Pharmaceutical preparation

The invention provides a pharmaceutical preparation in a gel form exhibiting a disinfecting and therapeutic activity.

GB 2068225 discloses dermatological compositions comprising hydrogen peroxide in a form of an aqueous solution and a gelling agent. As gelling agents, the following substances are taught in the specification: carboxyvinyl polymers, colloidal silicates, natural gums, starch, cellulose derivatives.

US 4401651 discloses a pharmaceutical preparation for application on wounds comprising gentian violet as an active agent and polyethylene glycol as a gelling agent. The document discloses also a preparation comprising iodine-polyvinylpyrrolidone complex as an active agent and polyethylene glycol.

The Polish patent application No P-332783 discloses a gelatinous pharmaceutical preparation comprising perhydrol or gentian violet, or iodine as active agents, combined with polyvinylpyrrolidone (iodopoly vinylpyrrolidone), with a viscosity of from 2000 to 10000 cnp. Hydroxycellulose was used as a gelling agent.

Preparations known from the prior art have a form of gel, which facilitates their precise application onto spots requiring treatment with the preparation, such as injuries, abrasions etc. A condensed preparation may be applied precisely onto a wound, excluding healthy skin around the affected spot. Critical for the process for the manufacture of such products and for their usability is the kind of gelling agent. It is important for the gelling agent to allow for thorough mixing of the components in a liquid form and provide a sufficient stability of the final preparations. In the case of active agents of high chemical and biological activity, such as e.g. hydrogen peroxide, numerous gelling agents are excluded.

The problem was solved by a preparation of the present invention.

A pharmaceutical preparation in a gel form, comprising hydrogen peroxide or gentian violet, or iodine as an active agent, a gelling agent, a solvent and optional auxiliary agents is provided, which comprises as a gelling agent a block copolymer of ethylen oxide and propylen oxide of formula HO(C ₂ H ₄ O) _a (C ₃ H ₆ O) _b (C ₂ H ₄ O) _a H, wherein a is an integer from 6 to 160, and b is an integer from 8 to 100, and the preparation comprises the gelling agent in amounts of from 10 to 40 parts by weight, and the active agent in amounts of from 0,5 to 15 parts by weight.

Preferably the preparation comprises gelling agent of formula HO(C ₂ H ₄ O) _a (C3H ₆ O)b(C ₂ H4θ) _a H, wherein a is an integer from 80 to 120, and b is an integer from 37 to 80.

As the solvent, the preparation preferably comprises water and/or an aliphatic alcohol, most preferably ethanol, in amounts of from 10 to 80 parts by weight.

As the auxiliary agent, the preparation preferably comprises a pH regulator, most preferably orthophosphoric acid, in such amounts that pH of the preparation is from 3,5 to 4,5.

As the auxiliary agent, the preparation preferably comprises a chelating agent, most preferably disodium edetate, in amounts of 0,1-0,5 parts by weight.

As the auxiliary agent, the preparation preferably comprises aliphatic alcohol, most preferably ethanol, in amounts of from 3 to 10 parts by weight.

The preparation of the invention preferably comprises the second active agent with the topical anesthetic activity, in amounts of from 0,1 to 10%. Most preferably as the anesthetic agent, the preparation comprises a substance selected from the group comprising benzocaine, lidocaine, mesocaine, mepivacaine, bupivacaine, articaine, diclonine, carbocaine.

The preparation of the invention, by the use of the block copolymer of ethylen oxide and propylen oxide as a gelling agent, acquires thermoreversible properties. It means the entirely reversible change of form depending on the temperature: from a liquid into a gel and again into a liquid. This property of the preparation of the invention is beneficial in many ways. Firstly, during the manufacture of the preparation the components are combined at below 15°C and the mixture is deaerated, a process being more efficient for liquid mixtures. The temperature is then increased to the room temperature, resulting in a conversion of the mixture into a gel form. Filling of unit dosage forms with the preparation can be carried out, when the preparation is a setting liquid or an already set gel. Secondly, the ready preparation is stable during at least 24 months and at a wide temperature range. The preparations examined at temperatures from 5 ⁰ C to 4O ⁰ C during 24 months retained the required contents of the active substance and the gel form at the proper temperature range during the entire

examined period. Thirdly, the density of gel can be controlled freely by proper choice of ethylen oxide and propylen oxide segments and their ratio. Thermoreversibility of the preparation has no impact on the contents of the active substance - after a change of the preparation form into the liquid form resulting from the temperature increase or decrease and returning to the gel form the contents of the active substance remains unchanged. Stability of the preparation at a wide temperature range allows to use the preparation in different climatic zones. The addition of the analgesic allows for a simultaneous disinfection of injuries and lessening or elimination of the accompanying pain.

The invention is further illustrated by the working examples. Example 1.

15 kg of water and 15 kg of hydrogen peroxide as a 30% aqueous solution and 7,5 kg of ethanol of 96 proof are mixed together. A solution of 0,15 kg disodium edetate in 80 kg of water is simultaneously prepared, the solution is cooled down to below 15°C and a gelling agent of formula HO(C ₂ H ₄ O) ₃ (C ₃ H ₆ OX(C ₂ H ₄ O) ₃ H, wherein a = 101 , b = 56, in an amount of 33 kg is introduced. After mixing the components, both solutions are combined, stirred for Ih, orthophosphoric acid (about 20Og) is added to reach pH level of 3,5-4,5 and stirred for additional 2 h in vacuo, at about 15°C. The composition is then left for complete gelling or formulated directly into unit dosage forms. The perhydride preparation in gel with 3% concentration of the active agent is obtained. Example 2.

15 kg of water and 15 kg of hydrogen peroxide as a 30% aqueous solution and 7,5 kg of ethanol of 96 proof containing 4,5 kg of lidocaine are mixed together. A solution of 0,15 kg disodium edetate in 75,5 kg of water is simultaneously prepared, the solution is cooled down to below 15 ⁰ C and a gelling agent of formula HO(C ₂ H ₄ O) ₃ (C ₃ H ₆ O) ₁₅ (C ₂ H ₄ O) ₃ H, wherein a - 101, b = 56, in an amount of 33 kg is introduced. After mixing the components, both solutions are combined, stirred for Ih, orthophosphoric acid (about 20Og) is added to reach pH level of 3,5-4,5 and stirred for additional 2 h in vacuo, at about 15°C. The composition is then left for complete gelling or formulated directly into unit dosage forms. The perhydride preparation in gel with concentration of the active agents of 3% (hydrogen peroxide) and 3% (lidocaine) is obtained. Example 3.

1 kg of gentian violet and 5 kg of benzocaine are dissolved in 64 kg of ethanol of 96 proof and cooled down to below 15°C. A gelling agent (dissolved in 10 kg of water) of formula HO(C ₂ H ₄ O) ₃ (C ₃ H ₆ O) ₅ (C ₂ H ₄ O) ₃ H, wherein a = 141 , b = 44, in an amount of 20 kg is then

introduced and the mixture is stirred for 2 h in vacuo at about 15 ⁰ C. The composition is then left for complete gelling or formulated directly into unit dosage forms. The preparation of gentian violet in gel with the active agent concentration of 1% (gentian) and 5% (benzocaine) is obtained.

Example 4.

1 kg of potassium iodide and 3 kg of iodine are dissolved in 56 kg of ethanol of 96 proof.

Simultaneously, 10 kg of water is cooled down to below 15°C and a gelling agent of formula

HO(C ₂ H ₄ O) ₃ (C ₃ H ₆ O) ₅ (C ₂ H ₄ O) ₃ H, wherein a=64, b=37, in amounts of 30 kg is introduced.

After mixing the components, both solutions are combined and stirred for additional 2 hrs in vacuo at about 15°C. The composition is then left for complete gelling or formulated directly into dosage forms. The iodine in gel with the active agent concentration of 3% of iodine and

1% of potassium iodide is obtained.

Example 5.

10 kg of PVP-Iodine is slowly added to 10 kg of propylene glycol with constant stirring by means of an anchor stirrer. The mixture is heated to 60°C and stirred for about 30 minutes until homogeneous. The mixture is then cooled to below 15°C and a gelling agent of formula

HO(C ₂ H ₄ O) ₃ (C ₃ H ₆ O) ₅ (C ₂ H ₄ O) ₃ H, wherein a=101, b=56, in an amount of 20 kg, dissolved in

DI water in an amount of 60 kg is added, followed by stirring for 3 hrs in vacuo at 15°C until the gel is homogeneous. The gel with the active agent concentration of 10% is obtained.

Example 6.

The preparations obtained according to Example 1 were tested for stability in a climatic chamber, at 40 ⁰ C, and humidity of 75°, for 24 months.

The preparations were stable upon storage within the test period.

The results are presented in the table below.

Example 7.

The preparations obtained according to Example 1 were tested for stability in a climatic chamber, at 5 ⁰ C, for 24 months.

The preparations were stable upon storage within the test period.

The results are presented in the table below.

Example 8, comparative

The preparations were prepared as in Example 1 except that as the gelling agent, carboxymethylcellulose (trade name Tylopur CB 3000 Gl) was used. The preparations were tested for stability in a climatic chamber, at 25°C and a humidity of 60° for 18 months. After 12 months the preparations were irreversibly turned from a gel to a liquid form, and the contents of the active substance was decreased to below the normal required level. The results are presented in the table below.