Stable solution of retinol palmitate and treatment of skin diseases

 

(57) Abstract:

The invention relates to chemical-pharmaceutical industry, refers to a stable solution palmitate, treatment of skin diseases and reducing the side effects of chemotherapy for cancer patients. The invention lies in the fact that a stable solution of retinol palmitate contains antioxidants butylacetyl and butylacetamide, dissolved in refined deodorized oil with reduced content of unsaturated fatty acids and limited content of peroxides and acids, an acid number of from 0.1 to 0.5 mg KOH/G, peroxide neg 5 to 10 mmol/g and sealed in vials filled with an inert gas. Also we propose a method for the treatment of diseases of the skin: follicular keratosis, congenital pachyonychia, seborrhea given biorhythm dividing epithelial cells. The invention provides the stability of the drug and efficacy in the treatment of severe skin diseases and as a stimulant and protector of leucopoiesis chemotherapy of malignant tumors. 2 S. and 4 C.p. f-crystals, 13 tables. 1 Il.

The invention relates to pharmaceutical industry and relates to the creation of a stable solution of retinol palmitate, and also used in the treatment of cancer patients with drugs.

Retinol palmitate is a biologically active form of vitamin A. In the form of retinol palmitate vitamin a is absorbed from the intestine and deposited in the liver.

Retinol palmitate is used in medical purposes. The drug is effective in skin, eye diseases, chronic diseases of the digestive tract, the lungs, is a natural immunostimulant and remedy the bone marrow and other blood-forming organs.

Retinol palmitate is a homogeneous dilution mass of a light yellow color with a melting point 26-28oC. Activity 1 mg corresponds 1817 IU of vitamin A. the Characteristic feature of the drug, which hinders the creation of a stable dosage forms based on it, is the sensitivity to light and oxygen.

To protect the drug from light it is easy enough to package the solution in a dark glass bottles and place them in a cardboard box. It is much harder to protect retinol palmitate from the ravages of oxygen.

In order to prevent oxidation of retinol palmitate dissolved in vegetable oils (soy, corn), contains lower than the GKO undergo oxidation and involve themselves in this process of retinol palmitate. Additional stabilization to the solution of retinol palmitate in oil is added antioxidants: tocopherol, dihydropyridines and its analogues [1], ethoxyquin (Santorin) [2].

However-tocopherol roads, it is also a very unstable connection that is hard to work in production. The ethoxyquin is harmful to health in our country is used only for livestock. The toxicity of dihydropyridines and its analogues studied insufficiently. Although the authors of the patent States that used in quantities equivalent of dihydropyridines non-toxic, however, insufficient data are available for the specified connection can be applied in medicine.

Known stabilizing solution of retinol palmitate in oil.

The closest in technical essence and the achieved result is a solution of retinol palmitate in oil and 5.5%, containing advanced blend of antioxidants of butylacetamide (BOT) and butylacetate (BOA) (FS 42-2364-85).

This product contains retinol palmitate, BOT in the amount of 1 g per 1 kg of retinol palmitate and BOA in the amount of 0.5 g per 1 kg of retinol palmitate. Retinol palmitate dissolved in affinirovan the active and safe drug. When some amount of vitamin a is destroyed, its content in the product is less, and that the drug becomes less effective. On the other hand, the decay products of retinol palmitate toxic and can cause allergies.

The disadvantages of this drug should be attributed to the low quality of the oil taken for the dissolution of retinol palmitate, while the quality of the oil is essential for the safety of the drug. In a known drug acid number of the solution of retinol palmitate in oil not more than 1.0 mg KOH/g peroxide value was not determined. Meanwhile, the problem of stability of the substance cannot be resolved satisfactorily, if not to limit the number of acids and peroxides in the oil (table 1 and 2). In addition, the vials with a solution close to the free access of air, and not in a stream of inert gas.

In order to get well-known drug, retinol palmitate dissolved in soybean or corn oil and do not use other oils. This leads to a narrowing of the resource base, which makes the manufacturing of the drug less favorable economically.

There is a method of applying a solution of retinol palmitate in oil (instructions for medicinescomplete avitaminosis and treatment of certain skin diseases, eyes, gastrointestinal tract and other organs. Method of application the following: the drug is taken orally after a meal, the highest daily dose of 100000 ME [3].

The known method of application does not meet the modern requirements of clinical pharmacology at three points.

First, retinol palmitate successfully used in the treatment of certain skin diseases for which treatment vitamin a has not been previously used. Such diseases include follicular keratosis, congenital pachyonychia, seborrhea. In the treatment of these diseases retinol palmitate was effective, and in some cases indispensable. In the above-mentioned instructions for use is not taken into account, the spectrum of skin diseases in which applies a solution of retinol palmitate narrowed.

Secondly, the known method of application does not take into account the mechanism of action of retinol palmitate; in particular, it is not consistent with the biorhythm of the division of epithelial cells and their differentiation.

Identified only one literary source, in which the preparation for external use containing retinol palmitate, it is recommended to use at night, but it is not the mechanism of action of vitamin a, And with premenopausal application does not take into account the fact that in large doses (300000 ME per day for adults) vitamin a exhibits not previously known therapeutic properties. In other words, in small doses (up to 100,000 IU/day) retinol palmitate acts otherwise than in large.

Vitamin a and its derivatives are the only currently, drugs, allowing varying degrees to control skin diseases associated with disruption of the processes of keratinization, sebaceous excretions and intact skin. Their application is based on normalizerbase effect on keratinization and epithelialization, and evidence that some patients along with disorders of keratinization found reduced levels of vitamin a in blood plasma or cell reynoldsville protein.

However, both abroad and in domestic practice, for the treatment of patients with inherited disorders of keratinization is used mainly tigazon [5]. Tigazon effective in the treatment of many dermatoses, goes well with antibacterial agents, appointed inside and externally, as well as treatment with ultraviolet irradiation. At the same time, giving a positive assessment tigazonu, we must not forget that this is a very toxic drug, not all the side effects of which are still known. Pona children which drug should be prescribed only in case of heavy flow and inefficiency of other preparations. Due to the high risk of teratogenic effect it is recommended to refrain from pregnancy at least three years. When treating tigazon necessarily x-ray examination of the skeletal system, and in young children and assessment of development indicators.

New derivative tigason - acitretin causes fewer adverse reactions, but this retinoid is also quite toxic [6].

Treatment of the oil solution of retinol palmitate in large (300,000 IU/day) doses leads to the same result as the treatment tigazon, but retinol palmitate is a natural substance for the body. In the body thereto evolutionary developed transport proteins, cell receptors and metabolic pathways. Therefore, retinol palmitate has low chronic toxicity in the body it is easily metabolized or disposed of.

Known schemes chemotherapeutic treatment of cancer patients not take into account the fact that retinol palmitate has the ability to reduce the risk of side effects.

The effectiveness of combination chemotherapy, t is novoobrazovanii, largely depends on the intensity of its work - the introduction of the estimated doses of cytostatics in the desired timing and the optimal time intervals between cycles. One of the main obstacles to optimizing chemotherapy is myelosuppression - oppression in the red bone marrow, accompanied by leukopenia (decrease in the number of leukocytes in the blood). The result has to interrupt commenced courses of treatment, lower doses of anticancer drugs and to expect recovery of hemopoiesis before repeated courses. In connection with the above, the use of retinol palmitate as a protector and promoter of leucopoiesis seems very promising. Retinol palmitate does not stimulate growth epithelialisation tumors and does not interact with drugs, and at the same time has some antitumor activity and protective effect against a number of harmful factors (e.g., carcinogens). However, retinol palmitate is not used as a drug that can protect the organs of the blood system from the damaging effects of drugs [7].

Well-known attempt to use retino the m case failed [8].

Object of the invention is the creation of a stable solution of retinol palmitate in oil, the use of this drug for the treatment of severe skin diseases based on knowledge of the mechanism of action of retinol palmitate, an extension of his testimony as a promoter and protector of leucopoiesis chemotherapy of malignant tumors.

The essence of the invention lies in the fact that medicinal products containing retinol palmitate and a blend of antioxidants BOT and BOA dissolved in vegetable refined deodorized oil (corn, soybean or rapeseed) with low content of unsaturated fatty acids and limited content of peroxides and acids (acid number of from 0.1 to 0.5 mg KOH/g; the peroxide is in the range from 5 to 10 mmol/kg) for the best protection against the oxygen sealed in vials filled with an inert gas.

According to the invention the drug is successfully used for the treatment of severe skin diseases for which treatment solution retinol palmitate't used before: seborrhea, congenital pachyonychia, follicular keratosis.

According to the invention a stable solution of retinol palmitate administered orally in accordance with biodel.

According to the invention a stable solution of retinol palmitate in the treatment of skin diseases associated with disruption of the processes of keratinization, sebaceous excretions and intact skin in doses of 300,000 IU/day) is much more efficient than in small (up to 100,000 IU/day).

According to the invention to reduce the risk of side effects from chemotherapy cancer patients a solution of retinol palmitate in oil administered orally based 4300 ME per 1 kg of patient's weight, but not more than 300000 ME in the day; course introduction start for 3-5 days before the start of cytostatic therapy and finish 10-15 days after its abolition.

The invention is illustrated by the following studies.

Studies suggest that the stability of the drug significantly increases when the acid number of the solution of retinol palmitate in oil ranges from 0.1 to 0.5 mg KOH/g, and the peroxide is in the range from 5 to 10 mmol/kg

In medical and pharmaceutical practice, the concentration of vitamin a is expressed in international units (ME). 1 mg of retinol palmitate corresponds 1817 ME. Will continue to use this unit.

Table 1 demonstrates the stability of the solution of retinol leaving the oil with a variety of acid and peroxide numbers. The study was performed under the conditions of free aeration air at a temperature of 60oC.

The quality of different samples of soybean oil are shown in table 2.

The results of the study (table 1) show that in samples of soybean oil of satisfactory quality (samples 1 and 2) the content of retinol palmitate decreases slowly and by the end of the storage period remains within that meets the requirements of the Federal Assembly of 42-2364-85, though it comes close to the lower limit of the norm. In samples of soybean oil low quality content retinol palmitate decreases rapidly and by the end of the retention period, the number falls well below the required, specified in the above-mentioned formstate (FS 42-2364-85).

Thus, the stability of the drug depends on the quality taken for the dissolution of retinol palmitate vegetable oils, i.e., the acid and peroxide value must be between 0.1 to 0.5 mg KOH/g and from 5 to 10 mmol/kg, respectively.

The fracture behavior of retinol palmitate presents curves 1-4 (drawing). The specified curves clearly show that the oxidation of the substance does not start, there is a certain induction period during which the content of retinol palmitate in the second speed, an avalanche. To ensure the stability of the drug, should as far as possible to prolong the induction period, to delay the oxidation process.

The vials with a solution of retinol palmitate sealed in a stream of inert gas, thus limiting the contact of the drug with oxygen. As the inert gas is preferable to use nitrogen as the density close to the density of air, and diffusion through the tube and the cap of the vial is slow.

Table 3 shows how the storage in vials, sealed in a stream of nitrogen, provides the best safety of the drug. The study was performed under conditions of accelerated aging, vials of medication is kept at a temperature of 60oC.

In addition, it is very important opened a bottle, in which a solution of retinol palmitate is not protected from oxygen in the air "cushion" of inert gas, do not store for a long time, to avoid rapid, avalanche-like destruction of the substance. It opened the bottle should be stored for not more than 14 days after opening.

Recent studies have shown that canola oil, properly cleaned, also suitable for dissolving retinol palm

The possibility of using rapeseed oil to obtain the product expands the resource base and makes production more profitable economically.

Studies have shown that the drug can be effective in the treatment of such skin diseases for which treatment solution retinol palmitate previously not used: follicular keratoses, congenital pachyonychia, seborrhea.

Follicular keratosis is a collective term that includes several forms of diseases characterized by impaired keratinization in the form be accompanied papules in the mouths of hair follicles. The traditional approach to the treatment of all forms approximately the same - the purpose of vitamins, nourishing creams, 1-2% salicylic ointment, salt baths, and ultraviolet irradiation. The study included 24 patients with follicular keratosis - 18 men and 6 women aged from 6 to 35 years. 19 patients had previously received treatment of various vitamins, including vitamin a (retinol acetate) in doses up to 33000 ME night and external mitigation means (cosmetic creams, salicylic ointment). Significant improvement was observed. All patients had multiple follicular papules located on the face, chest, with the TCI in children adults - 200000 - 300000 ME in the day. Children drug was administered in equal doses in the morning after Breakfast and at night, adults - only night. The treatment was carried out on an outpatient basis. Efficacy of treatment was evaluated by dynamic changes of the clinical signs recorded once a week.

Improvement occurred by the end of the second week of treatment is decreased hyperkeratosis, papules became more flat, 3-4 weeks showed a significant improvement. Upon completion of the course of treatment prescribed ointment with vitamin a, as supportive therapy.

As can be seen from table 5, a positive effect was achieved in all patients, of whom 12.5% - the result was no better than traditional therapy, 87.5%, which is a significant improvement.

Example 1.

Patient C. A., age 11. Diagnosis: follicular keratosis. With 4 years of age suffer from skin disease, exacerbation of spring and autumn, the full resolution of the rash in the summer of the sea. Previously treatment - cosmetics with vitamin a, homeopathic remedies, Essentiale-Forte without significant improvement. When viewed on the hips, thighs, shoulders, knees, and elbows sharp dry skin, against which are follicular papules at the dose of 200000 ME, externally - emollient cosmetic creams. To 4 weeks of taking the drug remained brownish spots on the location of lesions, papules resolved.

Congenital pachyonychia is a rare hereditary disorders of keratinization. For the disease characterized by thickening of the nail plate with subungual hyperkeratosis, Palmar-plantar keratoderma, with formation of blisters on the soles, follicular papules with hyperkeratosis, diffuse scaling on the shins, leukoplakia on the mucous membranes of the mouth, nose, larynx. There are cases of malignant degeneration lesions of leukoplakia on the second decade of life. Effective treatments for the disease have not been developed. We observed two children and one adult with congenital pachyonychia aged 5, 7 and 19 years, all three men. Retinol palmitate dose of 5,000 IU per 1 kg of body weight was administered to all patients for a long time is 3-5 months, given the slow growth of the nails. Evaluation of the results and methods of treatment are the same as for follicular keratosis. All patients achieved a favorable result to the end of the first month decreased keratinization of the palms and soles, continued appearance of blisters, papules became b is Shazli two and significantly regressed in one patient rash on the mucous membranes, on the ground keratoticheskie papules remained a point of secondary pigmentation. After three months, continued the trend of growth of unaffected nail. One patient in five months achieved a complete remission. Other patients stopped treatment after three months, several months after stopping treatment were noted deterioration of the nails, but other signs of the disease has not occurred.

Example 2.

Patient W. I. , 5 years. Diagnosis: congenital pachyonychia. Suffering from skin disease from 6 months of age, when marked by the appearance of blisters on the soles, desquamation of palms and soles, rash on the buttocks, thighs, shoulders and growth of thickened nails on hands and feet. For three years there have been changes in the mucous membranes of the oral cavity. Treatment of various bracing means, vitamins, externally - wound healing and softening ointments success is not given. At survey of the child have hyperkeratosis of palms and soles, rash, maceration of the skin of the interdigital folds, thickening of the nail plate and subungual hyperkeratosis, more pronounced in the distal. Follicular papules brownish-red color with Horny spines on the surface located on agodi nacen retinol palmitate dose of 100000 ME once a day at night. The treatment was carried out within three months. During treatment improved the condition of the nails remained changed only their distal part, remained slight desquamation of the palms, disappeared follicular papules (on their small plots of secondary pigmentation), were completely resolved rash on the mucous membrane. From our point of view, in the result the most important changes in the oral cavity because they are innate pachyonychia regarded as precancerous and pose a real threat to the lives of patients.

Seborrhea is a skin disease, which is based on the violation of the secretory function of the sebaceous glands expressed through increased allocation of qualitatively altered sebum. The disease is characterized by the tendency to chronicity, recurrence. Most often it is recorded in the period of puberty. Affects the scalp, face, chest and back. Commonly used therapy - obscheukreplyayuschie tools, trace elements (arsenic, phosphorus, iron, zinc), vitamins, antibiotics, externally - sinistrality cream, alcohol solutions with chloramphenicol, ester, boric acid, sulfur, tar, medicated shampoos.

The study included 18 patients with the scalp in the form of excess oil and hair loss, flaky skin (dandruff), redness, itching, 8 - simultaneously rash on the face (erythematous-squamous lesions on the cheeks and forehead, covered with yellowish greasy scales), two of them had similar lesions of the skin were on his chest. Retinol palmitate was administered in a daily dose of 200000-300000 ME depending on patient weight once a day at night. After 2 weeks of treatment, improvement was observed in all patients, by the end of the month was achieved full effect. Differences depending on the sex of the patients were noted. The results of treatment are presented in table 6.

This method of treatment in addition to high efficiency differs from others in that it is possible not to resort to an external treatment. This fact is especially important in the defeat of the scalp when applying ointments or solutions often gives hair unkempt appearance and/or odor.

Example 3.

Patient I. A., 28 years. Diagnosis: seborrhea. He complained of dandruff, excess oil and hair loss, itching, rashes on the face and chest with 12 years of age. The use of medicated shampoos, homeopathic medicines, vitamins, and corticosteroid ointments have been ineffective. Examination: the face of saln is e, thinning, thinning, scalp flakes. Assigned retinol palmitate dose 200000 ME, externally - wiping the face of non-alcoholic tonic. The improvement in the reduction of erythema and desquamation was noted after 2 weeks of taking the drug. To 4 weeks of taking the drug rash has resolved, the oiliness of the skin decreased, decreased hair loss.

Studies suggest that the optimal time of administration of the drug - late at night or early in the morning.

In recent years attracted the attention of scientists question about the mechanism of action of vitamin A. Although our ideas about it are far from completeness and perfection, some theoretical propositions can be considered proven and successfully used in medical practice.

Thus, the study of circadian rhythm proliferative activity (intensity divisions of epidermal cells under the influence of a Solution of retinol palmitate in oil helped to establish the optimal timing of the doses.

Example 4.

The study of the circadian rhythm of the proliferative activity of epidermal conducted on rats male Wistar rats weighing 120 10, Animals were killed every hour, took the skin back and counted the number of the th activity occurs at night: the cells begin to divide after midnight and complete this process by the morning.

Pharmacokinetic studies, put on rats male Wistar rats weighing 120 10 g, showed that after a single oral administration of the oil solution of retinol palmitate reliably increased and the maximum concentration of retinol palmitate in the blood is detected after 1 hour. After 2 and 4 hours, the concentration of retinol palmitate reduced after 6 hours reaches the level of intact animals (table 8).

Since the peak of the proliferative activity occurs at night, it was natural to assume that the optimal intake of vitamin a - 23 hours. Experiments to study the circadian rhythm of the proliferative activity of the epidermis in laboratory animals treated with oil solution of retinol palmitate oral, confirmed this assumption. Retinol palmitate, introduced in 23 hours, most actively stimulates the division of epidermal cells (table 9).

Finally, data from clinical trials show that the reception of the oil solution of retinol palmitate 23 hours is the most optimal (table 10).

Example 5.

In clinical trials involved young people aged 15 to 20 years with youthful acne, Loka is 0 IU/day. The best effect was achieved when the drug accounted for 23 hours.

Clinical trials, confirming that retinol palmitate at doses of 300,000 IU/day) is more effective than in small (up to 100,000 IU/day).

In accordance with dermatotropnoe effect of the drug, namely with the ability to influence the processes of keratinization, the function of the sebaceous glands and regeneration processes, retinol palmitate used in three main groups of diseases with impaired keratinization (I), violation of sebaceous excretions (II), and failure of intact skin (III).

Example 6.

1. Diseases with impaired processes of keratinization: ichthyosis, ihtiosiformnye the eritrodermii, psoriasis, Palmar-plantar keratoderma etc.

The group of patients with dermatoses violation of the processes of keratinization consisted of 73 people aged from 4 months to 42 years. All patients previously treatment retinol acetate, aevit and retinol-palmitate dose of up to 100,000 IU/day in adults was not effective.

Retinol palmitate caused improvement in ichthyosis, provided that the initial dose of the drug is high enough, at least 300,000 IU/day for adults and 5000 IU/kg/day in children. Prodolzhitelnost lips in two patients, of them one of the dryness of the conjunctiva.

II. Diseases with impaired processes sebaceous excretions: Papoose - pustular acne, acne conglobata.

In the group of patients with impaired processes sebaceous excretions included 37 people. Previous treatment with small doses of retinol palmitate was not effective. In this group of patients the best effect was achieved in the treatment of papules-pustular acne, acne conglobata effect is somewhat lower (table 11). The drug in high doses tolerated well, in the first month, all patients had a reaction exacerbation, which were independently without discontinuation of treatment.

III. Diseases associated with impaired intact skin.

In diseases with impaired intact skin the best results are achieved when the postoperative medication (table 11, surgical wounds), is also marked by intensive healing erosions (table 11, erosion). The majority of patients with epidermolysis bullosa under the influence of high doses of retinol palmitate was obtained a stable clinical effect (table 11, the bullous drug bullosa). Unwanted side effects: itching, dry skin and mucous membranes, cheilitis, etc. noted in the. In these cases, patients were prescribed the drug in a dose of 200,000 IU/day.

Research is proving that the solution of retinol palmitate can be successfully used in chemotherapy of cancer patients to reduce the risk of side effects.

Clinical trials showed a marked protective action of retinol palmitate on leucopoiesis in conditions of combined cytotoxic therapy.

Example 7.

The group of cancer patients who had radiation as a result of combination chemotherapy consisted of 50 people. Patients had a variety of diagnoses of chlamydia (LGR), non-Hodgkin lymphoma (NHL), breast cancer (breast cancer), malignant melanoma (MLB), the patients ' age from 15 to 74 years. Patients were admitted to the hospital to undergo refresher cytostatic therapy, but after the first course of chemotherapy was such a level of leucocytes in the blood, a second course of cytostatic therapy conduct was impossible. Intake of retinol palmitate dose of 300,000 IU/day once a day (after dinner) lasted 6 days before the start of chemotherapy cycle, the number of leukocytes was increased by an average of 2.7 x 109/l to 4.4 riminal basically a combination of cytostatics, such as rubomycin, cyclophosphamide, vincristine, cisplatin, and others. Intake of retinol palmitate dose of 300,000 IU/day once a day (after dinner) continued during the entire course of chemotherapy.

Quite distinct protective against radiation effect of retinol palmitate can be seen from table 12.

Out of 50 patients in 7 (14%) protective effect of retinol palmitate was absent, and the absence of effect associated with a specific history of clinical background (liver, kidney and bone marrow).

Despite the fact that the effect of retinol palmitate was studied in a very burdened primary and comorbidity group of patients with malignant neoplasms and exposed to combinations of drugs, signs of hypervitaminosis a and other serious side effects were observed.

Example 8.

In another group of patients with malignant tumors of the reproductive organs during chemotherapy treatment used cytostatic - thiotepa (synonym Thio-TEF). The use of the latter, as a rule, is accompanied by inhibition of the function of red bone marrow. This is manifested by anemia, leukopenia and thrombocytopenia. The severity of pool account in determining the effectiveness of conservative treatment. Retinol palmitate has the ability to stimulate hematopoiesis, increasing Erythro-, granulocyte and linfocitos.

Patients receiving retinol palmitate, subjectively easier to tolerate treatment with thiotepa. They do not develop or less pronounced signs of oppression functions of organs of the blood system, not growing signs of immunosuppression improves twilight vision.

The results of applying retinol palmitate was assessed by the state of twilight vision, the blood, the content of lymphocytes, tuberculin test.

Patients received retinol palmitate dose 300000 ME once a day at night, the introduction began for 4-5 days before the start of chemotherapy and was completed in 10-15 days after its abolition.

The obtained data are presented in table 13.

Twilight vision is an indirect indicator of the degree of saturation of the body with vitamin A. patients with malignant tumors of the threshold of the light sensitivity is significantly reduced. As saturation of the body with retinol-palmitate this indicator increases, sometimes dozens of times. In patients treated with thio-phosphamide on the background of retinol palmitate does not develop or is less of stereom even more oppressed reaction to intradermal injection of tuberculin. Persons receiving cytostatic against the backdrop of retinol palmitate, this does not occur: less common negative and paradoxical (pronounced swelling of the forearm) reactions.

The detected properties of retinol palmitate dose of 300,000 IU/day allow us to consider the drug as a stimulant of blood with chemotherapy for cancer patients.

Thus, the invention protects the conditions listed below.

The creation of a stable solution of retinol palmitate.

Retinol palmitate and antioxidant BOT and BOA dissolved in vegetable refined deodorized (corn, soy or canola) oil with a low content of unsaturated fatty acids and limited content of peroxides and acids (acid number of from 0.1 to 0.5 mg KOH/g; the peroxide is in the range from 5 to 10 mmol/kg); the resulting solution was sealed in vials filled with an inert gas, opened a bottle store no more than 14 days after opening.

The drug is effective in the treatment of diseases such as seborrhea, congenital pachyonychia, follicular keratosis. Way of application and dose stable solution of retinol palmitate in oil in the treatment of E. what about the morning within 4-12 weeks.

The drug can be successfully used to reduce the risk of side effects associated with chemotherapy for cancer patients. To this end, the solution of retinol palmitate in oil administered orally based 4300 ME per 1 kg of patient's weight, but not more than 300000 ME in the day; course introduction start for 3-5 days before the start of cytostatic therapy and finish 10-15 days after its abolition.

The invention is illustrated in the examples.

Example 9.

55,1 g retinol palmitate (in recalculation on 100% of the drug) (FS 42-2229-94), 1 g of butylacetamide (BOT) (FS 42-3460-97) and 0.5 g of butylacetate (BOA) (TU 6-09-3746-74) dissolved in soybean oil (acid number of 0.3 mg KOH/g peroxide value 6 mmol/kg). The resulting solution was Packed in vials, the vials are filled with nitrogen and sealed. Opened a bottle store no more than 14 days after opening.

Tested in examples 1 - 6.

Example 10 is carried out analogously to example 9. Instead of butter use soy oil, rapeseed oil (acid number of 0.3 mg KOH/g peroxide value 7 mmol/kg).

Tested in examples 7 and 8.

Thus, the resulting stable solution of retinol palmitate. The drug is effective in the treatment of certain skin disorders, for the treatment via retinol palmitate, the effectiveness of the drug increases. The drug can be successfully used in chemotherapy of cancer patients to reduce the development risk of side effects.

Sources of information

1. The UK patent N 1521913, MKI2A 61 To 31/595, publ. 16 Aug. 1978

2. Auth. St. Czechoslovakia N 172543, MKI2A 61 K 31/00, publ. 29.04.76.

3. Mashkovsky M. D. Medicines, ch. II. - N-3 - M, Medicine, 1996

4. Patent Germany N 3827467, MKI4A 61 K 7/06, publ. 23.02.89.

5. Shotmaster I. J., Pokryshkin Century. And., Pisarenko, M. F. and other Aromatic retinoids in the treatment of dermatoses. // Vestnik St.Petersburg University. dermatol. 1984. - N 3.-S. 42-45.

6. Bruckner-Tuderman L, C. Sigg, Geiger J. M., S. Gilardi Acitretin in symptomatic therapy for severe recessive X-linked ichthyosis. // Arch. Dermatol. 1988. -V. 124.-P. 529-532.

7. Pershin I.e. Methods experimental chemotherapy - M.: Medicine, 1971, -539 C.

8. Sergeev A. C. Correlation of biochemical and immunological parameters in colon cancer optimal doses of retinella and ascorbic acid. Bull.exp.biology and honey. 1983, N 9. - S. 90 - 93.

1. Stable solution of retinol palmitate dissolved in refined oil containing antioxidants butylacetyl and butylacetamide, great for the x fatty acids and limited content of peroxides and acids, when this acid number is from 0.1 to 0.5 mg KOH/g, peroxide is in the range from 5 to 10 mmol/kg, and sealed in vials filled with an inert gas.

2. Stable solution of retinol palmitate on p. 1, characterized in that it is dissolved in corn, soybean or rapeseed oil.

3. Stable solution of retinol palmitate on p. 1, characterized in that it is designed for the treatment of skin diseases: follicular keratosis, congenital pachyonychia, seborrhea.

4. Stable solution of retinol palmitate on p. 1, characterized in that it is designed for the treatment of skin diseases associated with disruption of the processes of keratinization, sebaceous excretions and intact skin at a dose of 300,000 IU/day.

5. Stable solution of retinol palmitate on p. 1, characterized in that it is the dose of 300,000 IU/day is designed as a stimulator of hematopoiesis in chemotherapy of cancer patients.

6. A method of treatment of skin diseases by oral administration of retinol palmitate, characterized in that in the treatment of diseases of the skin use a stable solution of retinol palmitate on p. 1, when this drug is administered in accordance with the biorhythm of dividing epithelial cells in the late evening and/or early morning dose

 

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The invention relates to medicine
The invention relates to medicine, namely to create tools for the treatment of alcohol intoxication

The invention relates to the field of medicine and is suitable for the treatment of seasonal and perennial allergic rhinitis, conjunctivitis, hay fever, urticaria, including chronic idiopathic urticaria, angioedema, psevdoallergicakie reactions caused by the release of histamine, itching dermatoses, allergic reactions to insect bites and itching of various etiology

The invention relates to a drug intended for intravenous

Antiseptic // 2163119
The invention relates to medicine and relates to an antiseptic for the treatment and prevention of diseases, including sexually transmitted

The invention relates to medicine, namely to the production of blood preparations

The invention relates to a synthetic derivative of vitamin D General formula I, where Q is CH2- or-CC - and-C1-C6alkylene; R1-H, C1-C4alkyl group YR1where Y -,- SO-, C1-C4alkyl, Z is H or a hydroxyl
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