gelatin (jelly strength: 150) were mixed and ground in a vibrating ball mill for 4 hours, and 25 g of concentrated glycerin was added and mixed for 30 minutes. Next, an amount equivalent to one drug (150 mg) was weighed out, and a soft capsule containing 10 mg of nifedipine per drug was prepared in the same manner as in Example 7-(c).

(c) The mixed pulverized product obtained in Example 8-(b) was prepared into a cylindrical shape (diameter: 6.5
2.3 mm thick; weight 100 mg).

Example 9 Soft capsule (a) containing lysozyme chloride 45g of gelatin (jelly strength: 150) was mixed with purified water
1 g of lysozyme chloride and 25 g of concentrated glycerin were added thereto under stirring to form a homogeneous solution. Next, the mixture was degassed under reduced pressure while preventing water evaporation, and poured into a molding machine at a temperature of 40°C. Hereinafter, by the same method as in Example 1-(a), a plate (length x width x thickness = 1.2 x 2.0 x 0.3 cm; weight) containing 10 mg of lysozyme chloride per agent was prepared.
A soft backbone of 1.5 g (weight deviation within 1%) was obtained. This was dried with ventilation at 25° C. for about 5 hours to obtain a final product (weight of 1 agent: 0.9 g).

(b) After 10 g of lysozyme chloride and 90 g of gelatin were mixed and ground in a vibrating ball mill for 30 minutes, 20 g of concentrated glycerin, 10 g of lactose and 20 g of mannite were added and the whole was mixed uniformly. Example 7 below
By the same method as in (b), a cylindrical soft capsule (diameter 8 mm, thickness 2 mm; weight 150 mg) containing 10 mg of lysozyme chloride per agent was obtained.

(c) 5 g of concentrated glycerin was added to 50 g of the mixed pulverized material obtained in Example 9-(b) and mixed uniformly in a mortar.
Weighed 330 mg each, equivalent to one drug, and prepared Example 7-
A plate-shaped soft capsule containing 30 mg of lysozyme chloride per agent was prepared in the same manner as in (c).

Below is a test example demonstrating the usefulness and improvement of the bioavailability of the soft capsule obtained in the above example.

In addition, the preparations used as comparative controls in the test examples were manufactured according to the tablet manufacturing method described in the general regulations for formulations of the Japanese Pharmacopoeia X, unless otherwise specified, and were sublingual tablets that complied with the general test method for formulations described in the Japanese Pharmacopoeia X. Or got a pill.

Test Example 1 Comparison of bioavailability of pindolol-containing preparations (concentration in rabbit serum) (a) Specimen and administration method White male rabbits (body weight 2.6 to 2.7
Kg, 3 birds per group). Each of the sublingual tablets obtained by the method described in "Japanese Pharmacopoeia X" was administered (dose 10 mg/
Kg). At this time, the tongue was fixed using a vinyl tube and tape to prevent swallowing of the administered preparation. Separately, (D) Pindolol was uniformly suspended in 1% carboxymethylcellulose and administered orally using a catheter (dose was 10%).
mg/Kg).

(b) Assay method After administration of each of the above (A), (B), (C) and (D)
5 ml of blood was collected every 0.25, 0.5, 1.0, 2.0, 4.0, and 6.0 hours, and serum was collected by centrifugation. Using 2 ml of this serum,
Fxperimentia), 25
The serum concentration of the unchanged drug (pindolol) was measured by a fluorescence assay method according to the method described in J.D., Vol., p. 802 (1969). The results are shown in FIG.

On the other hand, using 0.5 ml of serum each, pindolol glucuronide conjugate was converted to pindolol with β-glucuronidase (manufactured by Sigma, G-0501), and the serum concentration was measured by the above quantitative method. The results are shown in FIG. Note that no sulfuric acid conjugate could be detected.

(c) Results and Discussion As shown in Figure 1, the serum concentration was significantly higher in the oral administration groups (A, B, and C) than in the oral administration group (D). Group (C) administered with regular sublingual tablets showed a temporarily high concentration, but absorption at the initial stage of administration was slow and not sustained.
On the other hand, in the administration of the soft capsule of the present invention, in (A) pindolol is absorbed immediately after administration, and in (B) it is absorbed slightly later, but the serum concentration in both cases persists for 6 hours. Even after that, high concentrations (more than about 50 ng/ml on average) were maintained. The difference in concentration over time between these preparations is expressed by the following AUC (area under serum concentration: ng min-
ml ⁻¹ ×10 ⁴ , 0 to 6 hours).

(A) 2.59±0.51 (B) 2.99±0.58 (C) 1.72±0.43 (D) 0.57±0.02 Furthermore, as shown in FIG. It was confirmed that the change in serum concentration of the acid conjugate closely reflected the change in the unchanged form described above, and that the concentration was maintained at a high concentration above a nearly constant level. Note that AUC showed a higher value in the soft backbone of the present invention, as described below.

(A) 3.19±0.21 (B) 5.25±0.87 (C) 2.55±0.18 (D) 1.85±0.76 Test Example 2 Comparison of human bioavailability of allitein-containing preparations (plasma concentration) (a) Specimen and administration method (A) Soft bats monkey obtained in Example 2-(a) and (B) Allitein obtained by the method described in JP Each of the sublingual tablets was administered intraorally between the gums and cheeks, while (C) allantoin powder 217
mg/person was administered orally with 180 ml of water.

The subjects were fasted from 12 hours before administration until the end of the test.

(b) Assay method Before administration and after administration of (A), (B) and (C) above
3ml each every 0.5, 1.0, 2.0, 3.0 and 5.0 hours
Blood was drawn from each. For the determination of allantoin in plasma, allantoin was first converted to allantoic acid according to the hydrolysis method described in the literature [Portiers, Analytical Chemistry, Vol. 79, p. 612 (1977)], and then allantoin was converted to allantoic acid according to the method described in another literature. [Zalebunsky et al., Biochemical
Journal (Biochemical Journal), Volume 96,
218 (1965)] according to the method for quantifying allantoic acid. The plasma allantoin concentration after administration of the preparation was determined by subtracting the test values derived from plasma allantoin, allantoic acid, and biological components before administration. These results are shown in FIG.

(c) Results and discussion First, AUC (area under plasma concentration: μg・hr・
ml ⁻¹ , 0 to 5 hours) were as follows.

(A) 22.55±5.98 (B) 10.48±3.44 (C) 14.51±2.30 As shown in Figure 3, the plasma allantoin concentration after oral administration of (C) is C _nax (maximum plasma concentration)
was approximately 6 μg/ml, and T _nax (time to reach maximum plasma concentration) was 1 hour. In addition, when (B) is administered as a normal sublingual tablet, the plasma allantoin concentration rises very slowly, and C _nax is approximately 4 μg/ml.
T _nax takes 3 hours compared to oral administration.
It was observed that the absorption rate was slow and the AUC value also tended to be small.

On the other hand, in (A) oral administration of the soft buttock of the present invention, the plasma allantoin concentration at the initial stage of administration (0.5 to 1.0 hours) is almost similar to oral administration (C), but the subsequent changes are significantly different. I saw a difference. That is, with oral administration, the plasma allantoin concentration continues to decrease from 1 hour after administration, whereas with soft vacuolar administration, it remains at a relatively constant level (4 to 5 hours after administration).
6 μg ml), demonstrating the high durability of this formulation, which means that the AUC mentioned above is approximately
This was confirmed by the 1.6 times increase. Furthermore, compared to sublingual tablets (B), Soft Vaccal (A) had better absorption kinetics at the initial stage of administration, higher C _nax and longer duration, and exhibited an approximately 2.2 times higher AUC.

Test Example 3 Comparison of bioavailability of Oxendro-containing preparations (dog plasma concentration) (a) Specimen and administration method
(A) administering the soft buttock obtained in Example 5-(a), (B) administering the soft buttock obtained in Example 5-(b),
In addition, (C) tablets obtained by the method described in "Japanese Pharmacy

(b) Assay method After administering each of the above (A), (B), (C) and (D)
Blood was collected 0.5, 1, 2, 3, 5, 7, 10, and 24 hours later, and plasma was collected. This plasma was used in the literature [Itakura et al., Takeda Research Institute Annual Report, Vol. 37, 297]
Oxendrone in plasma was measured by high performance liquid chromatography according to the method described in Page (1978). The results are shown in FIG.

(c) Results and discussion First, AUC (area under plasma concentration, ng・hr,
ml ⁻¹ , 0 to 24 hours) were as follows.

(A) 120±4 (B) 226±30 (C) 36±22 (D) 500±83 Next, when calculating C _nax (maximum plasma concentration, ng/ml), (A) is 24, (B ) is 23, (C) is 12, (D) is 27n
g/ml.

As can be understood from FIG. 4, compared to oral administration (C), soft vacuolar administration (A and B) of the present invention has a faster absorption rate at the initial stage of administration.
It was revealed that C _nax also increased approximately twice and was sustained, which means that the above AUC is (A)
This was confirmed by the fact that it increased by 3.3 times in (B) and by 6.3 times in (B).

When oxendrone is administered orally, it is easily metabolized in the liver and gastrointestinal tract, and its plasma concentration is low and unsustainable, so that sufficient medicinal efficacy could not be expected. The application of soft capsules promoted absorption and improved bioavailability as seen in increased and sustained plasma concentrations. As a result, the soft capsule of the present invention is expected to be useful as a new formulation that can replace conventional injections.

[Brief explanation of the drawing]

Figures 1 and 2 show changes in the concentration of pindolol in serum of rabbits upon administration of pindolol-containing preparations. Here, FIG. 1 shows the concentration change of pindolol (unchanged substance), and FIG. 2 shows the concentration change of pindolol glucuronide conjugate. (A) is soft buccal administration of Example 3-(a), (B) is soft buccal administration of Example 3-(b), (C) is sublingual administration of a sublingual tablet, and (D) is The blood concentration changes after oral administration of each drug are shown. FIG. 3 shows the concentration change of allantoin in human plasma upon administration of allantoin-containing preparations. Here, (A) is Example 2
- (a) shows soft vacuolar administration, (B) shows sublingual administration of sublingual tablets, and (C) shows oral administration. FIG. 4 shows the change in concentration of oxendrone in dog plasma upon administration of a preparation containing oxenhydrone. Here, (A) is the soft capsule administration of Example 5-(a), (B) is the soft capsule administration of Example 5-(b), (C) is the oral administration of tablets, and (D) is the soft capsule administration of Example 5-(b). The case for each intramuscular injection is shown.

Claims (1)

[Claims] 1 1 part of drug for absorption through the oral mucosa and 0.5 to 150 parts of water-soluble protein that exhibits an absorption promoting effect
and 0.01 to 3 parts of an additive selected from the group consisting of polyhydric alcohols, vinyl polymers, celluloses, and fatty acid esters is added to 1 part of the water-soluble protein. A soft oral preparation that conforms to and holds its shape within the mouth.