JPS631287B2 - - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to compositions for treating hyperpigmented skin diseases and the like. Skin diseases such as skin hyperpigmentation (which often disfigures the face, as in the case of facial brown spots) are not only aesthetic problems, but also have treatment problems that have not yet been fundamentally solved. To date, only hydroquinone and its derivatives have shown some efficacy in in vivo studies in the treatment of skin hyperpigmentation. However, this results in the development of long-lasting, mildly discolored areas that sometimes cannot be cured as a side effect. This type of hyperpigmented skin disease includes certain pathological conditions that have more serious conditions and consequences, but under the generic names precancerous skin disease and carcinomatous skin disease (such as melanotic conditions and melanoma). It can be done. No effective medicine has yet been discovered for these skin diseases. It is an object of the present invention to provide a composition useful for the above-mentioned purposes, namely to normalize the color of skin affected by hyperpigmentation and to prevent and treat pre-cancerous and carcinomatous skin diseases. According to the invention, as active ingredient at least one
A composition for the treatment of hyperpigmented skin diseases or skin hyperpigmentation, comprising a dicarboxylic acid having 9 to 12 carbon atoms, or a pharmaceutically acceptable salt thereof, in a pharmaceutically acceptable carrier. is provided. Specific examples of dicarboxylic acids used in the present invention include pimelic acid, suberic acid, azelaic acid,
Sebacic acid, 1,9-nonanedicarboxylic acid, 1.
These include 10-decanedicarboxylic acid and 1,11-undecanedicarboxylic acid. Pharmaceutically acceptable salts include sodium salts. In a further preferred embodiment the dicarboxylic acid is azelaic acid. The compositions of the invention can be used by oral administration, subcutaneous injection, or topical application in the form of creams, ointments, or liniments. It has been discovered that the compositions of the invention are particularly capable of inhibiting the dopatyrosinase reaction and inhibiting the production of skin pigment (melanin) by a competitive mechanism. Although the exact mechanism of this action is not yet known, the inventors have observed a mechanism that represents or is related to that exhibited by the active ingredients of the present compositions. Although these observations are further helpful in understanding the present invention,
They should not be considered a definitive explanation of the mechanism or in any way limit the scope of the invention. Cause of skin disease and pigment deficiency or white freckles or spots (Piteiliasis versicolor)
Piteirosporum, a fungus that appears by the appearance of
Observations made in vitro and in vivo to study the effects of Orbicula have shown that bacteria normally found on the skin transform fatty acids necessary for survival and dissemination, producing dicarboxylic acids, which are later used to develop black skin. It was found to have a suppressive effect. At this point, the presence of pimelic acid, azelaic acid, and 1,9-nonanedicarboxylic acid (C ₁₁ ) was confirmed by gas chromatography and mass spectrometry from a Piteirosporum orbiticular culture test in which engineered oleic acid was added as a lipid supply after saponification. It is noteworthy that this was done. C ₉ and C ₁₁ membered dicarboxylic acids have shown substantial anti-tyrosinase activity in vitro;
and dicarboxylic acids with 12. The dicarboxylic acids or pharmaceutically acceptable salts described above can be used in a variety of pharmaceutically acceptable excipients depending on the therapeutic method. Thus, for example, they can be used in the form of an injectable suspension of the active substance in saline solution. On the other hand, if you want to use these locally, you can use them in the form of creams. Furthermore, they can be made into a form for oral administration. The amount of active ingredient included in the composition can vary somewhat. There is a need for a therapeutically effective amount of the dicarboxylic acid or derivative thereof. The amount of dicarboxylic acid or pharmaceutically acceptable salt thereof included in the compositions of the present invention will vary depending on the dosage form and/or treatment condition. Thus, for example, in the case of oral administration, the dosage constitutes all or substantially all of the dosage form. On the other hand, in dosage forms suitable for subcutaneous injection, the dosage is approximately
20 to 30% by weight, preferably about 25% by weight.
When the composition is a cream or liniment suitable for topical use, the dicarboxylic acid or derivative thereof is present in an amount of about 10 to 20% by weight, based on the total weight of the composition, preferably about
It is 15% by weight. It has also been discovered that it is advantageous to include stratum corneum exfoliants in the compositions of the invention. This is especially the case when the composition is intended to be applied to the skin. Examples of stratum corneum exfoliants used in this case include salicylic acid, vitamin A acid resorcinol, phenol, and cresol. The amount of stratum corneum exfoliant suitable for use will vary. It usually represents about 2% to about 4% by weight of the total weight of the composition. Evaluation of Active Ingredients Pharmacological studies and in vivo tests were carried out to evaluate the activity of the compositions according to the invention and thus of the respective active ingredients. 20−30 on ordinary synthetic medium with addition of oleic acid.
A saponifiable moiety with substantial tyrosinase inhibitory activity was obtained from mixed lipid extracts (from cells and fluid) of Pityrosporum orbichyula (species 4709) cultures grown for 1 day. This portion was subjected to thin layer chromatography (TLC) to separate a fraction with Rf = 1.3 that can inhibit the doper tyrosinase reaction. Gas chromatography and subsequent mass spectrometry quantitatively revealed the presence of a series of _C5 - _C9 dicarboxylic acids, mainly pimelic acid and azelaic acid, in this fraction. Although it was possible to completely exclude the tyrosinase-inhibiting activity of the glutaric acid (C ₅ ) moiety from comparative tests using pure acid samples, this activity was first evident in the C _7- membered group, and then in the C ₉ to C ₁₁ -membered portions. Maximum at . Especially in the enzyme activity test, azelaic acid has Ki=
It has been shown to be a competitive inhibitor of tyrosinase at 4.10 ^-4 M. The present invention will be explained in more detail with reference to the following examples. In these examples, azelaic acid, dodecanedioic acid, etc. are dicarboxylic acids themselves that do not have a mercapto group. Example 1 An azelaic acid-containing cream having the composition shown at the end of this example was applied to dark spots in the following patients for 30 days.
It was applied twice a day. (a) 20 patients with brown spots (b) 3 patients with Civatte's osteodermatosis (c) 10 patients with localized precancerous melanosis (malignant freckles) of Doublieuil At the end of treatment, the hyperpigmented areas in all patients (a) and (b) had clearly healed. All patients in (c) showed clinical and histological relief of disease. No trace of vitiligo was observed in the treated patients observed 5 years later. It cannot be overlooked that localized pre-cancerous melanosis falls within the category of pre-cancerous skin diseases. It is of fundamental importance that not only a clinical cure was obtained in this patient, but also a histological cure. Azelaic acid 15.0% by weight Chlorocresol 0.1〃 Titanium dioxide 1.0〃 Salicylic acid 2.0〃 Glycerol monostearate 2.0〃 Cetyl alcohol 3.0〃 Tween 80 5.0〃 Sodium lauryl ether sulfate 10.0〃 Ethanolamine lauryl ether sulfate
1.0〃 Olive oil 2.0% by weight Vitamin C 1.0〃 Make 100% with distilled water. Example 2 Ten patients with malignant mole disease were treated by topically applying an azelaic acid-containing cream having the following composition twice a day. Azelaic acid 20.0% by weight Chlorocresol 0.1〃 Titanium dioxide 1.0〃 Salicylic acid 3.0〃 Glycerol monostearate 2.0〃 Cetyl alcohol 3.0〃 Tween 80 5.0〃 Sodium lauryl ether sulfate 10.0% by weight Ethanolamine lauryl ether sulfate
1.0〃 Olive oil 2.0〃 Vitamin C 1.0〃 Make 100% with distilled water. Only patients who, due to the location and/or size of their disease, would otherwise require surgical treatment were tested. In 7 patients, complete clinical relief of histologically confirmed malignant mole disease was achieved following topical treatment. A treatment period of 9 to 12 months was required, but only one
Only one patient required 24 months of treatment. Two patients did not receive treatment long enough to achieve complete clinical relief. Apart from a small local inflammatory reaction and slight scabbing shortly after treatment initiation, the treatment was well tolerated without appreciable side effects. No adverse tissue reactions were observed in any patient. Treatment was discontinued after the mole had completely regressed. During the 18-month follow-up period after the completion of treatment, the patient was examined regularly once every two months, and no recurrence was observed. Example 3 Fifteen patients with malignant mole disease were treated with an azelaic acid-containing cream having the following composition. Azelaic acid 15.0% by weight Chlorocresol 0.1〃 Titanium dioxide 1.0〃 Salicylic acid 2.0〃 Glycerol monostearate 2.0〃 Cetyl alcohol 3.0〃 Tween 80 5.0〃 Sodium lauryl ether sulfate 10.0〃 Ethanolamine lauryl ether sulfate
10.0〃 Olive oil 2.0〃 Vitamin C 1.0〃 Make 100% with distilled water. In all patients, the affected area was on the face, irregular in shape, and variable in size.
The size ranged from 0.5 to 15 ^cm2 . The surface of the mole was flat or slightly raised and hardened. Patients (15 patients) were treated by applying azelaic acid-containing cream of the above composition to the affected areas twice a day. Continue this treatment for 6 to 14 days until the malignant mole is cured.
The treatment lasted for 6 months (this period varies from 6 to 14 months depending on the degree of malignant mole development). Complete healing was observed in 11 of the 15 patients within the above period. The remaining four patients stopped treatment before they were completely cured, but the results were individually satisfactory. Recurrence was observed in 3 of the 11 patients mentioned above, and the recurrence period ranged from 1 to 43 months after discontinuing treatment (the case at 0 months was due to new disease occurring in another location). In all three cases of recurrence, treatment was continued by applying an azelaic acid-containing cream of the above composition, and complete cure was achieved in all cases. Example 4 Five patients with malignant mole disease, one of whom was already at the melanoma stage, were treated by applying an azelaic acid-containing cream with the following composition to the affected area. Initial treatments (electrocoagulation, cryotherapy, X-rays) were unsuccessful, and surgical resection was refused. Azelaic acid 20.0% by weight Chlorocresol 0.1〃 Salicylic acid 4.0〃 Glycerol monostearate 2.0〃 Cetyl alcohol 3.0〃 Tween 80 5.0〃 Sodium lauryl ether sulfate 10.0〃 Ethanolamine lauryl ether sulfate
10.0〃 Olive oil 2.0〃 Vitamin C 1.0〃 Make 100% with distilled water. 2 1/2 azelaic acid-containing cream of the above composition
It was applied to the affected area twice a day for a period of ~6 months. 4 for 3 out of 4 patients with simple moles
Complete regression of the mole was observed after ~5 months of treatment. This degeneration was also confirmed by tissue examination. One patient did not continue treatment after 2 1/2 months. In the case of a patient with a malignant melanoma mole, complete regression of the affected area was observed after six months of treatment. Histological examination before treatment showed malignant mole melanoma (Clark level 3), but only a residual stain remained after treatment. Example 5 23 patients with affected areas clinically diagnosed as malignant melanoma
He treated several patients. First, select patients with metastatic disease in various locations, local or tissue affected areas, or affected areas more severe than the primary disease, and apply the azelaic acid-containing cream described in Example 1 twice a day. continued for 16 weeks,
Excision of the affected area was then performed in some cases. Finally, after acute and chronic toxicity studies and mutation studies on animals, other similar patients were given 10-15 g of azelaic acid daily in the form of oral capsules in addition to the above topical application. did. After confirming the beneficial effects of this therapy,
Patients with superficially spreading or nodular primary melanomas awaiting surgery received similar topical and oral doses for 2 to 12 weeks prior to surgical removal. Oral administration was continued for up to 4 months after surgery. The resected area was examined by light and electron microscopy. Although these results varied depending on tumor type and duration of azelaic acid administration, in all cases they were essentially similar and included the following features: Progressive lightening of the coloration was observed along with inhibition of expansion of the anterior edge of the affected area and subsequent degeneration of the affected area. It was observed that the nodal areas decreased in size and became flatter. Example 6 The following experiment was conducted to test the inhibitory effect on Harding-Passei melanoma when azelaic acid or dodecanedioic acid or their corresponding sodium salts were administered intraperitoneally, subcutaneously, or orally. Azelaic acid (C-9) or dodecanedioic acid (C-12) was administered to rats with melanoma transplants (bulb C albino rats).
or their corresponding sodium salts were administered intraperitoneally, subcutaneously, or orally for treatment. Treatment began 24 hours after the animals were inoculated with melanoma and continued for 3 weeks. The therapeutic compositions used and their administration methods (and dosages) are as follows. Note that "control" refers to a blank test composition that does not contain therapeutic ingredients. (a) Control 120μ of a salt solution having the following composition was injected intraperitoneally or subcutaneously once a day. Vitamin C 1.0% by weight Tween 80 2.5〃 Make up to 100% with salt water. (b) C ₉ Intraperitoneal (1) 120μ of a salt solution having the following composition was intraperitoneally injected once daily. Azelaic acid 1.0% by weight Azelaic acid dimethyl ester 5.0% by weight Vitamin C 1.0 Tween 80 2.5 Make 100% with salt water. (c) _C9 Subcutaneous (1) The composition of (b) above was subcutaneously injected once daily. (d) C ₁₂ Subcutaneous (1) 120μ of a salt solution having the following composition was subcutaneously injected once daily. Dodecanediosuccinic acid 1.0% by weight Dodecanediosuccinic acid dimethyl ester 5.0〃 Vitamin C 1.0〃 Tween 80 2.5〃 Make up to 100% with salt water. (e) C ₉ Oral (2) Orally administer an aqueous solution with the following composition at any time (i.e., let the test animal drink it). Azelaic acid sodium salt 2.0% by weight Vitamin C 0.1〃 Add water to make 100%. (f) C ₁₂ Oral (2) Orally administer an aqueous solution with the following composition as needed. Dodecanedioic acid sodium salt 2.0% by weight Vitamin C 0.1〃 Add water to make 100%. The results of these tests are shown in the table below. The numbers in the "Test" column of the table indicate whether the number of animals tested is 30 (sign) or 15.
This is a classification of the test contents according to (code). In the column "Therapeutic compositions and their method of administration (and dosage)" in the table "Control", "C ₉ i.p.
(1)”, “C ₉ subcutaneous (1)”, “C ₁₂ subcutaneous (1)”, “C ₉ oral (2)”
” and “C ₁₂ oral (2)” are the above (a), (b), (c), respectively.
Represents the contents of (d), (e) and (f). The "appearance date" in the table represents the date on which melanoma appears in the tested mouse after inoculation. The number ``15'' in the second line of the ``Number of deaths'' column in the ``Results after two weeks'' in the table is abnormally high, and this is due to the following two reasons. First, intraperitoneal injections caused a large shock to the test animals, which resulted in the death of test animals that were susceptible to shocks (by their natural nature). Second, it is assumed that such shock-sensitive animals would not have been able to tolerate the salt water used. 2 in the “Number of deaths” column of “Results after 3 weeks”
The number "1" in the first row is much lower than the number "15" above, but this is because the animals that are weak to shots have already died, so the remaining animals (only those that are strong against shots have survived) are in the third week. It is assumed that this is because most people do not die even if they enter the water. The results shown in the table show that intraperitoneal, subcutaneous, or oral administration of azelaic acid, dodecanedioic acid, or their sodium salts to rats inoculated with Harding-Passei melanoma (Barb C albino rats) significantly inhibited tumor growth. It shows that it was done. In addition, the following was also clarified by histological examination. (i) Initial delay in melanoma development in treated mice. (ii) Reduction in melanoma size and extent (for some treated mice). (iii) Melanoma formation in place of tumor; disappearance of melanoma appearance (for other treated mice). (iv) Presence of extensive necrotic areas in treated mice found on histological examination. 【table】

Claims (1)

[Claims] 1. At least one carbon atom as an active ingredient 9
1. A composition for treating hyperpigmented skin disease or skin hyperpigmentation, comprising a dicarboxylic acid having 1 to 12 or a pharmaceutically acceptable salt thereof in a pharmaceutically acceptable carrier. 2. A composition according to claim 1 in a form suitable for topical use. 3. The composition according to claim 1 or 2, which contains a skin stratum corneum exfoliant. 4. The composition according to claim 3, wherein the skin exfoliant is salicylic acid. 5. The composition according to claim 1, which is in an injectable form. 6. The composition according to claim 1, which is in an oral dosage form. 7. The composition according to any one of claims 1 to 6, wherein the active ingredient is azelaic acid.