JPS597682B2 - ointment base - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to an ointment base for topical administration of drugs, and more particularly, to an ointment base for topical administration of drugs, and more particularly, the present invention relates to ointment bases for topical administration of drugs, and more particularly, the present invention relates to ointment bases for topical administration of drugs. The present invention relates to an ointment base for preparing a stable ointment.

Ointments are semisolid formulations for topical administration of drugs that are rubbed or applied to the skin or mucous membranes to transfer and penetrate the drug into the skin or mucous membranes.

Therefore, it is important that the main drug contained in an ointment quickly and reliably transfers and penetrates into the affected area, and since ointments may be used for a long period of time depending on the type of main drug and the target of treatment, Not only the main drug but also the base itself must be able to be stored stably without any deterioration until the ointment is completely consumed.

One of the most important conditions for an ointment that satisfies these basic requirements is the selection of an appropriate base, and various ointment bases have been developed to date.

As one of them, recently propylene carbonate 0.5 ~
An ointment base consisting of a basic composition of 30% by weight and petrolatum and 30 to 99.5% by weight has been proposed (Japanese Patent Publication No. 1986-1).
(Refer to Publication No. 0613), this significantly improves the translocation permeability of the active ingredient into the skin or mucous membranes, but it is still not sufficient, and drawbacks include the unresolved resistance to unstable active ingredients. There is.

The present inventors have conducted extensive research with the aim of developing a high-performance ointment base that does not have such drawbacks, and as a result, an ointment base containing seven basic ingredients, ethylene carbonate, propylene carbonate, and petrolatum, has been developed. The present invention has been completed based on the discovery that a stable ointment with excellent drug (main drug) migration into the skin or mucous membranes, permeability, and resistance to drug deterioration can be provided.

Therefore, according to the present invention, there is provided an ointment base comprising ethylene carbonate, propylene carbonate and petrolatum as essential ingredients.

Ethylene carbonate and propylene carbonate used in the ointment base of the present invention are carbonate esters of ethylene glycol and glopylene glycol represented by the following formulas (I) and (■), respectively. Use in combination is an important feature of the invention.

In the present invention, by using ethylene carbonate and propylene carbonate, the migration and permeability of the drug into the skin or mucous membranes are greatly improved compared to when ethylene carbonate and glopylene carbonate are used alone. It was also found to be very effective in preventing the deterioration of unstable drugs.

The concentration of ethylene carbonate and glopylene carbonate in the ointment base of the present invention, which exhibits such excellent effects, can be varied widely depending on the type and amount of the drug (main drug) to be added to the ointment base. However, based on the weight of the ointment base, ethylene carbonate is generally 0.1
-10% by weight, preferably 0.2-5% by weight, more preferably 0.7-3% by weight,
Further, propylene carbonate is generally 0.1 to 10% by weight, preferably 0.2 to 5% by weight, and more preferably 0.

It can be within the range of 4 to 1.5% by weight. In addition,
In the following description, "% by weight" expressing the concentration of components in the ointment base is based on the weight of the ointment base unless otherwise specified.

Additionally, the ratio of ethylene carbonate to glopylene carbonate in the ointment base can be adjusted depending on the type and amount of the drug to be mixed, but in general, the weight ratio of ethylene carbonate/propylene carbonate is within the range of 7/1 to 1/2, preferably 4/1 to 1.5/
1, more preferably within the range of 3/1 to 2/1.

Furthermore, if the amounts of ethylene carbonate and propylene carbonate are too large, the ointment base itself may become unstable or phase separation may occur.
Generally, the total of both is 15% by weight or less, preferably 0.
The content of IO is desirably within the range of 4 to 5% by weight, more preferably 1 to 5% by weight, and most preferably 1 to 2% by weight.

The ointment base to which the present invention is directed is based on petrolatum, and petrolatum can generally account for at least 70% by weight, preferably 80-99% by weight of the ointment base.
．． It may be present in a concentration within the range of 5% by weight, more preferably 90-99% by weight.

Among the petrolatums that can be used, white petrolatum listed in the Japanese Pharmacopoeia is preferred.

The ointment base of the present invention may consist only of the above three essential components, ethylene carbonate, propylene carbonate and petrolatum, or in addition to these three components,
Other components conventionally used as additives for ointment bases may also be appropriately blended.

Other components that may be blended include, for example, dispersants, antioxidants, pH adjusters, thickeners, penetration enhancers, and the like.

Examples of dispersants that can be used include nonionic surfactants such as polyoxyethylene sorbitan monostearate, polyoxysorbitan monooleate, sorbitan monolaurate, sorbitan monopalmitate, sorbitan monostearate, and sorpitan sesquiolate. , and borax, and these may be used alone or in combination of two or more.

These dispersants, if used, can generally be used in amounts of 5% by weight or less, preferably 3% by weight or less.

In the present invention, among such dispersants, a mixture of about 80% by weight of cetanol and about 20% by weight of polyethylene glycol monostearate, known as "borawax", is particularly suitable. ,
If included, generally in an amount up to 3% by weight, and preferably from 0.5 to 2% by weight, more preferably 0,7%.
It can be used within the range of ~1.5% by weight.

Examples of antioxidants include phenols such as butylated hydroxyanisole and cyphthylhydroxytoluene, and tocopherols. II (Tenox I[) J, commercially available from about 20% by weight butylated hydroxyanisole, about 6% by weight probyl gallate, about 4% by weight citric acid and about 70% by weight propylene glycol. The following antioxidants are suitable.

These antioxidants can generally be used in amounts up to 0.7% by weight, preferably up to 0.05% by weight.

Examples of pH adjusting agents that can be used include organic acid salts such as lactic acid and citric acid, hydrochloric acid, and sodium hydroxide, which are used to adjust the pH of the ointment to within a range of about 3 to about 7. It can be used as appropriate.

Further, thickeners include waxes such as beeswax, spermaceti, paraffin, and microcrystalline wax, colloidal silica, stearyl alcohol, cetanol, lanolin, etc., and are generally used in an amount of 10% by weight or less. be able to.

Therefore, an ointment base suitable for the present invention can be composed of the following composition ratio: To the ointment base having the above composition ratio, an antioxidant, such as tocopherol or Tenox 2, is added in an amount of 0.01 to 0.01 to
It may be added in an amount of 0.7% by weight, especially 0.02 to 0.05% by weight.

The ointment base of the present invention is prepared by adding each of the above-mentioned ingredients according to a conventional method.
For example, ethylene carbonate, glopylene carbonate and bora wax are dissolved by heating at 70 to 75°C,
Add Tesox■ and mix while heating again, add the resulting mixture to white vaseline pre-dissolved at 70 to 75°C, stir and mix at a temperature of about 70°C until uniform,
It can be easily prepared by a method such as allowing the contents to cool while stirring until the temperature reaches about 30°C.

The ointment base of the present invention can be used as a base for preparing ointments for topical administration in a variety of pharmacies.

Examples of drugs that can be incorporated into the ointment base of the present invention include:
Synthetic corticosteroids such as triamcinolone, triamcinolone acetonide, amcinonide, fluocinolone acetonide, betamethasone pareto, etc.; Non-steroidal anti-inflammatory agents such as indomethacin, pufexamac; tetracycline, tetracycline hydrochloride, etc. Antibiotics such as chloramphenicol, nyscutin, and fradiomycin sulfate; antihistamines such as diphenhydramine and diphenhydramine hydrochloride, etc.

The ointment base of the present invention is particularly suitable for preparing ointments containing synthetic corticosteroids such as those described above, particularly amcinonide.

The amount of the synthetic adrenocortical hormone that can be incorporated into the ointment base of the present invention varies slightly depending on the type, etc., but is generally 0.005 to 5% by weight, preferably 0.005% by weight, based on the weight of the final ointment. It is appropriate that the amount is within the range of 0.05 to 1% by weight.

The ointment using the ointment base of the present invention has very excellent permeability of the drug contained therein into the skin or mucous membranes, and its excellent efficacy is demonstrated by the following vasoconstriction test using a synthetic adrenocorticosteroid. This can be demonstrated by

The results of toxicity tests are also shown for reference.

; Vasoconstriction test (medicinal efficacy test) In order to prove that the ointment of the present invention containing a drug, a synthetic corticosteroid hormone, is clinically useful, we conducted a vasoconstriction test in humans. Examination (Vasoco
restriction activity test
) was carried out.

In general, dermal ointments containing synthetic adrenocortical hormones produce a vasoconstrictive response when applied sealed to human skin, and there is a high correlation between this vasoconstrictive ability and clinical efficacy. [Ishihara: Clinical Evaluation 4 (3): 323-349, 1976].

This test method is commonly used as a method for screening the efficacy of ointments containing synthetic adrenocortical hormones.

The synthetic adrenocortical hormone agent used in this study was amcinonide (chemical name: 16α・17α-cyclopentylenedioxy-9α-fluoro-11β・2 1-cyhydroxy-1・4-pregnadiene-3・20-dione 21
-acetate) and is a new derivative of triamcinolone, a synthetic corticosteroid currently widely used clinically.

Test results: (1) The sample contained amcinonide, the main drug, at 0.1% and 0.1%.
×4-1%, 0. IX4”%, 0. IX4-”%
,0. Tests were conducted using 6 types of ointment bases A to F below, with 6 levels of successive 4-fold dilutions of I x 4'' and 0.1 x 4''% (the total number of samples was 36).

The concentration of the active ingredient and the composition of the ointment base for each sample used in this test are shown in the table below.

(2) On the upper back of 10 healthy subjects (male), the above
Six samples were randomly assigned, and an appropriate amount of each sample was applied to a commercially available patch test unit and sealed.

The sealing time was 4 hours, the sample was removed and wiped, and the judge made the judgment twice, 2 hours and 5 hours after the seal was removed.

Judgment criteria depend on the strength of the pallor phenomenon associated with amcinonide's vasoconstriction reaction, and are categorized into ``pronounced pallor'' (+10), ``fairly obvious pallor'' (+), and ``slight pallor'' (±).
) and "no response" (-), and (++) and (+) were defined as positive vasoconstriction reactions.

Also, ED,,,. (50% Effective
Dose) value was calculated.

Results: As shown in Tables 1 and 2 below, the judgment results 2 hours and 5 hours after seal removal showed that amcinonide-containing ointment using the ointment base of the present invention was superior to propylene carbonate or ethylene carbonate as a control. This shows that the results are better than those using an ointment base containing Kanomi.

Toxicology test An ointment base shown in Example 1 described later and an ointment containing 0.5% by weight of amcinonide were prepared using Sprague
An acute toxicity test was conducted in which the drug was applied externally once to the backs of male Dawley rats (10 rats per group) and observed for 7 days.

The administration method and dosage were as follows: The back and abdomen were shaved, and the above ointment base and ointment were applied to the IOP/ky from the back to the subscapular region, and the animals were sealed with Saran wrap for 24 hours.

As a result, there were no deaths in both the ointment base and amcinonide ointment groups, and no abnormal findings were observed.

Stability test The ointment base of the present invention is very stable, and has excellent stability even in ointments containing drugs such as the synthetic adrenocortical hormones, nonsteroidal anti-inflammatory agents, antibiotics, and antihistamines.

This is evidenced by Table 3 below.

Moreover, the ointment base of the present invention also has the effect of effectively suppressing the deterioration (deterioration resistance) of unstable drugs such as tetracycline and fradiomycin sulfate. It also becomes possible to prepare ointments containing these drugs.

Such deterioration resistance effect of the ointment base of the present invention can be demonstrated by the following stability test using tetracycline.

Next, the present invention will be explained in more detail with reference to Examples.

Example 1 Ethylene carbonate, propylene carbonate and borawax are dissolved by heating to 70-75°C, Tenox Ⅰ and amcinonide are added and mixed while heating again.

The resulting mixture is added to white vaseline previously dissolved at 70-75°C, and stirred and mixed at a temperature of about 70°C until uniform.

The contents are left to cool while stirring until the temperature reaches about 30°C, thereby obtaining an amcinonide ointment preparation.

Example 2 The above ingredients are treated in the same manner as in Example 1 to prepare an ointment formulation.

Example 3 The above ingredients are treated in the same manner as in Example 1 to prepare an ointment formulation.

Example 4 The above ingredients are treated in the same manner as in Example 1 to prepare an ointment formulation.

Example 5 An ointment formulation is prepared by the same method as in Example 1, except that triamcinolone acetonide is used instead of amcinonide.

Example 6 An ointment formulation is prepared by the same method as in Example 1, except that betamethasone pareto is used in place of amcinonide.

Example 7 Appropriate amount (part) of white petrolatum, ethylene carbonate,
Glopylene carbonate, Borawax and Tenox (1) are heated and dissolved at 55-60°C, tetracycline is added and mixed while heating again.

The resulting mixture is added to the remaining white petrolatum, previously dissolved at 55-60°C, and stirred and mixed at a temperature of about 60°C until uniform.

Allow to cool while stirring until the contents reach approximately 30°C.

Example 8 <Prescription> Appropriate amount (part) of white petrolatum, ethylene carbonate,
Propylene carbonate and borax wax 70-7
Dissolve by heating to 5°C, add Buch Examax, and mix while heating again.

The resulting mixture is added to the remaining white petrolatum, which has been previously dissolved at 70 to 75°C, and stirred and mixed at a temperature of about 70°C until uniform.

Allow to cool while stirring until the contents reach approximately 30°C.

Claims (1)

[Scope of Claims] 1. An ointment base comprising ethylene carbonate, propylene carbonate and petrolatum as essential ingredients. 2 Based on the weight of the ointment base, 0.1 to 10% by weight of ethylene carbonate and o. The ointment base according to claim 1, containing i to 10% by weight. 3 Based on the weight of the ointment base, 0.2 to 5% by weight of ethylene carbonate and 0% of propylene carbonate.
．． The ointment base according to claim 1, containing 2 to 5% by weight. 4. The ointment base according to claim 1, which contains 0.4 to 10% by weight of ethylene carbonate and propylene carbonate in total, based on the weight of the ointment base. 5. The ointment base according to claim 1, which contains 1 to 5% by weight of ethylene carbonate and glopylene carbonate in total, based on the weight of the ointment base. 6. The ointment base according to claim 1, which contains ethylene carbonate and propylene carbonate in an ethylene carbonate/propylene carbonate weight ratio of 7/1 to 1/2. 7 Ethylene carbonate and propylene carbonate at an ethylene carbonate/propylene carbonate weight ratio of 4/1 to 1. The ointment base according to claim 1, which contains the ointment base in the range of 5/1. 8 Based on the weight of the ointment base, add petrolatum to 80 to 9
The ointment base according to any one of claims 1 to 7, containing 9.5% by weight. 9 Vaseline is 90-99% based on the weight of the ointment base.
The ointment base according to any one of claims 1 to 8, containing % by weight. 10. The ointment base according to any one of claims 1 to 9, further containing Polawax. 11. The ointment base according to claim 10, which contains O, 5 to 2% by weight of borax, based on the weight of the ointment base. 12. The ointment base according to claim 11, which contains 0.7 to 1.5% by weight of borax based on the weight of the ointment base. 13 Based on the weight of the ointment base, 0.2 to 5% by weight of ethylene carbonate, 0.2 to 5% by weight of glopylene carbonate, 80 to 99.5% by weight of petrolatum, and 0.5% of bora wax. An ointment base according to claim 1, comprising ~2% by weight. 14. The ointment base according to any one of claims 1 to 13 for incorporating a synthetic adrenocortical hormone agent. 15. The ointment base according to claim 14, wherein the synthetic adrenocortical hormone agent is amcinonide.