RU2123326C1 - Pharmaceutical composition with photosensibilizing agent - Google Patents

Abstract

FIELD: medicine, oncology. SUBSTANCE: invention proposes an ointment of the following composition, wt.-%: hematoporphyrine or its derivatives, or liposomal forms of hematoporphyrine, or dimegin 0.07-2.0; dimethylsulfoxide or dimexide 30-45, and ointment base - the rest. Composition is used for photodynamic therapy of patients with malignant tumors. EFFECT: broadened pattern of assortment of medicinal form. 8 ex

Description

 The invention relates to the pharmaceutical industry and relates to the creation of new dosage forms in the form of an ointment with photosensitizers, which can be used in medical practice, in particular during photodynamic therapy.

 It is known to use in medical practice when conducting photodynamic therapy of malignant tumors of the main localizations as photosensitizers of hematoprofirin derivatives of various degrees of purification under various trade names, for example, photosan, photogem, photofrin I, photofrin II.

 However, to date, these drugs have been used in dosage form as an injection solution. The injectable dosage form of the above drugs was administered intravenously, in a jet, at a dose of 0.5 - 6.0 mg / kg of the patient’s body weight, while the patient was in a darkened room for 48-72 hours before laser irradiation of the tumor. Studies have shown that the use of an injectable dosage form of photosensitizers in some cases leads to pronounced changes in the oxidative-antioxidant balance, which clinically manifests itself in the form of an inflammatory reaction, often accompanied by tissue edema. The presence of such complications indicates the need to develop new dosage forms of photosensitizers for use in medical practice during photodynamic therapy.

 Known composition for photodynamic therapy of tumors, which may be an ointment, gel, cream or solution (US 4753958). This composition contains a hematoporphyrin derivative as a photosensitizer. As auxiliary materials, it may contain water, liquid alcohols, liquid glycols, liquid lanolin, etc. Moreover, N-methylpyrrolidone is an obligatory component among the carriers. For topical use, a carrier combination called "AZONE" in combination with N-methylpyrrolidone is recommended.

 The objective of the invention was to expand the range of dosage forms for photodynamic therapy of malignant tumors.

 According to the claimed invention, there is provided a dosage form in the form of an ointment containing, as a photosensitizer, hematoporphyrin, or derivatives of hematoporphyrin, or liposomal forms of hematoporphyrin, or dimegin in an amount of 0.07 - 2.0 wt.%, The solvent is dimethyl sulfoxide, dimexide in an amount of 30% - 45% and the fat base is the rest.

 As a form-forming ingredient, a fatty base, petrolatum and / or lanolin can be used.

 As a photosensitizer, the composition may contain various hematoporphyrin derivatives, such as hematoporphyrin dimers (photofrin I, photofrin II, photogem, photosan), and hematoporphyrin oligomers containing up to 8 molecules. The above solvents are taken in an amount of not more than 30 ml - 45%, since a further increase in the amount of solvent only leads to an excessive consumption of this reagent and to a thinner consistency of the ointment, which, in turn, can cause ointment to spread when applied to the patient’s skin, and a decrease in its amount leads to incomplete dissolution of the photosensitizer. When using a liposome form of a hematoporphyrin derivative or a liposomal form of hematoporphyrin as photosensitizers, dimethyl sulfoxide with the addition of sorbitol phosphate buffer is used.

A method of obtaining the inventive composition in the form of an ointment includes dissolving a portion of the photosensitizer in the above amount of solvent, heating the solution to 35-40 ^° C and pouring the solution into a mass containing petrolatum and / or lanolin.

 The invention is illustrated by the following non-limiting examples.

 Example No. 1 preparation of 0.25 wt.% Ointment with hematoporphyrin.

Dissolve 0.25 wt.% Hematoporphyrin in 35.3 wt.% Dimethyl sulfoxide. The solution is heated to 40 ^o C and poured with vigorous dissolution into a mass containing 44.45 wt.% Petrolatum and 20 wt.% Lanolin as an ointment base. The resulting mass is stirred until homogeneous and stored in a container of dark glass.

 Example No. 2 preparation of 0.07 wt.% Ointment with hematoporphyrin derivatives in an alkaline buffer with a pH of 8.3.

Dissolve 0.07 wt. % hematoporphyrin derivative in 35.3 wt.% dimethyl sulfoxide. Filter through a filter. Heated to 40 ^o C and poured into a mass containing 30 wt.% Petroleum jelly and 34.63 wt.% Lanolin. The resulting mass is stirred until homogeneous and stored in a container of dark glass.

 Example No. 3 preparation of 2.0 wt.% Ointment with hematoporphyrin.

2% by weight of hematoporphyrin are dissolved in 35.3% by weight of dimethyl sulfoxide. The solution is heated to 40 ^o C and poured with vigorous dissolution into a mass containing 42.7 wt.% Petrolatum and 20 wt.% Lanolin as a base. The resulting mass is stirred until homogeneous and stored in a container of dark glass.

 Example No. 4 preparation of 0.5 wt.% Ointment with dimegin.

Dissolve 0.5 wt.% Dimegin in 35.3 wt.% Dimexide. The solution is filtered and heated to 35 ^o C and poured with intensive dissolution into a mass containing 44.2 wt.% Petroleum jelly and 20 wt.% Lanolin as a base. The resulting mass is stirred until homogeneous and stored in a container of dark glass.

 Example No. 5 preparation of 0.5 wt.% Ointment with hematoporphyrin.

Dissolve 0.5 wt. % hematoporphyrin in 44.5 wt.% dimethyl sulfoxide. The solution is heated to 40 ^o C and poured with vigorous dissolution into a mass containing 40 wt.% Petroleum jelly and 15 wt.% Lanolin as a base. The resulting mass is stirred until homogeneous and stored in a container of dark glass.

 Example No. 6 preparation of 0.07 wt.% Ointment with liposomal derivatives of hematoporphyrin.

0.025 wt.% Of the liposome form of hematoporphyrin in 35.3 wt.% Of dimethyl sulfoxide is dissolved. The solution is heated to 35 ^o C and poured with vigorous dissolution into a mass containing 49.675 wt.% Petroleum jelly and 15 wt. % lanolin. The resulting mass is stirred until homogeneous and stored in a container of dark glass.

 Examples of therapeutic efficacy of the claimed pharmaceutical composition.

Example N 7
Patient A., 64 years old. Diagnosis: basal cell carcinoma of the nose wing on the right.

 An ointment containing 0.07 wt.% Hematoporphyrin derivative is applied to the surface of the ulcer. After a one-hour exposure, copper vapor laser was irradiated for 15 minutes. At the control examination after 1 month there is no data for the presence of basal cell carcinoma.

Example 8
Patient P., 72 years old. Diagnosis: lymphoma of the skin of the right thigh.

 An ointment containing 2.0 wt.% Hematoporphyrin was applied to the surface of the tumor. After 1.5 hours of exposure, the tumor is irradiated with a copper vapor laser for 20 minutes. Two weeks after the photodynamic therapy session, complete ulceration of the ulcer at the site of the lysed tumor was noted.

 The given examples of the results of a clinical study of an ointment with a photosensitizer indicate its therapeutic effectiveness. It should be noted that in each case, depending on the depth and nature of capillary dysplasia, an ointment with a certain photosensitizer content is used.

Claims (1)

 A pharmaceutical composition with a photosensitizer in the form of an ointment for the photodynamic therapy of malignant tumors, characterized in that it contains hematoporphyrin or hematoporphyrin derivatives or liposomal forms of hematoporphyrin or dimegin in an amount of 0.07 - 2.0 wt.%, In as a solvent - dimethyl sulfoxide or dimexide in an amount of 30 - 45 wt.%, the fat base is the rest.