JP4672302B2 - Stable local anesthetic composition - Google Patents

Description

  The present invention relates to a local anesthetic composition excellent in storage stability, characterized in that basic oxesasein or a salt thereof is dispersed in a pharmaceutically acceptable hydrocarbon.

  Local anesthetics are used to treat local itching and pain such as mucous membranes and skin due to hemorrhoids, stomatitis, periodontal disease, caries, tooth extraction or surgery. Lidocaine is known as a representative local anesthetic, but lidocaine has an anti-arrhythmic action although it has excellent immediate effect, and may cause serious side effects such as shock depending on its usage. There is. Moreover, the time for which lidocaine exhibits the surface anesthetic effect is as short as about 2 hours, and a sufficient and sustained pain effect cannot be expected. Therefore, development of a preparation containing a local anesthetic that is safer and longer in duration than lidocaine is desired.

Further, as a topical skin preparation containing basic oxesasein as a local anesthetic, “skin external preparation containing basic oxesasein as an active ingredient for treating pain inside the skin surface excluding defective skin” Known (Patent Document 1). However, this external preparation for skin is intended to treat pain inside the skin surface excluding defective skin, for example, herpes zoster pain, and its application is limited.
Furthermore, an invention relating to "an analgesic composition in which a free base type oxesasein is dispersed in a bioadhesive dispersion medium incompatible with this" is known (Patent Document 2). However, in this analgesic composition, when blended with a base such as lanolin, fatty acid triglyceride or olive oil, there is a concern that the storage stability is not sufficient and the expected effectiveness cannot be exhibited.

Vaginal diseases that are local diseases of the rectum include hemorrhoids, anal fissures, etc., and are accompanied by pain, itchiness, swelling, bleeding, etc. of the affected area, and particularly pain in the affected area gives extreme pain to the patient. There are products that use local anesthetics alone in suppositories or ointments, etc., as conventional antiepileptic agents, but their effects generally disappear in a relatively short time and cannot be said to be sufficient. . In addition, wounds on the skin such as cuts, scratches, scratches, acne, jumps, and velvets, skin rashes, sores, rashes, hives, insect bites, athlete's foots, bugs, and other localities associated with tooth extraction, surgery, etc. Relief of general pain and itching is important in reducing the patient's pain and suppressing the act of damaging the affected area with nails or external factors in order to avoid the pain and itching. However, it is not sufficient because its effect usually disappears in a short time.
JP2002-97134 JP-A-11-12169

  The present invention is excellent in long-term storage stability, has excellent immediate effect and long-lasting in suppressing various pains and itchiness, has good formulation uniformity, and has improved transmucosal or transdermal absorbability. An object of the present invention is to provide a basic oxesazein local anesthetic composition which is effective and effective at a low concentration.

  As a result of diligent research to solve the above problems, the present inventors dispersed an active ingredient, basic oxesasein or a salt thereof, in a pharmaceutically acceptable hydrocarbon, thereby having a stable and excellent characteristic. The present invention has been completed by finding that a local anesthetic composition can be obtained.

That is, the present invention
(1) A local anesthetic composition excellent in storage stability, wherein basic oxesasein or a salt thereof is dispersed in a pharmaceutically acceptable hydrocarbon,
(2) The local anesthetic composition excellent in storage stability according to the above (1) substantially free of lanolin, fatty acid monoglyceride or olive oil,
(3) The preservation according to (1) above, wherein the pharmaceutically acceptable hydrocarbon is one or more selected from petrolatum, liquid paraffin, paraffin, squalane, squalene and gelled hydrocarbon. A local anesthetic composition with excellent stability,
(4) The local anesthetic composition having excellent storage stability according to (3), further comprising a microcrystalline wax,
(5) The local anesthetic composition having excellent storage stability according to the above (4), wherein the content of the microcrystalline wax is 3 to 10% by weight based on the composition,
(6) The basic oxesasein or a salt thereof is blended in an amount of 0.1 to 10% by weight with respect to a pharmaceutically acceptable hydrocarbon, and is described in any one of (1) to (5) above A local anesthetic composition with excellent storage stability,
(7) The local anesthetic composition excellent in storage stability according to any one of (1) to (6), further comprising a corticosteroid,
(8) The local anesthetic composition having excellent storage stability according to any one of (1) to (7), wherein the local anesthetic composition is an ointment or a suppository,
(9) The local anesthetic composition having excellent storage stability according to (8), which is administered to any mucosa in the rectum, vagina or oral cavity,
(10) The local anesthetic composition having excellent storage stability according to (8), which is applied to an anus, vagina, or a damaged site around the mouth, a postoperative wound or a disease thereof,
(11) The local anesthetic composition having excellent storage stability according to (8), wherein the local anesthetic composition is applied to pain or itch of a manic disease,
(12) The local anesthetic composition having excellent storage stability according to any one of (1) to (7), which is applied to stomatitis, periodontal disease or caries pain,
(13) The local anesthetic composition having excellent storage stability according to any one of (1) to (7), which is applied to prevention of pain before and after surgery, tooth extraction or treatment,
(14) A method for producing a local anesthetic composition having excellent storage stability, wherein basic oxesazein or a salt thereof is dispersed in a pharmaceutically acceptable hydrocarbon at room temperature to 60 ° C. and molded, and (15 ) One or more pharmaceutically acceptable hydrocarbons selected from microcrystalline wax and petrolatum, paraffin, squalane, squalene and gelled hydrocarbon are heated to 80-90 ° C and dissolved and mixed to 50-60 ° C. A method for producing a local anesthetic composition excellent in storage stability, characterized by adding and stirring 40-50 ° C. liquid paraffin in which basic oxesasein or a salt thereof is dispersed in the resulting mixture;
About.

The local anesthetic composition of the present invention exhibits excellent storage stability for a long period of time and is very effective in suppressing various pains and itching. In addition, its immediate effect and sustainability are excellent in its action and effect, and it has formulation uniformity.
The local anesthetic composition of the present invention can be applied to mucosa (for example, rectal mucosa, vaginal mucosa, oral mucosa, etc.) or transdermally.
The local anesthetic composition of the present invention exhibits excellent effects such as no side effects and effectiveness at low concentrations.

Examples of the pharmaceutically acceptable hydrocarbon in which the basic oxesasein or a salt thereof as an active ingredient is dispersed include petrolatum (white petrolatum, yellow petrolatum), liquid paraffin, paraffin, squalane, squalene, gelated hydrocarbon, or a mixture thereof. Is mentioned. Here, as the gelled hydrocarbon, for example, liquid paraffin obtained by gelling with polyethylene and semi-solidified, for example, a trade name Plastic Base can be mentioned.
The hydrocarbon is preferably used as one or a mixture of two or more selected from petrolatum (white petrolatum, yellow petrolatum), liquid paraffin, paraffin, squalane, squalene, and gelled hydrocarbon. More preferred is a mixture of white petrolatum and liquid paraffin, and particularly preferred is a mixture of white petrolatum and liquid paraffin with a ratio of 7: 3 to 9: 1 (white petrolatum: liquid paraffin). .
Moreover, it is preferable to mix | blend microcrystalline wax further with the said 1 type, or 2 or more types of mixture. The content of the microcrystalline wax is about 3 to 10% by weight, preferably about 4 to 7% by weight, based on the composition. By blending the microcrystalline wax, the degree of separation of the liquid oil from the local anesthetic composition is reduced, and the local anesthetic composition is solid or semi-solid even at a relatively high temperature (for example, around 40 ° C.). Can be maintained.

  Basic oxesazein or a salt thereof is generally added in an amount of about 0.1 to 10% by weight, preferably about 0.25 to 2.5% by weight, based on the pharmaceutically acceptable hydrocarbon.

  The local anesthetic composition of the present invention may contain one or more drugs other than the local anesthetic agent. Such drugs are not particularly limited.For example, prednisolone, prednisolone acetate, prednisolone acetate valerate, hydrocortisone, hydrocortisone acetate, hydrocortisone butyrate, dexamethasone or glycyrrhetinic acid, which are anti-inflammatory corticosteroids, are used. , Vitamins such as tocopherol acetate, retinol acetate, retinol acetate palmitate, ergocalciphenol, pyridoxine hydrochloride, pyridoxamine hydrochloride, pyridoxamine phosphate, pyridoxal hydrochloride, pyridoxal phosphate, riboflavin or riboflavin butyrate aspirin as an antipyretic analgesic analgesic, Acetaminophen, phenacetin, diclofenac sodium, indomethacin, mefenamic acid, aminopyrine or ibuprofen, etc. Wound healing agent lysozyme chloride, allantoin or alcloxa, etc., sulfadiazine, sulfisomidine, sulfisomidine sodium or homosulfamine etc. as sulfa drugs, erythromycin, tetracycline, tetracycline hydrochloride, oxytetracycline hydrochloride as antibiotics or antifungal agents , Streptomycin sulfate, gentamicin sulfate, fradiomycin sulfate, kanamycin sulfate, clotrimazole, miconazole or miconazole nitrate, and / or the bactericidal agent acrinol, alkylpolyaminoethylglycine, isopropylmethylphenol, cetylpyridinium chloride, decalinium chloride, Berberine chloride, benzalkonium chloride, cetrimide, chlorhexidine hydrochloride, chlorhexidine gluconate solution, It can be blended phenol or resorcinol and the like. Of these medicinal components other than the local anesthetic, a corticosteroid having an anti-inflammatory action is preferable, and prednisolone acetate is particularly preferable. As hemorrhoid diseases are accompanied by symptoms such as swelling and bleeding in addition to pain and itch, the combination of prednisolone acetate and basic oxesasein, which can be expected to relieve swelling and bleeding, is effective in treating hemorrhoids .

  As the dosage form of the local anesthetic composition of the present invention, it can be applied to any mucous membrane or skin in the rectum, vagina and oral cavity, more specifically, the anus, the vagina and the area around the mouth, the postoperative wound or Although it will not specifically limit if it is applicable to those diseases (for example, hemorrhoids, stomatitis, periodontal disease, caries, etc.), ointment, suppository, gel, lotion, cream, emulsion, liquid, spray An ointment or a suppository is preferable.

  A preferred local anesthetic composition of the present invention is exemplified by an ointment, and the preferred composition is, for example, about 0.5 to 2.5% by weight of basic oxesasein, about 0.03 to 0.2% by weight of prednisolone acetate, white petrolatum About 56 to 93% by weight and about 2 to 40% by weight of liquid paraffin, more preferably about 3 to 10% by weight of microcrystalline wax.

  Further, as a preferred local anesthetic composition of the present invention, a suppository is exemplified, and the preferred composition is, for example, basic oxesasein per suppository (about 1-2 g, preferably about 1.2-1.9 g). About 0.5 to 2.5% by weight, about 0.01 to 0.2% by weight of prednisolone acetate and about 2 to 7% by weight of liquid paraffin, and further about 3 to 10% by weight of microcrystalline wax. More preferred.

These preparations can be appropriately produced according to the dosage form by uniformly mixing the raw materials so that the raw materials are sufficiently dispersed. For homogenous mixing, for example, a homogenizer or a propeller stirrer is used. For example, when producing an ointment, basic oxesazein or a salt thereof can be dispersed in a pharmaceutically acceptable hydrocarbon at room temperature (about 25 ° C.) to 60 ° C. to obtain an ointment. More specifically, for example, microcrystalline wax and white petrolatum are heated to about 80 to 90 ° C. and dissolved and mixed to form a white petrolatum layer. Separately, basic oxesasein or a salt thereof is dispersed in liquid paraffin at room temperature (about 25 ° C.) to 55 ° C., preferably about 40 to 50 ° C., and cooled to about 50 to 70 ° C., preferably about 50 to 60 ° C. It is poured into a white petrolatum layer, stirred and mixed for a certain time and cooled to obtain an ointment.
In the case of producing a suppository, basic oxesasein or a salt thereof is dispersed in a pharmaceutically acceptable hydrocarbon at room temperature (about 25 ° C.) to 60 ° C., and a suppository base (eg, hard fat, cacao butter, macro Goal, etc.) for a certain period of time and mixed uniformly to form a suppository.
For example, basic oxesazein and prednisolone acetate are dispersed in liquid paraffin at room temperature (about 25 ° C.) to 55 ° C., preferably about 40 to 50 ° C., then heated and dissolved in advance at about 80 to 90 ° C., and mixed. Disperse the mixture of wax and hard fat to a temperature adjusted to about 40-50 ° C. This is stirred for a certain time and mixed uniformly. Further, the temperature is adjusted to a constant temperature of about 30 to 50 ° C., preferably about 35 to 40 ° C., and about 1.0 to 2.0 g, preferably about 1.2 to 1.9 g is filled in a suppository mold, Solidify at about 15-25 ° C. to obtain a suppository.
In the case of producing gels, lotions, creams, emulsions, solutions, and sprays, a dispersion of the above-mentioned hydrocarbon and basic oxesasein or a salt thereof is appropriately molded by a method known per se to obtain a desired formulation. can do. Furthermore, if necessary, a solubilizing agent, a pH adjuster, a humectant, an antiseptic, a thickener, a surfactant, a solvent, and the like may be added as appropriate. These additives are preferably substantially free of lanolin, fatty acid monoglycerides or olive oil. The presence of lanolin, fatty acid monoglyceride or olive oil does not give favorable results for the storage stabilization of the composition of the present invention.

  The local anesthetic composition of the present invention thus obtained is formulated in a state where the basic oxesasein or a salt thereof, which is an active ingredient, is uniformly dispersed in a pharmaceutically acceptable hydrocarbon, so that the active ingredient is stable and It exists in a uniform state. Therefore, when such a composition is applied topically, the active ingredient can be brought into uniform contact with the surface of the local mucous membrane or skin, so unlike conventional dispersion preparations, absorption, action onset, duration, etc. It becomes easy to control. As a result, the local anesthetic composition of the present invention exhibits excellent storage stability for a long period of time, immediate action and persistence of local anesthetic action, formulation uniformity, improved transmucosal and transdermal absorption, and no side effects. Or, it has many excellent properties of exhibiting medicinal effects at low concentrations.

  The content of basic oxesazein or a salt thereof in the local anesthetic composition of the present invention can be appropriately selected depending on the patient's condition, dosage form, etc., but is generally about 0.1 to 10% by weight, preferably about 0.25 to 2.5% by weight. In the case of an ointment, an appropriate amount may be applied to the affected area once or twice a day for adults. In the case of a suppository, one piece is inserted into the anus once or twice a day for use. can do.

  Preferred examples and test examples in the present invention will be described below, but the present invention is not limited to the following examples.

0.75% by weight basic oxesasein
Prednisolone acetate 0.05% by weight
Liquid paraffin 20% by weight
White petrolatum appropriate amount Manufacturing method: White petrolatum was heated to 70 ° C., dissolved and mixed, and then 55 ° C. to obtain a white petrolatum layer. Separately, basic oxesazein and prednisolone acetate were dispersed in liquid paraffin at 40 ° C. and charged into the white petrolatum layer. This was stirred and mixed for a certain time and cooled to obtain an ointment.

Basic Oxesasein 1% by weight
Prednisolone acetate 0.1% by weight
Liquid paraffin 15% by weight
Microcrystalline wax 5% by weight
Appropriate amount of white petrolatum Manufacturing method: Microcrystalline wax and white petrolatum were heated to 85 ° C., dissolved and mixed, and then set to 55 ° C. to obtain a white petrolatum layer. Separately, basic oxesazein and prednisolone acetate were dispersed in liquid paraffin at 45 ° C. and charged into the white petrolatum layer. This was stirred and mixed for a certain time and cooled to obtain an ointment.

0.25% by weight basic oxesasein
Hydrocortisone acetate 0.5% by weight
Liquid paraffin 20% by weight
Appropriate amount of white petrolatum Production method: White petrolatum is heated to 70 ° C and dissolved and mixed. Separately, basic oxesazein and hydrocortisone acetate were dispersed in liquid paraffin at 40 ° C. and charged into a white petrolatum layer at 55 ° C. This was stirred and mixed for a certain time and cooled to obtain an ointment.

[Comparative Example 1]
0.75% by weight basic oxesasein
Prednisolone acetate 0.05% by weight
15% by weight of medium chain fatty acid triglycerides
2.5% by weight of glyceryl monostearate
White petrolatum appropriate amount Production method: White petrolatum and glyceryl monostearate are heated to 75 ° C. and dissolved and mixed. Separately, basic oxesazein and prednisolone acetate were dispersed in a medium chain fatty acid triglyceride at 40 ° C. and charged into a white petrolatum layer. This was stirred and mixed for a certain time and cooled to obtain an ointment.

[Comparative Example 2]
0.75% by weight basic oxesasein
Prednisolone acetate 0.05% by weight
Purified lanolin 33% by weight
Appropriate amount of white petrolatum Production method: Purified lanolin and white petrolatum were heated to 60 ° C. and dissolved and mixed, basic oxesazein and prednisolone acetate were added thereto, and the mixture was stirred and cooled for a certain time to obtain an ointment.

[Test Example 1]
The ointments obtained in Example 1, Comparative Example 1 and Comparative Example 2 were placed in glass sample bottles, respectively, and stored for 14 days in a 60 ° C. incubator with the lid on the screw closed.
After 14 days of storage, each sample was stirred uniformly, and the basic oxesasein content of each sample was measured by HPLC as an ointment at room temperature. The drug content (basic oxesasein content) of each sample measured after storage for 14 days was calculated as a percentage (%) with respect to the drug content at the time of manufacture, and this was used as the residual rate (%) of the drug content of each sample. The results are shown in Table 1.

  Compared with the ointments of Comparative Examples 1 and 2, the ointment of Example 1 showed almost no decrease in drug content, and a clear improvement in stability was observed.

[Test Example 2]
The ointments obtained in Examples 1 to 3 and Comparative Example 2 were filled into aluminum ointment tubes and stored under conditions of a temperature of 40 ° C. and a relative humidity of 75%. After storage for 2, 4 and 6 months, the content of basic oxesasein was measured using HPLC. The residual ratio (%) of basic oxesasein when the start of the test was taken as 100% was calculated for 2, 4 and 6 months after the start of the test. The results are shown in Table 2.
The ointments of Examples 1 to 3 were found to have a higher residual rate of basic oxesasein than the ointment of Comparative Example 2.

[Test Example 3]
30 g of the ointment of Example 1 or 2 was packed in a stainless steel cone wire mesh (300 mesh, φ = 50 mm × height 60 mm) placed on a beaker (50 mL), and this was stored in a thermostat at 25 ° C. The amount of the separated liquid collected in the beaker was measured every time period (1, 4, 6, 8 days). The amount of the separation liquid was calculated as the difference between the weight of the beaker at the start of the test and the weight of the beaker on each measurement day (including the separation liquid generated from the start of the test to each measurement day). The amount of the separation liquid on each measurement day was expressed as a percentage (%) with respect to 30 g of the ointment, and the results are shown in Table 3.
In both the ointments of Examples 1 and 2, the degree of separation of the liquid oil from each ointment was stable at 0.5% or less. The separation liquid from the ointment of Example 2 to which microcrystalline wax was added was less than in Example 1.

The local anesthetic composition of the present invention can be applied to the skin such as pain and itching of hemorrhoid diseases, stomatitis, periodontal disease, tooth decay or tooth extraction, cuts, scratches, scratches, acne, jumpy skin, face itch, etc. It is useful as a pharmaceutical that can be applied to wounds, rashes, sores, rashes, hives, insect bites, athlete's foots, and sores, or local pain and itching associated with surgery.

Claims (15)

A local anesthetic composition excellent in storage stability, wherein basic oxesazein or a salt thereof is dispersed in a pharmaceutically acceptable hydrocarbon and does not contain lanolin . Furthermore, the local anesthetic composition excellent in the storage stability of Claim 1 which does not contain a fatty acid monoglyceride or olive oil.   The pharmaceutically acceptable hydrocarbon is one or two or more selected from petrolatum, liquid paraffin, paraffin, squalane, squalene and gelled hydrocarbon, and has excellent storage stability. Local anesthetic composition.   The local anesthetic composition having excellent storage stability according to claim 3, further comprising microcrystalline wax.   The local anesthetic composition having excellent storage stability according to claim 4, wherein the content of the microcrystalline wax is 3 to 10% by weight based on the composition.   The storage stability according to any one of claims 1 to 5, wherein the basic oxesasein or a salt thereof is blended in an amount of 0.1 to 10% by weight based on a pharmaceutically acceptable hydrocarbon. Local anesthetic composition.   Furthermore, a corticosteroid is contained, The local anesthetic composition excellent in the storage stability in any one of Claims 1-6 characterized by the above-mentioned.   The local anesthetic composition having excellent storage stability according to any one of claims 1 to 7, wherein the local anesthetic composition is an ointment or a suppository.   9. The local anesthetic composition with excellent storage stability according to claim 8, wherein the composition is administered to any mucosa in the rectum, vagina or oral cavity.   The local anesthetic composition having excellent storage stability according to claim 8, which is applied to an anus, vagina, or an injured site around the mouth, a postoperative wound or a disease thereof.   The local anesthetic composition having excellent storage stability according to claim 8, wherein the local anesthetic composition is applied to pain or itch of a manic disease.   The local anesthetic composition having excellent storage stability according to any one of claims 1 to 7, which is applied to stomatitis, periodontal disease or caries pain.   The local anesthetic composition excellent in storage stability according to any one of claims 1 to 7, which is applied to prevention of pain before and after surgery, tooth extraction or treatment. The local anesthetic composition having excellent storage stability according to any one of claims 1 to 13, wherein basic oxesazein or a salt thereof is dispersed in a pharmaceutically acceptable hydrocarbon at room temperature to 60 ° C and molded. Manufacturing method. One or more pharmaceutically acceptable hydrocarbons selected from microcrystalline wax and petrolatum, paraffin, squalane, squalene and gelled hydrocarbon are heated to 80-90 ° C and dissolved and mixed to obtain 50-60 ° C. 14. A local anesthetic composition having excellent storage stability according to any one of claims 3 to 13, wherein the mixture is mixed with 40 to 50 ° C liquid paraffin in which basic oxesazein or a salt thereof is dispersed and stirred. Manufacturing method.