BG100780A - Medicamentous form for external application and method for its preparation - Google Patents

Abstract

The medicamentous form includes Galantamin or its pharmaceutically acceptable salt as active substance in a suitable ointment base of hydrogenous type. The method for the preparation of the medicamentous form guarantees its stability. The gel can be diluted in water for reducing the concentration of the active component where it preserves its consistence. It is used for local, dosage and control stimulation of the acetylcholinomediated transmission of the nervous impulse by individual penetration in the skin or the mucous membranes or by the application of physiotherapuetical methods.

Description

The invention relates to a plaster formulation for external use based on Galantamine or a pharmaceutically acceptable salt thereof, applicable either alone or by physiotherapy methods, and to a method for preparing the formulation.

II. BACKGROUND OF THE INVENTION

Galantamine hydrobromide-based dosage forms are known for oral and parenteral administration, namely, ampoule, tablet, and syrup.

The topical application of an aqueous solution of Galantamine hydrobromide - ampoules of Nivalin is known for electrophoresis treatment. The gauze or cotton swab or hydrophilic pad is irrigated with the ampoule solution and placed on the restricted surface of the skin to be electrophoresed. It is applied to a surface of 6/6 cm or 4/9 cm with 1-2 ml of 0.25% nivalin solutio, with an intensity of 0.1

2 mA / cm - 0.2 mA / cm for 10 to 15-20 minutes, usually 15 sessions. If necessary, treatment should be repeated after 30 days. Electrophoresis is more effective with combination therapy. It is indicated in the treatment of plexitis, radiculitis, neuritis, etc.

(Mpipgpyagya Pmryapmiya Gptyaphya

QQ / 1 Ί

Thus, the external administration of ampoules containing an agent of Venus A is unacceptable, unacceptable and dangerous because the dosage regimen is inaccurate. When irrigating gauze and cotton or hydrophilic pillows, part of the ampoule solution remains on them and is lost, dripping over the patient's body, resulting in inaccuracy in dosage. The distribution of the active ingredient is uneven, with some concentrations being high in some areas and too low in others. In addition, physiotherapy procedures are performed

in single sessions, which does not ensure a uniform and constant action of the drug in the treated area. Irrigated gauze and / or cotton or hydrophilic pads are placed only in very limited places and areas, and the requirement to use physiotherapy and electrophoresis equipment limits the ability to extend treatment indications, e.g. directly on the genital organs in impotence. Administration by electrophoresis only requires, in any case, the need for qualified medical staff and special physiotherapy equipment, and the treatment is accompanied by known disadvantages of electrophoresis: in some patients there is intolerance to galvanic current; burns can occur if an overdose occurs; in acute distances it is possible to aggravate the pain syndrome; there is a risk of skin infections on the treated area using poorly sterilized hydrophilic pads. A disadvantage of electrophoresis treatment is the relatively lower penetration of the drug into the patient's body.

No known external formulation of galanthamine or a pharmaceutically acceptable salt thereof, suitable for treatment by spontaneous penetration into the skin or mucosa, or by convenient, ultra-phoresis, is known

...... l ·.

• · both by medical staff and at home and field conditions, with accurate dosage regimen and even distribution of the active ingredient over the treated area. There is no known method for preparing such a plaster dosage form.

The object of the invention is to provide a plaster dosage form for external use based on Galantamine or a pharmaceutically acceptable salt thereof, with accurate dosage options

and dosage regimen, prolonged exposure to the substance, uniform distribution of the preparation in the areas to be treated, relatively deeper penetration of the active ingredient into the body, the dosage form being administered as independently by the patient at home or in the field, and by ultra-phonophoresis, eliminating the body's overall effect on M-cholinomimetic reactions and avoiding the use of an expensive, non-intended ampoule form, and creating a method and obtaining form.

III. TECHNICAL NATURE

According to the invention, the topical dosage form contains, as active ingredient, Galanthamine or a pharmaceutically acceptable salt thereof, for example, Galantamine hydrobromide, included in solution form in a suitable hydrogel-type ointment base. The ointment base includes macrogol, 1,2-propanediol, carboxyvinylpolymer, sodium edetate, an alkalizing agent, a preservative, a suitable type of purified water, optionally a penetrant, in the following weight%: Galantamine 0.2 to 0.6 or a pharmaceutically acceptable salt thereof salt from 0.25 to 0.6, macrogol from 5.0 to 10.0, 1,2-propanediol from 10.0 to 15.0, carboxyvinylpolymer from 1.0 to 1.5, sodium edetate from 0.07 to

0.1, alkaline agent quantum satis to pH 7.0. preservative from

0.2 to 0.4, purified water of appropriate quality for a plaster base up to 100.0, optionally a penetrant of 1.0 to 10.0, optionally a flavoring, may flavored water. A solution of alkali is used. sodium hydroxide or triethanolamine, or other pharmaceutically acceptable reagent. Water is used as water with suitable properties for plastering. Dimethyl sulfoxide 1.0 - 10.0 or urea is used as a penetrant

1.0 - 3.0, Mdmei combination with electrolyte, 1.0 to 3.0, and urea 1.0 to 3.0, added to the base. Nipagin and a range of 0.2 to 0.4 or sodium benzoate of 0.2 to 0.5 are used as a preservative. If a lower concentration of the active ingredient is required, the gel can be diluted with water, while maintaining its consistency.

The method according to the invention consists in dissolving preservatives and sodium edetate in part of the water.

The carboxyvinylpolymer is dispersed in the resulting solution. The dispersion is gelled with a 20% aqueous solution with the gelling agent and towards

the aqueous polyol solution of galantamine or a pharmaceutically acceptable salt thereof is added to the finished gel. In either case, penetrants or the electrolyte may also be added with the urea.

The dosage form / preparation is to be administered as prescribed.

The penetrant formulations are modeled for self-administration. Compositions without penetrant, but with electrolyte, are modeled for introduction by ultraviophoresis.

The preparation is packed in well-sealed packages that do not interact with it, preferably membrane tubes, with a dispenser.

Store in a cool, dark place.

IV. ADVANTAGES

A plaster formulation for external use has been devised based on Galantamine or a pharmaceutically acceptable salt thereof, as well as a process for the preparation thereof. The formulation is capable of accurate dosage and dosage regimen, and a prolonged exposure to the active ingredient, avoiding the overall influence of the body with the manifestation of M-cholinomimetic reactions. It is suitable for treatment both by spontaneous penetration with or without cure-

Bin mass in the skin and / or mucous membranes, and by ultra-phoresis, with all the advantages of such treatment over the oral and steam administration of the agent. It is convenient for application both in the presence of medical staff and physiotherapy equipment, as well as in the home and field conditions by the patient. The form allows for uniform application and accurate dosing, as well as for the extension of the treated field, acting simultaneously along the length of the damaged nerve and the area innervated by it.

In addition, the type of dosage form makes it possible to expand the use of Galantamine and its pharmacokinetics.

acceptable salts for its use in sexology in some functional forms of impotence, since it is possible for the active ingredient to be applied directly and continuously to the male and female genitalia. It is also suitable for use in medical cosmetics for the revitalization of facial expressions, including by rubbing around the eyes and mouth. It is also used for first-degree domestic burns by spreading on the burned area, which improves trophy. The ability to apply it easily through spontaneous penetration of the skin repeatedly increases the use of the form to refresh, tone and nourish the skin, and therefore a beneficial effect on the psycho-emotional state of the individual. When using kdp ex ptlp η m n η r \ tl m rm nn <- »η η ntr / l

The exact dosage from the use of the ampoule form for external use is avoided. The use of expensive finished dosage form is not avoided - the ampoule form, which makes the therapy more expensive. The use of the plaster form avoids drug loading of the patient's body, but is characteristic of the oral and parenteral forms. The incorporation of Galanta Mine or its pharmaceutically acceptable salt under the form of an aqueous solution in a hydrogel-type plaster base facilitates the transport of ions in depth by ultra-phoresis.

The formulation process is easy to carry out, guarantees a stable plaster form and enables the preparation to be diluted with water to the desired concentration if necessary at a low concentration, while maintaining its gel consistency.

V. APPLICATION OF THE INVENTION

It is used for local, measurable area and volume, dosed and controlled stimulation of acetylcholine-mediated transmission of nerve impulses. It is applicable to Nakhchilikh diseases indicated for external, topical treatment with reversible acetylcholinesterase inhibitors. Peripheral nervous system diseases - neuritis, polyneuritis, mechanical nerve damage, incl. in carpal tunnel syndrome, where there are disorders of neuromuscular conduction. It is used in some forms of impotence, in medical cosmetics, in maxillofacial surgery, in sports medicine, etc. It is applied along the length of the damaged nerves and the area innervated by them. It is ^{applied in} D ^e P ^ma tology in neurodermatitis to improve trophic and innervated skin. It can be used in physiotherapy by ultra-phonophoresis.

Penetrant formulations are modeled for self-administration and non-penetrant formulations are designed for electrolyte • to to to • to

In all cases, dosing of the gel is required, given the properties of Galantamine or its pharmaceutically acceptable salt.

VI. EXAMPLES OF IMPLEMENTATION

EXAMPLE 1. COMPOSITION OF THE PHARMACEUTICAL FORM. 1.1. Galantamine 0.3 Macrogol 7.0 1,2-propanediol 13,0 p Carboxyvinylpolymer 1.0 Sodium edetate 0.08 Triethanolamine to pH 7.0 Nipagin 0.27 Range 0.03 ^Mr TO 100,0 1.1.1. Composition as in example 1.1. Dimethyl sulfoxide (ύΛ ^ Ο) 3.0 1.1.2. Composition as in example 1.1. 5.0 Dimethyl sulfoxide 1.1.3. Composition as in example 1.1. Dimethyl sulfoxide 7.0 1.1.4. Composition as in example 1.1. Dimethyl sulfoxide 10,0

1.1.5. Composition as in Example 1.1.

Urea

2.0 • 4 • ·

1.1.6. Composition as in Example 1.1.

Magnesium sulfate . 7Hg> 0

1.0

Urea

2.0

1.1.7. Composition as in Example 1.1.

Magnesium sulfate . 7H ₉ 0

0.5

Urea

3.0

1.2. Galantamine hydrobromide

0.35

Basis as in Example 1.1.

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1.2.1. Composition as in Example 1.2. Dimethyl sulfoxide 2.5

1.2.2. Composition as in Example 1.2. Dimethyl sulfoxide 5.0

1.2.3. Composition as in Example 1.2.

Dimethyl sulfoxide

7.0

1.2.4. Composition as in Example 1.2.

Dimethyl sulfoxide

10.0 • ·

1.2.5. Composition as in an example 1.2. Urea 2.0 1.2.6. Composition as in an example 1.2. m ^ 5'o ₄ . ? n _{2 about} 1.0 Urea 2.0 1.2.7. Composition as in an example 1.2. Month ₄ . ? n _{2 about} 0.5 Urea 3.0 1.3. Galantamine 0.4. Macrogol 7.5 1,2-propanediol 12,0 Carboxyvinylpolymer 1.0 Sodium edetate 0.09 Triethanolamine TO pH 7.0 Nipagin 0.2 Range 0.05 Water Yes 100,0 1.3.1. Composition as in an example 1.3. DM50 3.0 1.3.2. Composition as in an example 1.3. DM $ oh 5.0 1.3.3. Composition as in an example 1.3. flMSo 7.0

• · · ·

• · ·

1.3.4.

Composition as in Example 1.3.

DM5O

10,0

1.3.5.

Composition as in Example 1.3.

giving

2.0

1.3.6.

Composition as in Example 1.3.

mfr about ₄ . 7H ₂ 0

Urea f

1.4.

Galantamine hydrobromide

0.5

2.5

0.5 included in the base as in Example 1.3.

1.4.1. Composition as DMZO in Example 1.4. 3.0 1.4.2. Composition as DM $ 0 in Example 1.4. 4.0 1.4.3. Composition as DM $ Oh in Example 1.4. 6.0 1.4.4. Composition as DM50 in Example 1.4. 9.0 1.4.5. Composition as Urea in Example 1.4. ' ^X ' ⁵ 1.4.6. Composition as Urea in Example 1.4. 2.5

• · · · ll ·

1.4.7. Composition as in Example 1.4.

Magnesium sulfate . 7H 2 O

0.5

Urea

2.5

1.4.8. Composition as in Example 1.4.

Magnesium sulfate . 7H _? 0

1.0

Urea

2.5

EXAMPLE 2. METHOD OF OBTAINING THE AGENT.

Preservatives are dissolved in some of the water and the sodium is eaten at. The carboxyvinylpolymer is dispersed in the resulting solution. The resulting dispersion was gelled with a 20% aqueous solution of the gelling agent and water-polyol solution of galantamine or galanthamine hydrobromide was added to the finished gel.

In the case of a penetrant formulation, it is added together with the aqueous polyol solution of galanthamine or galanthamine hydrobromide.

If a lower concentration of the gel is needed, it is diluted with the necessary additional amount of water, while maintaining its gel consistency.

When using Magnesium sulfate. 7HgO in combination with urea the two ingredients are pre-mixed.

EXAMPLE 3. CLINICAL OBSERVATIONS.

Mazilkovat.a dosage form is administered clinically to patients - volunteers, contingent of Medical University Sofia, generally divided into 4 groups:

- patients with peripheral polyneuropathy (PPNP) and complaints of tingling of the fingers, without carpal tunnel syndrome (SKT);

- patients with PDNP and SCT without surgery for SCT;

- patients with PPNP after surgery for SCT;

- patients with isolated complaints of tremors, insensitivity or pain in the arm with arterio-venous fistula.

The ointment formulation is applied to the forearm, palms and fingers by smearing a thin layer and rubbing in the morning and evening, at a dose of 0.015 g of active substance or 0.03 g per day for 30 days.

RESULTS:

All patients received subjective relief of complaints, until the pain and / or pain disappeared completely. Sensitivity to warm, cold and touch has improved, and active movements have been restored.

Patients with uncomplicated peripheral polyneuropathy and those with isolated disorders in the arteriovenous fistula arm responded best and most rapidly. Patients with SCT without surgery were less affected. Patients with SST surgery received rapid relief of pain syndrome and sensation.

EXAMPLE 4. PLACE OF APPLICATION.

- in the case of medical evidence in the field of neurology, lubrication is performed by rubbing along the damaged nerve and / or the area innervated by it. Maybe in the vertebrae at the point of origin of the relevant peripheral nerves;

- in medical cosmetics indications, the lubrication is performed by rubbing around the eyes and / or mouth on the small wrinkles or on the skin area, which should be refreshed, toned or improved nourishment;

- in the field of sexology, the drug is administered by smearing directly on the genitals.

EXAMPLE 5. DOSES AND DOSES BY RIVS. DRUG INSERT

FORM.

• · ft ft ft ft • ft ft

The preparation is prescribed by a doctor. It's smeared

2-3 times a day in a layer up to 0.05 mg / cm in treatment without physiotherapy procedures - with self-administration, with spontaneous penetration of the preparation with ice. Using physiotherapy methods, the preparation is applied in a layer up to 25 mg / cm3.

In patients with chronic renal insufficiency without hemodialysis, the application is performed once daily. In patients undergoing hemodialysis, the dosage is 2 times daily as the active ingredient is eliminated by dialysis.

The preparation can be administered both once and for 1-2 months, depending on the disease process.

Claims (2)

Patent Claims' CLAIMS 1. An external application for oral administration, characterized in that it contains, as an active ingredient, Galanthamine or a pharmaceutically acceptable salt thereof, for example, Galantamine hydrobromide, included as a solution in a suitable hydrogel-type ointment base, including macrogol, 1 , 2-propanediol, carboxyvinylpolymer, sodium edetate, alkalizing agent, preservative, suitable type of purified water, optionally penetrant or electrolyte, optionally flavoring, may flavored water, in the following weights and%: Galantamine from 0.2 to 0.6 or a pharmaceutically acceptable salt thereof from 0.25 to 0.6, macrogol from 5.0 to 10.0, 1.2-propanediol from 10.0 to 15.0, carboxyvinylpolymer from 1.0 to 1.5, sodium edetate from 0.07 to 0.1, alkalizing agent quantum satis to pH 7.0, preservative from 0.2 to 0.4, purified water with suitable properties for plaster base up to 100.0, optionally a penetrant of 1.0 to 10.0, which is an alkalizing agent using a solution of sodium hydroxide or triethanolamine, or other pharmaceutically acceptable reagent, and dimethyl sulfoxide and xylchurkia 1.0 as the penetrant; 10.0 and / or urea 1.0-3.0 and, as an electrolyte, magnesium sulfate .7HgO from 0.05 to 1.0 alone or in combination with urea 1.0-3.0 added to the base; as a preservative, nipagine and a range of 0.2 to 0.4 or sodium benzoate of 0.2 to 0.5 are used; if a lower concentration of the active ingredient is required, the gel may be diluted with water, while maintaining its consistency. A method for the preparation of the ointment dosage form according to claim 1, characterized in that the preservatives and sodium edetate are dissolved in part of the water, and in the semi-dispersion is gelled with a 20% aqueous solution with the gelling agent and onto the finished gel an aqueous polyol solution of galanthine or its pharmaceutically acceptable salt is added, in which case either the penetrants or the electrolyte may be added, with the urea, the penetrant compositions being modeled for self-administration and the compositions without penetrant, but with the electrolyte - for the newspaper ultraviophoresis.