HU202109B - Process for producing pharmaceutical compositions containing nicotinic acid for treating leg ulcer, improving formation of a scar and inhiditing rough cicatrization - Google Patents

Abstract

The present invention relates to a process for the preparation of a topical pharmaceutical composition comprising nicotinic acid as an active ingredient, whereby nicotinic acid, as is known in the art, is optionally combined with one or more other known pharmaceutical agents for wound healing and / or prevention of infections. or with other excipients, is converted into a topical pharmaceutical composition for use in the treatment of leg ulcers and known as healing and wound healing, with known drug-technology operations, for use in topical treatment containing 0.2 to 95% by weight of nicotinic acid. Scope of the description: 6 pages without figure EN 202 109 B -1-

Description

FIELD OF THE INVENTION The present invention relates to a process for the preparation of a nicotinic acid-containing pharmaceutical composition for the treatment of foot ulcer, wound healing and anti-coarse scar therapy. 5

Foot ulcer (ulcus cruris) is nowadays regarded as a folk disease. According to H. W. Spier (Med. Wchr. 0.5 to 2% suffer from ulcer cruris. According to domestic statistics, the 10 morbidity per 1000 inhabitants can be estimated at 0.3-1.7. Some statistics show that 6068% of people with leg ulcers are over 50 years old and 9,698% of patients have heavy physical work.

To date, the treatment of leg ulcers with medication has not been resolved. Current practice is that antibiotics are the primary treatment for the treatment of leg ulcers. The disadvantage of antibiotic treatment is that it develops resistance in many pathogens, so that the drug used for treatment should be changed almost weekly according to the results of ongoing resistance tests during treatment.

Antibiotics sensitize the treated living organism to other infections, so they should only be used with extreme caution in long-term treatment. Most patients develop various allergies as a result of antibiotic treatment. A further disadvantage is that the antibiotic treatment alone is only able to prevent infection of the foot, i.e. to "keep the disease down", but does not cause wound healing.

It is precisely because of this latter phenomenon that it is often the case that antibiotic treatment is supplemented with a treatment with a peeling agent, either by adding the antibiotic with the peeling agent or by abandoning the antibiotic after the wound cleaning antibiotic treatment and it is continued only with a peeling agent. The main exfoliators used are salicyl, Preu balm, panthenol, neogranormone. The disadvantage of using peeling agents is that they cause allergies to the patient during prolonged treatment such as salicylic hypersensitivity. The duration of healing of leg ulcers, even when using peeling agents, is very long, about 3-5 months, and in about 40% of cases complete healing is not achieved. In these cases, only a surgical solution is indicated, which is indicated for the majority of patients, precisely because of their old age and the associated poor physical condition.

In addition to the peeling agents used to treat leg ulcers, various wound dressing powders are sometimes used in combination with antibiotics to promote wound healing. Such 55 scarlet ports are described in the Handbook of Medicines (Medicina Publisher, Budapest, 1988). On page 187 of the manual, Vextran is mentioned as a wounding powder, which causes pain when absorbed. The combination Dermaforine 60 described on page 206 contains, among other things, zinc and mercury compounds and can cause side effects such as rash, itching and local inflammation. In many cases, the use of the currently known wound dressing powders does not prevent rough wound healing.

Surprisingly, in our lengthy experiments we have found that leg ulcers can be effectively treated with formulations containing nicontinic acid. It has also been found that formulations containing nicotinic acid promote wound healing and prevent rough scarring of wounds.

The medical effects of nicotinic acid are the subject of numerous publications. 288 and 490-491 in Dr. Béla Issekutz, Drug Order (3rd Edition, Medicine, Budapest / 1979 /). The conclusion is that nicotinic acid can be effectively used to treat skin disease known as pellarga, which is nowadays only in underdeveloped countries; has a potent vasodilator effect, such as in the treatment of hypertensive headaches, migraine and peripheral vascular disorders, and in combination with hypertensive agents in the treatment of hypertension; increases gastric hydrochloric acid production and can be used as an adjuvant in the treatment of anacid gastritis; its permeability-reducing effect can be used as an adjunct to edema treatment; it is also useful in the treatment of multiple sclerosis and X-ray. Nicotinic acid can be used as an adjuvant in the treatment of schizophrenia at a daily dose of 3-6 g (Arch. Gen. Psychiat. 28, 308 (1973)). Nicotinic acid lowers serum cholesterol and β-lipoprotein (EP 87 864) and can be used alone or as an adjunctive therapy in the treatment of vasoconstriction.

Nicotinic acid reduces photosensitivity, making it suitable for the treatment of porphyria and other photodermatoses. As an activator of carbohydrate metabolism, it lowers blood glucose levels (Chain 101/1967 /) and plays an important role in the regulation of pigment metabolism. Nicotinic acid also has a hepatic protective effect (German Patent Publication No. 3,505,572).

In each of the therapeutic areas listed, nicotinic acid is used in the form of internal preparations, such as tablets, capsules, injection solutions and the like.

For topical treatment, lipid soluble derivatives of nicotinic acid, in particular nicotinic acid esters and nicotinic acid amide, are used; experience shows that nicotinic acid is not absorbed through the skin, but these derivatives are.

In topical treatment, lipid soluble nicotinic acid derivatives are used primarily for the treatment of peripheral circulatory disorders, rheumatoid arthritis and certain dermatological disorders. For example, Tomanol salbe ointment, which contains a nicotinic acid benzyl ester in combination with acetylsalicylic acid and phenylbutazone, has been found to be useful in rheumatic diseases. For similar purposes, Dermadure Gel, which also contains nicotinic acid benzyl ester, may be used; the same composition is also suitable for the treatment of peripheral circulatory disorders and dermatosclerotic conditions. Nicodan percutan, which contains nicotinic acid propyl ester, has been used successfully in some dermatological disorders. It can be used for the above purposes

Known formulations (e.g. Bayolin, Dilexpal, Algipan baume, Xanthinol nicotinate, etc.) contain other nicotinic acid esters as active ingredients.

Other publications also indicate that topical formulations may contain nicotinic acid as an active ingredient. No. 52,705. and 87,864. European patents describe compositions for the treatment of acne vulgaris inflammation, which contain nicotinic acid or nicotinic acid amide as active ingredients. Locally applicable ointments are also included in the formulation. The German patent specification discloses compositions for external treatment of rheumatic diseases which contain heparin as an active ingredient together with an analgesic or antiinflammatory agent and / or nicotinic acid, nicotinic acid salt or nicotinic acid ester. No. 2,406,967.

The German patent specification discloses a deodorant and antiperspirant agent which may contain nicotinic acid amide or nicotinic acid as an active ingredient.

The nicotinic acid is not required to be absorbed through the skin in the therapeutic areas listed, since only a superficial effect is sufficient.

During our studies, we were surprised to find that nicotinic acid can be used with good results in the topical treatment of leg ulcers. Topical treatment with formulations containing nicotinic acid achieved a high percentage of recovery even in cases where treatments with known formulations were ineffective in a large proportion of cases. In our experience, treatment with nicotinic acid formulations has significantly reduced the time required for healing, compared to the 35 known active substances. It has also been found that formulations containing nicotinic acid, when applied topically, promote wound healing and prevent rough 40 scarring of the wounds.

Among the known effects of nicotinic acid listed above, vasodilatation is associated with the process of wound healing (including ulcer healing) in that it is important for wound healing to provide adequate blood supply to the tissue around the 45 wounds (the perinocrotic zone). However, ulcers and other processes within the wounds are only remotely related to the blood supply to the wound. In the initial stages of the wound healing process, the formation of a fibrin network that fills the wound cavity plays a crucial role, which is due to the activation of coagulation-promoting factors. In our experience, nicotinic acid-treated ulcers develop a wound-filling fibrin network earlier than the control group of 55 known wound-healing agents, suggesting that, in addition to its known biological effects, nicotinic acid activates coagulation-promoting factors. In the closing phase of wound healing, the exact opposite effect, the disruption of the fibrin net system, is required, which requires activation of the fibrinolytic system. It is extremely surprising to discover that nicotinic acid also enhances the activity of the fibrinolytic system. This bi-directional and contradictory resultant effect could not be expected based on the known effects of nicotinic acid 65.

The present invention therefore relates to a process for the preparation of a topical pharmaceutical composition containing nicotinic acid as an active ingredient. In accordance with the present invention, the active ingredient is formulated in a manner known per se, with conventional pharmaceutical carriers and / or other excipients, to form a medicament for the treatment of leg ulcers, wound healing and anti-coagulant activity.

Formulations for topical administration according to the invention may be in the form of ointments, lotions, solutions, gels, balms, creams or sprays.

Known biologically active substances used in wound healing and / or infection prevention, such as antibiotics, bacteriostats, anticoagulants, vitamins and exfoliators, form a separate class of excipients for use in the compositions of the invention. Because nicotinic acid itself is effective in the treatment of foot ulcers and other wounds, and its action is only complementary but not synergistically enhanced by other biologically active substances, it is not necessary to add further biologically active substances.

The pharmaceutical compositions according to the invention contain from 0.2 to 95% by weight of nicotinic acid. In particular, nicotinic acid content of the compositions suitable for the treatment of foot ulcer is generally not more than 50% by weight, preferably 0.5 to 15% by weight, preferably

It can be 3-10% by weight. Compositions suitable for promoting wound healing and preventing rough scarring preferably contain from 10 to 70% by weight, particularly preferably from 15 to 40% by weight, of nicotinic acid.

The carrier for the compositions may be organic or inorganic solid, semi-solid or liquid carriers conventionally used in the preparation of pharmaceutical compositions for external administration. An example of this is the following:

solid carriers are talc, urea, zinc oxide, colloidal silicon dioxide, lactose, glucose, magnesium stearate, bentonite, magnesium carbonate, and mixtures thereof;

liquid carriers: water, propylene glycol, glycerol, natural and synthetic oils;

semi-solid carriers: white petroleum jelly, waxes, natural and synthetic fats

Depending on their type, the formulations may contain, for example, the following excipients: surfactants, such as fatty soaps, fatty alcohol sulfates, alkaline soaps, polyethylene oxides; preservatives such as Nipagin M, Nipasol, benzalkonium chloride, chlorhexidine and benzoic acid; antioxidants such as BHT, BHA and ascorbic acid; buffering agents; gelling agents such as agar, tragacanth, methylcellulose, hydroxyethylcellulose and derivatives thereof, propellants such as dichlorodifluoromethane; foam consistency enhancers such as cetyl, stearyl and palmityl esters and the like.

The following examples of pharmaceutical compositions are provided:

-3HU 202109Β

Example 7 Suspensions

Nicotinic acid 10.0 g 15.0 g 30.0 g 50.0 g

Propylene glycol 90.0 g 85.0 g 70.0 g 50.0 g 5

Example 2 Ointments

Nicotinic acid 10.0 g 150.0 g 30.0 g 50.0 g 10

White Vaseline 90.0 g 85.0 g 70.0 g 50.0 g

Example 3 Spray Powders

Nicotinic acid 10.0 g 15.0 g 30.0 g 50.0 g

Talc 90.0 g 85.0 g 70.0 g 50.0 g

Example 4

Spray Powders 20

nicotinic acid salicylic Acid Alumina usts Fo-No Magnesium bicarbonate Zinc Oxide talc 10.0 g 30.0 g 3.0 g 3.0 g 9.0 g 9.0 g 30.0 g 20.0 g 30.0 g 20.0 g 20.0 g 20.0 g 25 Example 5 Powder aerosol 30 Nicotinic acid (micronized) Isopropyl myristate Urea (micronized) propellant 0.5-50% by weight 8,0-10tömeg% 5.0-10% by weight gives 100.0% by weight 35 Example 6 Emulsion nicotinic acid Surfactant fat Phase water Phase 0.5-80% by weight 0.5-7.5% by weight 10-45% by weight gives 100% by weight 40

The composition may be cationic 45 or anionic emulsifiers or nonionic surfactants (e.g., Myrj, Brij, Tween,

Span etc.), as fatty phase paraffin, lanolin, synthetic oils (Lutrol EHO, Miglyol) or natural oils (olive oil, castor oil, soybean oil, 50 cod liver oil) and as water phase water or water and water miscible polyols (glycerol, propylene glycol, etc.) .).

Example 7 55

ointments

Nicotinic acid 0.5 g 20.0 g 50.0 g

Ointment base 99.5 g 80.0 g 50.0 g

The compositions may contain, for example, an ointment base such as lanolin, petroleum jelly, polyethylene glycol of a molecular weight of from 200 to 10,000 or propylene glycol. If necessary, a surfactant with an HLB of between 15 and 17 can be added in an amount of 5-6% by weight. 65

Example 8

Ointment

Nicotonic acid 0.5-50.0 wt%

13-15 HLB emulsifier 2.0-8.0% by weight Cetyl stearyl alcohol 2.0-8.0% by weight

Fat phase 10.0-50.0% by weight

Distilled water gives 100.0% by weight

The composition may contain, for example, the substances listed in Example 6 as the fat phase. If necessary, a preservative such as benzalkonium chloride, chlorhexidine or benzoic acid may be added. Higher fat formulations preferably contain an antioxidant such as BHT, BHA or ascorbic acid.

Example 9

Ointment

Nicotinic acid 0.5-70.0% by weight

Cetyl alcohol 1.0-7.5% by weight

Fat phase 10.0-50.0% by weight

Distilled water gives 100.0% by weight

The composition may contain, for example, the substances listed in Example 6 as the fat phase. If necessary, a preservative such as benzalkonium chloride, chlorhexidine or benzoic acid may be added. Higher fat formulations preferably also contain an antioxidant

Example 10 Gel

Nicotinic acid Gel-forming Neutralizing solution Preservative Distilled water

0.5-80.0% by weight 0.3-2.0% by weight 1.0-4.0% by weight

0.05-0.2% by weight gives 100.0% by weight

The composition may, for example, be a gelling agent such as Cabopol 934, 937 or 940, or natural gelling agents such as agar, tragacanth, methylcellulose or hydroxyethylcellulose, as a neutralizing solution aqueous ammonia, aqueous sodium hydroxide solution or aqueous triethanol. amine solution, and as a preservative, for example, the substances listed in Example 7.

Example 11 Foam aerosols

nicotinic acid 0.5 g ISG 25g 50g Polawax 0.5 g 8g 8g 8g Carbowac 91, Og 62g 52g 27g propellant 8.0g 15g 15g ISG

Example 12

Emulsion aerosol formulation

nicotinic acid

Foam consistency enhancer Emulsifier Preservative Distilled water

0.5-30.0% by weight 1.5-5.0% by weight 0.5-4.5% by weight

0.05-0.2% by weight gives 100.0% by weight

The composition may contain, for example, cetyl, stearyl or palmityl esters as foam consistency enhancing mother-4HU 202109Β.

Example 13

Paste

Nicotinic acid 30-90% by weight

Carrier adl00% by weight

The composition may contain as a carrier natural and synthetic oils, fats, waxes and mixtures thereof. Antioxidants may also be added to higher fat formulations.

The results of the efficacy studies are described below.

A) Cure for Foot ulcer:

The age, gender, and age distribution of patients enrolled in the studies is presented in Table I.

Table I

Nicotine acid handled traditions tionally handled Medical history: Post-thrombotic 76 34 primary varicosity 38 10 other origin (mixed) 20 7 Breakdown by gender: male 80 30 woman 54 21 Age breakdown: In 30 years 0 1 30-60 years 40 14 Over 60 years 94 36

In all patients included in the study, the ulcer could not be treated with any other treatment (eg, surgically or plastically). After pre-cleaning the ulcer, patients were treated once daily with 10% nicotinic acid (ointment, custard powder or suspension); conventional treatment was with gentamicin, solcoseril, enogranormone, salicylic acid solution, Vioform ointment, Mikulic ointment and Debrisan powder. The development of the patients' condition is shown in Π. in Table.

II. spreadsheet

The condition of the patients Nicotine acid handled traditions tionally handled Healed 110 25 improved 16 9 Unchanged or treatment aborted 8 17

The average healing and granulation time observed in cured patients is reported in Table HL.

III. spreadsheet

Nicotine acid handled traditions tionally handled Average healing time, day 51,224.3 ± 90 ± 10.2 Average granulation time, day 30 75

B) Examination of wound healing and anti-coagulant effects:

Male rat lambs weighing 170 ± 35 g from OFA strain (LATI) were used for the study. Prior to the start of the study, the animals were quarantined for one week; the animals were provided with standard pressed mouse and rat food and tap water as desired. Healthy animals showing no clinical signs of disease were used for the studies. The studies were performed on groups of 10-10 rats.

The rats were anesthetized with 100 mg / kg of Inactin administered intravenously and 1.5-1.5 cm long skin incisions were made on the right and left sides of the animal's back. 100 mg, 15% and 95% by weight of nicotinic acid and talcum powder, respectively, were applied to the wounds on the right side, and 100 mg of talc was applied to the left wounds. The wounds were sutured with 3 stitches and fixed with a gauze-covered adhesive patch. The sutures were removed 7 days after incision. Wound healing was monitored daily and recorded

Control incisions (incisions on the left side of the animals treated with vehicle / talc only) healed for 7 to 10 days after incision with significant scab and scar formation. The wounds were free of inflammation and discharge.

From day 3 onwards, healing of wounds treated with 95% w / w nicotinic acid started spectacularly with very little sponge formation. On day 5, all wounds were completely healed.

The wounds treated with the 15% by weight nicotinic acid heat powder started to heal on day 4 and the wounds on days 6-7. day they were completely healed without scarring.

Claims (2)

CLAIMS 1. A process for the preparation of a topical pharmaceutical composition containing nicotinic acid as an active ingredient, characterized in that the active ingredient is mixed with conventional pharmaceutical carriers and / or other excipients for the treatment of leg ulcers and for the treatment of wound healing and anticancer activity. 28) 2. A method for the topical formulation comprising nicotinic acid as an active ingredient 202109Β, characterized in that the active ingredient prepared in a known manner is mixed with conventional pharmaceutical carriers and / or other excipients to form a medicament for the treatment of foot ulcer. (Priority: September 23, 1987)