DE3340347A1 - Use of flurbiprofen and ibuprofen - Google Patents

Abstract

The use of flurbiprofen (3-fluoro-4-phenylhydratropic acid) or ibuprofen (p-isobutylhydratropic acid) or their salts or esters for controlling infections caused by herpes viruses of types I and II by systematic administration or topical application is described. Suitable dosage forms are likewise described.

Description

Use of flurbiprofen and ibuprofen

Use of Flurbiprofen and Ibuprofen The invention relates to a new application of the known compounds flurbiprofen (3-fluoro-4-phenylhydratropic acid) and ibuprofen (p-isobutylhydratropic acid) including its salts or esters. These compounds are suitable for prophylactic and therapeutic treatment of herpes viruses types I and II by systemic administration or topical Application.

Flurbiprofen, a non-steroidal anti-inflammatory or anti-inflammatory drug is used in rheumatic and degenerative diseases of the joints and to reduce the stickiness of (blood) platelets.

From ibuprofen, which is also known to be an anti-inflammatory or non-steroidal adverse drug drug is known to be used for Treatment of various medical findings, e.g. inflammation, arthritis, Toothache, to reduce the stickiness of the (blood) platelets and to treat suitable for heart attacks.

Te-Wen Chang is reported in "Journal of Infection" 2, pp. 374-376 (1980) the oral administration of ibuprofen to children with primary herpes simplex infection described.

The treatment of herpes simplex virus relapses is in "CUTIS", Volume 30 (October 1982).

Herpes virus type I "here and below herpes simplex virus Type I "to understand.

Under NHerpes virus type II "here and in the following is herpes simplex virus Type II "to understand.

According to the invention, the active compounds used are flurbiprofen (3-fluoro-4-phenylhydratropic acid) and ibuprofen (p-isobutylhydratropic acid) including its alkyl esters with 1 to including 8 carbon atom (s) in addition to the isomeric forms and the pharmacological acceptable salts are used.

The esters can be methyl, ethyl, propyl, isopropyl, Act butyl, isobutyl, tert-butyl, pentyl or octyl esters.

Pharmacologically acceptable salts are, for example, the alkali metal, Alkaline earth metal and ammonium salts.

The preparations provided according to the invention are preferably used for systemic administration to humans and animals in the form of unit doses or Dosing units such as tablets, capsules, pills, powders, granules, suppositories, sterile parenteral solutions or suspensions, sterile non-parenteral solutions or suspensions and oral solutions or suspensions and the like in appropriate amounts of active ingredient. Topical forms of application are ointments, jellies, creams, Lotions, sprays, shower preparations, etc.

For oral administration it can be either solid or liquid forms can be prepared by dosing units.

Powder is obtained by simply crushing or grinding the active one Ingredient to a suitably fine size and blending with one in the like Way crushed or ground extender. The extender can consist of one edible carbohydrates such as lactose or starch. Appropriately is a sweetener or sugar and a (good) tasting bl is used.

Capsules are obtained by preparing a powder mixture as described Way and filling the same preformed gelatin shells. Appropriately is add a lubricant to the powder mixture before filling as an aid for the filling process, e.g., talc, magnesium stearate, calcium stearate and the like are added.

Soft gelatin capsules are obtained by mechanical encapsulation of a Slurry the active ingredients with an acceptable vegetable oil, lighter liquid petroleum jelly or some other inert bl or triglyceride.

Tablets are obtained by preparing a powder mixture, granulating or crushing, adding a lubricant and compressing the whole into tablets.

The powder mixture is obtained by mixing an appropriate one Way of crushed active ingredient with an extender or a (powder) base, such as starch, lactose, kaolin, dicalcium phosphate, etc.

The powder mixture can be moistened with a binder, e.g. corn syrup, a gelatin solution, a methyl cellulose solution or acacia slime, and Granulate by pressing through a sieve. As alternative for granulation, the powder mixture can also be comminuted in that it is through the tablet machine is sent and the obtained, incompletely formed Tablets are broken or crushed into pieces. The pieces can then to prevent sticking to the tableting tools by adding stearic acid, of a stearate, talc or a mineral oil made slippery "or" lubricated " will. The lubricated "or" lubricated "mixture eventually becomes tablets pressed.

The tablets can expediently be provided with a protective coating Form of a sealing or enteric shellac coating, a sugar or methyl cellulose coating and a carnauba wax polish coating be provided.

There can also be flowable unit dosage forms for oral administration, e.g. syrups, elixirs and suspensions, each of which is a teaspoonful " contains a given amount of active ingredient for administration. The water soluble Shapes can be used to prepare a syrup along with sugar, flavorings and dissolve preservatives in an aqueous vehicle. You get an elixir using a w> 3 alcoholic carrier with suitable sweeteners along with a flavor. Of the insoluble forms can be used together with a suitable carrier with the inclusion of a suspending agent, e.g. acacia gum, Tragacanth, methyl cellulose and the like suspensions are produced.

Flowable unit dosage forms are used for parenteral administration from an active stock part and a sterile carrier, preferably Water. The active ingredient can vary depending on the form and concentration required either suspended or dissolved in the vehicle. When preparing solutions The water-soluble active ingredient can be dissolved in water for injection and before filling into suitable vials or ampoules and sealing them sterilized by filtration. Appropriately, aids are in the carrier, e.g. local anesthetics, preservatives and buffers, dissolved. Parenteral suspensions is obtained in practically the same way, but with the active ingredient instead to be dissolved in the carrier is suspended therein. In this case, however filtration sterilization is not carried out. The active ingredient can in this case before suspending in the sterile vehicle by the action of Ethylene oxide can be sterilized. Appropriately, the preparation becomes more even Distribution of the active ingredient a surfactant or wetting agent added.

In addition to oral and parenteral administration, the Use rectal and vaginal routes of administration. For example, the active Component can be administered in the form of a suppository. To make relevant Preparations can be carriers with an MP at about body temperature or easily soluble Carriers are used. Examples of substances that can be used as carriers are cocoa butter and a wide variety of polyethylene glycols (Carbowaxes).

Topical ointments are obtained by dispersing the active ingredient in a suitable ointment base such as petrolatum, lanolin, a polyethylene glycol or a mixture thereof. Appropriately, the active Ingredient before dispersing in the ointment base using a colloid mill using light-colored liquid petroleum jelly as a pulverizing aid "fine" distributed. Topical creams and lotions are obtained by dispersing the active Ingredient in the blood phase prior to emulsifying the blood phase in water.

The term "unit dose" or "dose unit" or "dosage unit" stands for physically separated entities that are administered as a single dose to humans and animals can be administered. Each unit contains besides the required pharmaceutical Extender, carrier or diluent, any one for bringing about the desired ones amount of active material given therapeutic effect. The rules for the relevant dosage units are dictated and are directly dependent on a) the special properties of the active material and the desired effect and b) the rules that are familiar to the galenical expert regarding the manufacture of a preparation form of such active material for administration to humans and animals.

Examples of suitable dosage units are tablets, capsules, pills: Suppositories, powder packets, granules, cachets, coated tablets, full teaspoons, E spoonful, dropper full, ampoules, vials, subdivided multiples of the above Administration forms and other administration forms.

With systemic administration of flurbiprofen or ibuprofen or of their salts or esters on humans can be found in the most effective way Treating herpes virus types I and II wounds and relapses Reduce. Topical applications represent suitable prophylactic measures.

Virus relapses occur after the primary infection wounds have healed on. The relapse is not the result of renewed infection, but occurs spontaneously (without infectious contact) presumably as a result of stress.

The active compounds used according to the invention reduce or prevent relapses when administered systemically.

For the treatment of infections with herpes viruses of types I and II one uses the same amounts of flurbiprofen or its salts and esters as in the treatment of other conditions in which flurbiprofen has been shown to be effective Has. As a rule, about 0.25 mg to about 5.0 mg / kg of body weight is administered and day in a single dose or in several doses or up to 300 mg / day in several Doses to adults. In the case of topical application, the dose is active Ingredient about 1 to about 20% w / w.

For the treatment of infections with herpes viruses of types I and II one uses the same amounts of ibuprofen or its salts and esters as with the treatment of other conditions in which ibuprofen has been shown to be effective. As a rule, about 2.5 mg to about 50 mg / kg of body weight and day are administered in a single dose. With topical application, the concentration is sufficient Active ingredient from about 1 to about 20% w / w.

The following examples are intended to illustrate the invention in more detail.

EXAMPLE 1 1 - Hard gelatine capsules Made up of the following ingredients: Flurbiprofen 50 g lactose 100 g corn starch 20 g talc 20 g magnesium stearate 2 g are 1000 double hard gelatin capsules for oral administration with 50 mg each Flurbiprofen produced.

During the production of the capsules, this is done with the help of an air micronizer finely divided flurbiprofen added to the other finely powdered ingredients, whereupon the whole thing is mixed thoroughly and encapsulated in the usual way.

The capsules obtained are suitable for oral administration of one Capsule; 4 times / day for the treatment of infections with herpes viruses of types I and II.

When replacing the 50 g Flurbiprofen are used in the manner described by 25, 75 or 100 g flurbiprofen capsules each with 25, 75 or 100 mg flurbiprofen manufactured.

EXAMPLE 1 2 - Soft gelatin capsules by suspending each 25 mg of flurbiprofen, finely divided with the help of an air micronizer, in 0.5 ml Corn oil (encapsulation aid) and encapsulate the resulting mixture one-piece soft gelatin capsules for oral use, each containing 25 mg flurbiprofen manufactured.

The capsules obtained are suitable for oral administration of two Capsules times / day for the treatment of infections caused by herpes viruses of types I and II.

Example 1 3 - Tablets Made from the following ingredients: Micronized Flurbiprofen 100 g lactose 75 g corn starch 50 g magnesium stearate 4g light liquid Vaseline 5 g, 1000 tablets are made with 100 mg flurbiprofen each.

When producing tablets, this is done first with the help of an air micronizer finely divided Flurbiprofen added to the other ingredients, whereupon the whole thing is thoroughly mixed and crushed. The pieces obtained in this way are granulated by pressing through a No. 16 sieve, whereupon the obtained granules is compressed into tablets with 100 mg flurbiprofen each.

The tablets obtained are suitable for oral ingestion of one Tablet 3 times / day for the treatment of infections caused by type I herpes viruses and II.

When replacing the 100 g of flurbiprofen, as described above with 25 or 50 g flurbiprofen tablets each containing 25 mg or 50 mg flurbiprofen manufactured.

Example 1 4 - Oral suspension consisting of the following ingredients: Flurbiprofen, aluminum salt, micronized 20 g citric acid 2 g benzoic acid 1 g Sucrose 700 g tragacanth 5g lemon oil 2g made up with deionized water 1000 ml becomes 1000 ml of an aqueous suspension for oral ingestion containing 100 mg Flurbiprofen, aluminum salt prepared per teaspoonful (5 ml).

During the preparation the citric acid, benzoic acid ' the sucrose, tragacanth and lemon oil dispersed in so much water that 850 ml of suspension can be obtained. Then this is done with the help of an air micronizer Finely distributed aluminum salt of the flurbiprofen is stirred into the syrup until it is in it is evenly distributed. Finally, it is made up to 1000 ml with water.

The oral suspension is suitable when administered in one dose of a teaspoonful (5 ml) 3 times / day to fight infections of herpes viruses of types I and II.

Example 5 From the following components: Flurbiprofen, Sodium salt 150 g made up to 1000 ml with water for injections is a sterile aqueous solution for parenteral (IV) injection with 150 mg flurbiprofen, Sodium salt prepared per 1 liter.

Sterilized flurbiprofen, sodium salt, is added to the sterilized water entered, whereupon the whole thing is filled into sterile containers and sealed therein will.

The aqueous solution obtained is suitable in a dose of 1 liter every 12 hours for the treatment of infections caused by herpes viruses of types I and II.

Example 1 6 - Cream Made from the following ingredients: Flurbiprofen 50 g glyceryl monostearate, self-emulsifying 150 g Spermaceti 100 g propylene glycol 50 g polysorbate 80 5 g methyl paraben 1 g made up with deionized water 1000 ml are prepared 1000 g of a topical cream.

During the preparation, the glyceryl monostearate and spermaceti are first used melted at a temperature of 70 -800C. The methyl paraben is roughly 500 g of water dissolved, whereupon the resulting solution at a temperature from 75 - 800C in the given order with propylene glycol, polysorbate 80 and Flurbiprofen is added. Now the methyl paraben mixture is slowly under constant Stir into the glyceryl monostearate and spermaceti melt. The addition takes at least 30 minutes with constant stirring until the temperature has reached 40 - 75 C has fallen. The pH of the finished cream is adjusted by adding 2.5 g of citric acid and 0.2 g of dibasic sodium phosphate in about 50 g of water adjusted to 3.5. Finally enough water is added to bring the final weight to 1000 g will.

The preparation is stirred to allow it to cool and solidify remains homogeneous.

The cream obtained is suitable for application on the wounds Treatment of wounds caused by herpes viruses of types I and II. Through application prophylaxis is achieved before the infestation.

B e 1 s p i e 1 7 - Hard gelatine capsules Made of the following ingredients: Ibuprofen 100 g lactose 100 g corn starch 20 g talc 20 g magnesium stearate 2 g 1000 double hard gelatin capsules for oral administration with 100 mg ibuprofen each manufactured.

During the capsule production this is done with the help of an air micronizer finely divided ibuprofen added to the other finely powdered ingredients, whereupon the whole thoroughly mixed and in the usual known manner is encapsulated.

The capsules obtained are suitable for oral administration of two Capsules 4 times / day for the treatment of infections with herpes viruses of types I and II.

Replacing 100 g of ibuprofen is obtained in the manner described with 300, 400 or 600 g ibuprofen capsules each with 300, 400 or 600 mg ibuprofen.

EXAMPLE 1 8 - Soft gelatin capsules By suspending with the aid an air micronizer finely divided ibuprofen in 0.5 ml corn oil (encapsulation aid) and encapsulating the whole, one-piece soft gelatin capsules for oral use are obtained Take with 300 mg ibuprofen each time.

The capsules obtained are suitable for oral administration of two Capsules 4 times / day to combat infections caused by herpes viruses of types I and II.

Example 1 9 - Tablets Made from the following ingredients: Ibuprofen, micronized 300 g lactose 75 g corn starch 50 g magnesium stearate 4g light liquid Vaseline 5 g, 1000 tablets are made with 300 mg ibuprofen each.

During tablet production, this is done with the help of an air micronizer finely divided ibuprofen added to the other ingredients, whereupon the whole thing is thoroughly mixed and crushed. The pieces obtained are through Granulated by pressing through a No. 16 sieve, whereupon the resulting granules become Tablets containing 300 mg ibuprofen each are compressed.

The tablets obtained are suitable for oral administration of one or two tablets 4 times a day for the treatment of infections caused by herpes viruses of types I and II.

As described above, when using 400 resp. 600 g ibuprofen instead of the 300 g ibuprofen tablets, each with 400 mg or 600 mg ibuprofen.

Example 1 10 - Oral suspension consisting of the following ingredients: Ibuprofen, aluminum salt, micronized 20 g citric acid 2 g benzoic acid 1 g sucrose 700 g tragacanth 5g lemon oil 2g made up to 1000 ml with deionized water 1000 ml of an aqueous suspension for oral ingestion with 100 mg ibuprofen, Aluminum salt prepared per teaspoonful (5 ml).

When preparing the suspension, the citric acid, Benzoic acid, Sucrose, tragacanth and lemon oil are dispersed in enough water that 850 ml Suspension can be obtained. Then it is finely divided with the help of an air micronizer The ibuprofen aluminum salt is stirred into the syrup until it is evenly distributed is.

Finally, the whole thing is made up to 1000 ml with water.

The suspension obtained is suitable for administration of a teaspoonful (15 ml) 4 times / day to combat infections caused by herpes viruses of types I and II.

Ex. 1 11 From the following ingredients: Ibuprofen, sodium salt 350 mg of water for injection made up to 1000 ml becomes a sterile aqueous Solution for parenteral (IV) injection with 350 mg ibuprofen, sodium salt per liter prepared.

Sterilized ibuprofen, sodium salt is added to the sterile water, whereupon the whole thing is filled into sterile containers and sealed therein.

The aqueous solution obtained is suitable in a dose of 1 liter every 8 hours for the treatment of infections caused by herpes viruses of types I and II.

B e i s p i e 1 12 - Cream composed of the following ingredients: Ibuprofen 50 g glyceryl monostearate, self-emulsifying 150 g Spermaceti 100 g propylene glycol 50 g Polysorbate 80 made up to 5 g methyl paraben ig with deionized water 1000 g 1000 g of a topical cream are prepared.

When preparing the cream, the glyceryl monostearate and Spermaceti melted at a temperature of 70 -0 80 C. Furthermore, the methyl paraben dissolved in about 500 g of water. The solution obtained is at 0 a temperature of 75 - 80 ° C in the order given with propylene glycol, polysorbate 80 and ibuprofen offset. Finally, the methyl paraben mixture is slowly added with constant stirring stirred into the glyceryl monostearate and spermaceti melt. The encore lasts at least 30 min with continuous stirring, 0 until the temperature has reached 40 - 45 C has fallen. The pH of the finished cream is determined by incorporating 2.5 g Citric acid and 0.2 g sodium dibasic phosphate in about 50 g water to 3.5 set. Finally, the whole thing is mixed with water to a final weight of 1000 g filled up. The preparation is stirred to keep it homogeneous until it cools and wr + arren to keep.

The cream obtained is suitable for application to the wounds Treatment of wounds caused by herpes viruses of types I and II. When applied Prophylaxis can be achieved before the infestation.

EXAMPLE 13 According to Examples 1 to 12, one obtains when using methyl, ethyl, isopropyl or octyl esters or sodium, potassium or ammonium salts of the compounds used in the examples mentioned, preparations with equimolar amounts of the esters or salts.

Claims (3)

PATENT CLAIMS Use of p-isobutylhydratropic acid, 3-fluoro-4-phenylhydratropic acid or an alkyl ester of 1 to 8 carbon atom (s) inclusive including the isomeric forms or pharmacologically acceptable salts thereof in the prophylactic or therapeutic treatment of herpes viruses of the types I and II. 2. Use of p-isobutylhydratropic acid according to Claim 1. 3. Use of 3-fluoro-4-phenylhydratropic acid according to Claim 1.