JPS6237602B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention relates to suppositories with a novel composition. More specifically, the drug can be prepared by containing salicylic acid and/or salicylic acid derivatives together with one or more drugs selected from the group consisting of peptide hormones, enzymes, polysaccharides, anticancer drugs, and antibiotic substances. This invention relates to a suppository with improved absorption. 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 into capsules and covering them with a gelatin film. Administering drugs into the rectum with any suppository has the following advantages: (1) side effects can be avoided; in other words, some drugs may cause gastrointestinal disorders when administered orally, or muscle contractures when injected; However, this 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 the drugs absorbed from the rectum do not pass through the liver the first time. Because it passes through the drug route, inactivation of the drug in the body can be avoided, and depending on the drug, it is better absorbed than when taken orally.Furthermore, when administered orally, the utilization rate of the drug differs before, during, and after meals. Although it is common, suppositories are not easily affected by meals; (3) administration is relatively simple and reliable, and there are few restrictions on administration; in other words, unlike injections, there is no pain during administration, and administration is reliable; Advantages include that suppositories can be administered even in cases where oral administration is difficult, such as vomiting, nausea, unconsciousness, or postoperatively. 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 is injection, and diabetic patients are forced to give daily subcutaneous injections, which causes mental and physical pain. It is said to be very large. Due to the origin of insulin, metal salts, and the formation of complexes with other proteins, the efficacy of insulin can be maintained for a long time, and injections have been developed 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 intensive research, it was surprisingly possible to combine salicylic acid and/or salicylic acid derivatives with one or more drugs selected from the group consisting of peptide hormones, enzymes, polysaccharides, anticancer drugs, and antibiotics. When producing and administering suppositories containing drugs, drugs that are insufficiently absorbed by normal oral or rectal administration, as well as drugs that are not absorbed or are substantially hardly absorbed by normal oral or rectal administration. The present invention was achieved by discovering that even drugs are efficiently absorbed from the rectum. That is, the present invention includes one or more drugs selected from the group consisting of peptide hormones, enzymes, polysaccharides, anticancer drugs, and antibiotics, and salicylic acid and/or salicylic acid derivatives. This is a suppository with special characteristics. The drugs used in the present invention are not particularly limited, but include drugs that are not absorbed, substantially hardly absorbed, or insufficiently absorbed by normal rectal administration or oral administration, and specific These include insulin, angiotensin, pasopressin, felipressin, protirelin, gonadotropin-releasing hormone, corticotropin, prolactin, somatotropin, thyrotropin, luteinizing hormone, calcitonin, kallikrein, parathyrin, glucagon,
Peptide hormones such as oxytocin, gastrin, secretin, serum gonadotropin; polysaccharides such as heparin and chondroitin sulfate; trypsin, α-chymotrypsin, papain, serratiopeptidase, promelain, semi-alkaline peptidase, lysozyme chloride, protease Enzymes such as , hyalurondase, urokinase, streptokinase, and cytochrome C; prostaglandins such as prostaglandin _F2α and prostacyclin; 1α-hydroxycholecalciferol, 1α,25-dihydroxycholecalciferol, Oil-based vitamins such as 1α,24-dihydroxycholecalciferol and 24,25-dihydroxycholecalciferol; carbocone, 5
-Fluorouracil, methotrexate, actinomycin C, actinomycin D, cartinophylline, mitomycin C, pleomycin hydrochloride, guunorubicin hydrochloride, doxorubicin hydrochloride,
Neocarzinostatin, chromomycin A ₃ , L
- Anticancer drugs such as asparakinase, picipanil, podophyllotoxin, vinblastine sulfate, vincristine sulfate; carpenicillin sulbenicillin sodium, cephalothin sodium, cephalolidine, cefazolin sodium, cefapirin, amphotericin B, cefacetrill sodium, Antibiotics such as cefapine sodium, ceftesol sodium, streptomycin sulfate, pyomycin sulfate, capreomycin sulfate, and enbiomycin sulfate; animal and plant extracts;
Examples include bacterial cell extracts, and one or more of these may be used within a pharmaceutically acceptable range. In particular, peptide hormones; enzymes; polysaccharides; anticancer drugs; and antibiotics are preferably used. Salicylic acid derivatives used in the present invention include sodium salicylate, acetylsalicylic acid, salicylsalicylic acid, aspirin aluminum, choline salicylate, methyl salicylate, salicylamide, ethenzamide, exalamide, diflunisal, aspirin lysine salt, etc. within the range permitted by
One or more of these may be used. In particular, sodium salicylate and acetylsalicylic acid are 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. There is no particular restriction on the amount of salicylic acid and/or salicylic acid derivatives used, but it should be used within a pharmaceutically acceptable range,
For example, in cases where the usual dose is indicated, it is preferably used at less than the usual dose, particularly at one-fifth or less of the usual dose. 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; Triolein and tristearin Glycerin medium-long chain carboxylic acid esters such as glycerin acetoacetate; glycerin-substituted carboxylic acid esters such as glycerin acetoacetate; polyethylene glycols and their derivatives such as macrogol and cetomacrogol; one or two of these The above is used. In particular, one or more of Witepzole, cacao butter, glycerin esters, and polyethylene glycols are preferably used. Further, there is no restriction at all that the preparation of the present invention may contain commonly used surfactants, preservatives, coloring agents, flavoring agents, etc., if necessary. The preparation of the present invention contains one or more drugs selected from the group consisting of the above-mentioned peptide hormones, enzymes, polysaccharides, anticancer drugs, and antibiotics, and salicylic acid and /Or the above-mentioned salicylic acid derivatives are dissolved or dispersed. That is, the sitz is characterized by containing one or more drugs selected from the group consisting of peptide hormones, enzymes, polysaccharides, anticancer drugs, and antibiotics, and salicylic acid and/or salicylic acid derivatives. It is a drug. The method for producing the formulation of the present invention involves taking predetermined amounts of the base, drug, and salicylic acid and/or salicylic acid derivative, heating if necessary, and using a stirrer or a grinder to uniformly dissolve or dissolve each component. The solution is dispersed, poured into a mold, and then cooled, or the solution is 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, 0.02 parts of porcine insulin,
15 parts of sodium salicylate 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 an insulin suppository weighing 1 g. Hereinafter, the present invention will be explained in more detail with reference to Examples. Example 1 4.0 g of sodium salicylate was dispersed in 16.0 g of fractionated coconut oil, and porcine insulin was added.
4.85 mg was accurately weighed using an electric balance, and stirred thoroughly 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. One capsule of this drug contains
Contains 3.2 international units of insulin. This drug was administered rectally to white native male domestic rabbits (body weight 3.0 to 3.5 kg), and was administered for 30 minutes and 1 hour before and after administration.
Blood sugar levels were measured at 2 and 3 hours, and absorption of insulin from the rectum by the preparation of the present invention 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 1 as the degree of decrease (%) relative to the blood sugar level before administration.

[Table] As a control example, when a suppository containing no sodium salicylate was administered from the above formulation, almost no decrease in blood sugar level was observed. Example 2 The same procedure as in Example 1 was carried out except that 4.0 g of acetylsalicylic acid was used instead of sodium salicylate, and the results shown in Table 2 were obtained.

[Table] Example 3 1.4g of sodium salicylate in 18.6g of cocoa butter
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. Approximately 80mg of this was heated slightly to make it fluid and placed in a suppository container prepared for rats.
The suppository was poured in such an amount as to give a suppository with a diameter of about 3 mm and a length of about 6 mm by cooling and solidifying. This drug was administered rectally to male SD rats (body weight 190-120 mg).
Serum calcium concentrations were measured at 1, 2, 3, and 5 hours after administration, and the absorption of calcitonin from the rectum by the formulation of the present invention was investigated. 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 3 as the degree of decrease (%) in calcium value relative to the serum calcium value before administration.

[Table] Example 4 Using 1.4 g of acetylsalicylic acid in place of sodium salicylate in Example 3, and using [Asu _1.7 ]-eel calcitonin in place of salmon calcitonin, and in the same manner as in _Example 3, 80 mg per 80 mg.
Suppositories containing 0.69 MRC units of calcitonin were prepared and administered into the rectum of rats in exactly the same manner as in Example 3, to obtain the degree of decrease in serum calcium levels as shown in Table 4.

[Table] Example 5 18.2g of cocoa butter and 1.4g of sodium salicylate
was added and mixed well in a mortar, and further 375 mg of heparin sodium was added and mixed well to obtain a well-balanced composition for suppositories. This is heated slightly to fluidize it, poured into a container, cooled and solidified, and weighed
1.4 g of 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, 25 ml of blood was taken per blood sample, and two 1 ml samples were made for measurement. The results are shown in Table 5 as a ratio to the blood coagulation time before administration.

[Table] Example 6 2.4 g of acetylsalicylic acid was dispersed in 1.76 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 6.

[Table] Example 7 3.8 g of methyl salicylate was dispersed in 16.0 g of fractionated coconut oil, and 4.85 g of porcine insulin was added.
g was accurately weighed using an electric balance, and stirred well 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. One capsule of this drug contains 3.2 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 glucose 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 7 as the degree of decrease (%) relative to the blood sugar level before administration.

[Table] Example 8 2.1 g of choline salicylate was added to 18.6 g of cacao butter, and the mixture was thoroughly kneaded in a mortar. salmon calcitonin
0.103 mg was weighed out using an electric balance, and the above base was gradually added thereto in a mortar and mixed to obtain a homogeneous suppository composition. This was heated slightly to make it fluid, poured into a suppository container prepared for rats at a concentration of about 80 mg, and cooled to solidify to a diameter of about 3 mm.
A suppository with a length of about 6 mm was obtained. This drug was administered rectally to SD male rats (body weight 190-120 mg), 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 8 as the degree of decrease in calcium value (%) relative to the serum calcium value before administration. Example 9 The same procedure as in Example 8 was carried out except that 2.5 g of lysine salicylate salt was used instead of choline salicylate, and the results shown in Table 8 were obtained.

[Table] In addition, in the formulation in which choline salicylate was not used in Example 8, and in the formulation in which salicylic acid lysine salt was not used in Example 9, almost no decrease in serum calcium values was observed.

Claims (1)

[Claims] 1. Comprising one or more drugs selected from the group consisting of peptide hormones, enzymes, polysaccharides, anticancer drugs, and antibiotics, and salicylic acid and/or salicylic acid derivatives. A suppository characterized by: 2. The suppository according to claim 1, wherein the salicylic acid derivative is sodium salicylate and/or acetylsalicylic acid.