JPS631923B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention relates to suppositories with a novel composition. More specifically, ascorbic acid and/or sodium ascorbate may be included together with a drug that is not absorbed, is substantially not absorbed, or is insufficiently absorbed by normal rectal administration or normal oral administration. This invention relates to suppositories with improved absorption of such drugs. Traditionally, drug administration methods include oral administration using tablets, capsules, granules, syrups, etc.
Common methods include injection methods such as subcutaneous injections, intramuscular injections, and intravenous injections, and local administration methods such as nasal drops, eye drops, ointments, and creams. Suppositories, or preparations that allow the absorption of phthalate, have also been attracting attention recently. Suppositories include suppositories that have drugs dissolved and dispersed in solid fats such as cacao butter and uitepsol, suppositories that have drugs dissolved and dispersed in hydrophilic bases such as macrogol, and liquid oils such as medium-chain fatty acid triglycerides and vegetable oils. Gelatin capsule suppositories are known, which are capsules made by dissolving and dispersing drugs in a capsule and covering the drug with a gelatin film. Administering any drug into the rectum using any suppository has the following advantages: (1) side effects can be avoided; In other words, some drugs can cause gastrointestinal disorders when administered orally, or muscle contractures when injected, but these can be avoided with suppositories. (2) Drug utilization is often high; in other words, there are almost no acids or enzymes in the rectum, so drugs are less likely to be broken down, and more than half of drugs absorbed from the rectum do not pass through the liver the first time. Because it passes through the route, inactivation of the drug in the body can be avoided, and depending on the drug, absorption is better than when taken orally.Furthermore, when administered orally, the utilization rate of the drug differs before, during, and after meals. However, suppositories are not easily affected by meals. (3) Administration is relatively simple and reliable, and there are few restrictions when administering; in other words, there is no pain during administration unlike with injections, and administration is reliable, and administration of oral agents is possible in cases such as vomiting, nausea, unconsciousness, and post-surgery. Advantages include that suppositories can be administered even in difficult cases. Although there are many advantages to administering drugs rectally in the form of suppositories, it is important to note that drugs that are not absorbed, substantially poorly absorbed, or poorly absorbed by normal oral administration, such as drugs with high molecular weight, Certain drugs have the disadvantage that they are not absorbed, or are substantially poorly absorbed, or are poorly absorbed even in suppositories. Insulin, heparin, cephaloridine, etc. can be mentioned as typical drugs that are hardly absorbed by normal rectal administration or normal oral administration as mentioned above. For example, the only practical method of administering insulin to date has been injection, and diabetic patients are forced to administer daily subcutaneous injections.
It is said that the mental and physical pain caused is extremely great. Due to the origin of insulin, metal salts, and the formation of complexes with other proteins, injections with long-lasting efficacy have been developed, and efforts are being made to reduce the number of injections. On the other hand, insulin is being purified to reduce its side effects, and as a result insulin is being administered frequently. In this way, insulin injections can be administered either by daily injection or by one injection.
In addition to the mental and physical pain caused by multiple injections per day, local allergic reactions, lipodystrophy, eczema, and anaphylactic shock may occur. For this reason, research into dosage forms other than injections for insulin preparations has been actively conducted, including suppositories, nasal preparations, inhalers, eye drops, oral preparations,
Sublingual tablets are being researched, but they are not yet a satisfactory method, and none have been put into practical use. Therefore, the present inventors believed that if a suppository could be developed that overcomes these drawbacks, it would be a highly desirable drug administration method for patients.
As a result of extensive research, it has surprisingly been found that when producing and administering suppositories containing drugs and ascorbic acid and/or sodium ascorbate, absorption is insufficient through normal oral or rectal administration. The present invention was achieved based on the discovery that not only drugs but also drugs that are not absorbed or substantially hardly absorbed by normal oral or rectal administration can be efficiently absorbed from the rectum. That is, the present invention includes a drug that is not absorbed, substantially hardly absorbed, or insufficiently absorbed by normal rectal administration or normal oral administration, and ascorbic acid and/or sodium ascorbate. It is a suppository characterized by: Such drugs used in the present invention include drugs that are not absorbed, are substantially not absorbed, or are insufficiently absorbed by normal rectal administration or oral administration, and specifically include insulin, angiotensin, etc. , peptide hormones such as vasopressin, felipressin, protirelin, gonatropin-releasing hormone, corticotropin, prolactin, somatotropin, thyrotropin, luteinizing hormone, calcitonin, kallikrein, parathyrin, glucagon oxytocin, gastrin, secretin, serum gonadotropin; heparin, Polysaccharides such as chondroitin sulfate; enzymes such as trypsin, α-chymotrypsin, papain seratiopeptidase, promelain, semi-alkaline peptidase, lysozyme chloride, protease, hyalurondase, urokinase, streptokinase, cytochrome C; prostaglandin F ₂ α, prostaglandins such as prostacyclin; 1α-hydroxycholecalciferol, 1α・25-dihydroxycholecalciferol, 1α・24-dihydroxycholecalciferol, 24・25-dihydroxycholecalciferol Oil-based vitamins; carbocone, 5-fluorouracil, methotrexate, actinomycin C, actinomycin D, cartinophilin, mitomycin C,
Anticancer drugs such as bleomycin hydrochloride, guunorchicine hydrochloride, doxorubicin hydrochloride, neocarzinostatin, chromomycin A ₃ , L-asparakinase, picibanil, podophyllotoxin, vinblastine sulfate, vincristine sulfate; carbenicillin, sulbenicillin sodium, cephalothin Sodium, cephaloridine, cefazolin sodium, cefapirin, amphotericin B, cefamatril sodium, cefapine sodium,
Antibiotics such as ceftizole sodium, streptomycin sulfate, biomycin sulfate, capreomycin sulfate, and enbiomycin sulfate; animal and plant extracts, fungal cell extracts, etc.; One or more of these are used. In particular, peptide hormones; enzymes, polysaccharides; anticancer drugs; and antibiotics are preferably used, and peptide hormones, polysaccharides, and antibiotics are more preferably used. Although the amount of the drug to be used cannot be determined unconditionally depending on the type of drug, it is preferable to use an amount at which sufficient medicinal efficacy can be expected. The amount of ascorbic acid and/or sodium ascorbate to be used is not particularly limited, but it should be used within a pharmaceutically acceptable range. For example, if the usual dose is indicated, it should be less than the usual dose. It is desirable to use it in Preferably, the amount is 0.5 to 30% by weight, more preferably 2 to 20%, and even more preferably 5 to 15% by weight, based on the total weight of the suppository. All commonly used bases can be used as bases for the suppositories of the present invention, including cocoa butter,
Oils and fats mainly composed of triglycerides such as palm fat, palm kernel oil, coconut oil, fractionated coconut oil, lard, and uitepsol; Waxes such as lanolin and reduced lanolin; Hydrocarbons such as petrolatum, squalene, squalane, and liquid paraffin; Medium- and long-chain fatty acids such as capric acid, lauric acid, stearic acid, and oleic acid; Higher alcohols such as lauryl alcohol, cetanol, and stearyl alcohol; Fatty acid esters such as butyl stearate and dilauryl malonate; Triolefin and tristearin Glycerin medium-long chain carboxylic acid esters such as glycerin acetoacetate; glycerin-substituted carboxylic acid esters such as glycerin acetoacetate; polyethylene glycol and its derivatives such as macrogol and cetomacrogol; one or two of these The above is used. In particular, uitetupzol, cocoa butter, glycerin esters,
One or more types of polyethylene glycols are preferably used. Further, there is no restriction at all that the formulation of the present invention may contain commonly used surfactants, preservatives, coloring agents, flavoring agents, etc., if necessary. The preparation of the present invention is prepared by dissolving or dispersing the above-mentioned drug and ascorbic acid and/or sodium ascorbate in the above-mentioned suppository base. i.e. for the total weight of drug and suppositories
This suppository is characterized by containing 0.5 to 30% by weight of ascorbic acid and/or sodium ascorbate and being substantially free of water. Here, "substantially free of water" refers to ascorbic acid and/or sodium ascorbate whose drying loss is 0.20% or less (1 g, silica gel, 24 hours) according to the Japanese Pharmacopoeia drying loss test method. This means that the amount of water is 0.10% or less based on the total weight of the suppository. The manufacturing method of the preparation of the present invention involves taking a predetermined amount of the base, drug, and ascorbic acid and/or sodium ascorbate, heating if necessary, and using a stirrer or a grinder to uniformly dissolve each component. Alternatively, the liquid may be dispersed, poured into a mold, and then cooled, or the liquid may be filled and sealed into gelatin capsules using a capsule filling machine. An example of an embodiment of the present invention is as follows. 100 parts of cocoa butter, 0.01 part of salmon calcitonin,
Seven parts of ascorbic acid was taken and uniformly dissolved and dispersed using a grinder, heated to 40°C, and the solution was poured into a suppository container and cooled to produce a calcitonin suppository weighing 1 g. Hereinafter, the present invention will be explained in more detail with reference to Examples. Example 1 Sodium ascorbate in 18.6g of cocoa butter
1.43g was added and kneaded well in a mortar. 0.103 mg of salmon calcitonin was weighed out using an electric balance, and the above base was gradually added and mixed in a mortar to obtain a homogeneous suppository composition. This is heated slightly to make it fluid, and then poured into a suppository container prepared for rats.
The mixture was poured to a concentration of 80 mg, and cooled and solidified to obtain a suppository with a diameter of about 3 mm and a length of about 6 mm. This drug was administered rectally to SD male rats (body weight 190-160 g), and the serum calcium concentration was measured at 1, 2, 3, and 5 hours after administration. I looked into it. Serum calcium was measured using a calcium measurement kit manufactured by Yatron, and 5 rats were used for each blood collection. The results are shown in Table 1 as the degree of decrease (%) in calcium value relative to the serum calcium value before administration.

[Table] Example 2 Using 1.4 g of ascorbic acid in place of sodium ascorbate in Example 1, and using [Asu ^1.7 ]-eel calcitonin in place of salmon calcitonin, the other conditions were exactly the same, and the amount per 80 mg was
A suppository containing 0.69 MRC units of calcitonin was prepared and administered to the rectum of rats in exactly the same manner as in Example 1, to obtain the degree of decrease in serum calcium level as shown in Table 2.

[Table] Example 3 Add 1.4 g of ascorbic acid to 18.5 g of cacao butter, mix well in a mortar, and add heparin sodium.
375 mg was added and mixed well to obtain a homogeneous suppository composition. This was heated slightly to fluidize it, poured into a container, cooled and solidified, and weighed 1.4
g suppositories were obtained. This drug was administered rectally to white native male domestic rabbits (body weight 3.0-3.5 kg), and was administered for 20 minutes, 40 minutes, and 1 hour after administration.
Whole blood coagulation times at 2 hours, 3 hours, and 4 hours were measured by the Lee-White method. Using five domestic rabbits, 2.5 ml of blood was taken per blood sample, and two 1 ml samples were made for measurement. The results are shown in Table 3 as a ratio to the blood coagulation time before administration.

[Table] Example 4 2.4 g of sodium ascorbate was dispersed in 17.6 g of Witepzol W-35, and 6.0 g of cephaloridine was added thereto, and the mixture was thoroughly ground in a mortar to obtain a homogeneous suppository composition. The above composition was packed into a gelatin capsule to make a suppository so that the amount of cephaloridine was 40 mg/Kg according to the weight of the test animal, a domestic rabbit. This drug was administered rectally to white native male domestic rabbits (body weight 3.0 to 3.5 kg), and blood concentrations were measured 1, 2, and 3 hours after administration. Blood concentration was measured by the cylindrical plate method (Nippon Ki). Three rabbits were used, and approximately 2.5 ml of blood was collected each time. The results are shown in Table 4.

[Table] Example 5 Ascorbic acid added to 18.0g of fractionated coconut oil
Disperse 2.0g and add 14.55ml of porcine insulin.
was precisely weighed and added using an electric balance, and stirred well in a mortar to obtain a homogeneous dispersion. 500 ml of the dispersion was filled into gelatin capsules for suppositories to obtain gelatin capsule suppositories. One capsule of this drug contains 9.6 international units of insulin. This drug was administered rectally to white native male domestic rabbits (body weight 3.0 to 3.5 kg), and blood sugar levels were measured before and 30 minutes, 1 hour, 2 hours, and 3 hours after administration. The absorption of insulin from the rectum was investigated. Five domestic rabbits were used, and 0.5 ml of blood was collected each time. Blood sugar levels were measured by the glucose oxidase method. The results are shown in Table 5 as the degree of decrease (%) relative to the blood sugar level before administration.

[Table] Example 6 The same procedure as in Example 1 was performed except that sodium ascorbate was used instead of ascorbic acid, and the results shown in Table 6 were obtained.

[Table] Example 7, Comparative Examples 1-2 Ascorbic acid in 19.0g of fractionated coconut oil
1.0 g of porcine insulin was dispersed, and 7.3 mg of porcine insulin was further accurately weighed using an electric balance, added thereto, and thoroughly stirred in a mortar to obtain a homogeneous dispersion. A gelatin capsule suppository was obtained by filling 500 mg of the dispersion into a gelatin capsule for suppositories (Example 7). One capsule of this drug contains approximately 4.8 international units of insulin. Comparative Example 1 1.0 g of ascorbic acid was dispersed in 19.0 g of fractionated coconut oil, and 7.3 mg of porcine insulin, which was accurately weighed using an electric balance, was suspended in 0.2 ml of purified water, and the mixture was stirred well in a mortar. A homogeneous dispersion was obtained. of the dispersion in gelatin capsules for suppositories.
Gelatin capsule suppositories were obtained by filling 505 mg. One capsule of this drug contains approximately 4.8 international units of insulin. Comparative Example 2 Ascorbic acid in 19.0g of fractionated coconut oil
1.0g and 7.3 porcine insulin accurately weighed on an electric balance
mg was suspended (partially dissolved) in 1.0 ml of purified water and stirred well in a mortar to obtain a homogeneous dispersion. of the dispersion in gelatin capsules for suppositories.
Gelatin capsule suppositories were obtained by filling 525 mg. One capsule of this drug contains approximately 4.8 international units of insulin. White native male domestic rabbit (clean grade, weight
Three types of suppositories prepared as above were administered into the rectum of 3.0 to 3.7 kg), and 30 days before and after administration.
Blood sugar levels were measured at minutes, 1 hour, 2 hours, and 3 hours, and the rectal absorption of insulin by the preparations of the present invention and comparative preparations was investigated. A group of 5 rabbits was used, and 1.0 ml of blood was collected each time. Measurement of plasma glucose level, ie, blood sugar level, was performed by the glucose oxidase method. The results are shown in Table 7 as the degree of decrease (%) relative to the blood sugar level before administration.

【table】

Claims (1)

[Scope of Claims] 1. 0.5 to 30% of the total weight of drugs and suppositories that are not absorbed, are substantially not absorbed, or are insufficiently absorbed by normal rectal administration or normal oral administration. % by weight of ascorbic acid and/or sodium ascorbate, and is characterized in that it is substantially free of water. 2. The suppository according to claim 1, wherein the drug is one or more selected from the group consisting of peptide hormones, enzymes, polysaccharides, anticancer drugs, and antibiotics. 3. The suppository according to claim 1, which is one or more selected from the group consisting of drug peptide hormones, polysaccharides, and antibiotics. 4. The suppository according to any one of claims 1 to 3, wherein the peptide hormone is calcitone. 5. The suppository according to any one of claims 1 to 3, wherein the peptide hormone is insulin. 6. The suppository according to any one of claims 1 to 3, wherein the polysaccharide is heparin.