Delivery system in the form of gel for local application

FIELD: pharmaceutics.

SUBSTANCE: the suggested composition has got viscosity being below of about 15000 cP and pH being approximately 3.0-9.0 for treating human skin diseases. He suggested composition consists of (a) therapeutically efficient quantity of, at least, one compound being useful in treating the above-mentioned disease; (b) pharmaceutically acceptable, partially bound polymer of polyacrylic acid being compatible with the compound; (c) not obligatory, a solvent being mixed with water, (d) not obligatory, a conserving agent, (e) not obligatory, a component of butyric phase and acceptable surface-active substance, and (f) water. The suggested composition is useful to treat inflammatory skin disease, acne or acne erythematosa. The composition of low viscosity has got its advantage in the fact that it is applied more accurately when in contact with a container that doses the composition in the form of drops.

EFFECT: higher efficiency of application.

23 cl, 15 ex, 19 tbl

 

The SCOPE of the INVENTION

This invention relates to a composition for the treatment of skin diseases in humans and method of using and manufacturing such compositions.

The LEVEL of TECHNOLOGY

Skin diseases are a common problem in childhood, in adolescence and in adulthood. Skin diseases can include, for example, acne, inflammatory diseases such as atopic dermatitis or red acne.

The ordinary acne (acne vulgaris) is a follicular disease characterized by the inflammation of hair follicles and sebaceous glands, such as comedones, papules, pustules, cysts and nodules. The disease predominantly of adolescence (and often cause emotional distress), acne is generated by endogenous and is the result of multifactorial influences. Main progressive factors in the development of acne include hyperkeratosis of the follicular epithelium, increased production of sebum and the growth of Propionibacterium acnes. These factors primarily responsible for hyperkeratosis lining layer of follicles, including the retention of keratin and sebum, and free fatty acid by - products of the metabolism of P. acne, which can lead to inflamed acne papules and pustules.

Although acne can be influenced by exogenous and hormonal factors, issled the study was focused on eliminating P. acne, the most common causes of inflammation. To date, the pathogenesis of acne is not fully understood, and to date there is no method of treatment of this disease. Many drugs for systemic and local applications, such as tetracycline used to treat and control acne. None of them, however, has not led to success.

Acne treatment is a typical example premedication treatment”based on what the doctors use the simultaneous treatment of different means. Search for the best acne treatment has been extended and has not been interrupted in the last few decades. Improved cosmetic properties to maintain eligibility for the user, the use of local treatment system instead of drugs to reduce toxicity and side effects and the introduction of new medicines and drugs is important for the treatment of acne.

On first use of the antibiotic, erythromycin for acne treatment said Fulton (Fulton, J.E.Jr. and Pablo, G.Topical antibacterial therapy for acne. Study of the family of erythromycins. Arch. Dermatol. 110: 83-86, 1974). Local application of such potent tools gives the advantage of reduced side effects, especially those caused by the action of systemic drugs, such as nausea, gastrointestinal disorders, diarrhea, and vaginal excessive time is egenie yeast fungi.

Lincomycine antibiotics were used for the local treatment of acne (U.S. patent No. 3969516). Lincomycin commercially made decision Upjohn Co. (now Pharmacia & decision Upjohn) in the form of a solution, gel, lotion and swabs of cleocin T (Cleocin). Gel cleocin T was improved solution cleocin T by eliminating alcohol and easy application on the skin to treat acne. This gel has a basis of carbomer 934, NF.

Atopic dermatitis is a polygenic disease with an inherited predisposition, which is strongly influenced by environmental factors. This condition affects infants, children, adolescents and adults and is allergic in nature. The distribution is symmetrical, usually involving the face, neck and area of the bend. Atopic dermatitis is a chronic, recurrent and usually with the presence of itching. Local treatment often includes local application of corticosteroids, such as desonide, hydrocortisone valerate, fluoqinolona acetonide, triamcinolone acetonide, betamethasone valerate, hydrocortisone butyrate, halobetasol propionate, betamethasone dipropionate, clobetasol propionate, diflorasone diacetate, fluticasone propionate, budesonide, or the like.

Red acne is a chronic inflammatory skin rash on nose, face and other krasney the x areas of the skin. The disease is most common in women in middle age and is characterized by erythema, papules, pustules (pimples), telangiectasia and enlarged sebaceous glands. The main etiology is not entirely clear; however, vasomotor lability and menopause are predisposing factors. The microorganism Demodex folliculorum is often detected in the content inflamed pustular follicles and possibly plays a role in this skin disease. Treatment includes topical application of metronidazole and oral antibiotics tetracycline type.

BRIEF description of the INVENTION

One aspect of the present invention is a composition having a pH from about 3.0 to about 9.0 in, and a viscosity of less than about 15,000 centipoise (CP), for the treatment of skin diseases in humans. The composition contains (a) a therapeutically effective amount of at least one compound suitable for the treatment of such disease, (b) a pharmaceutically acceptable polymer is polyacrylic acid that is compatible with this connection, (C) optionally, mixed with water, the solvent, (d) optionally, a preservative, (e) optionally, an oil phase and surfactant, and (f) water.

Another aspect of this invention is the composition described above, in combination with the container, which is exactly on the indicates excess portion of the composition to a patient for local use.

Another aspect of this invention is the composition described above in conjunction with the accompanying instructions for use in the treatment of skin diseases.

Another aspect of the present invention is a method of treatment of skin disease in humans, comprising applying the composition described above, the affected area of skin of a subject having such a disease in the quantity and for a time sufficient to improve the condition of skin disease.

Another aspect of the present invention is a method of obtaining a composition of this invention by combining water with a therapeutically effective amount of a suitable compound and the polymer, and, optionally, mixed with water, solvent and preservative. If desired lotion, forming an oil phase for combining with the aqueous phase.

All aspects of this invention will become apparent upon further reading of the descriptions and claims of this patent application.

DETAILED DESCRIPTION

This invention offers a new delivery system in the form of a gel or lotion for topical application for the treatment of skin diseases, especially common acne. One of the unique aspects of this system is the use of a polymeric substance which provides the material in the form of a gel, which is the region which gives a very low viscosity, but which is cosmetically excellent and contributes to the implementation process by providing a fluid composition, which easily flows through the tip.

Composition

One aspect of the present invention is a composition having a pH from about 3 to about 9 and a viscosity of less than about 15000 SP for the treatment of skin diseases in humans. This composition contains a therapeutically effective amount of at least one compound suitable for the treatment of such disease, pharmaceutically acceptable, partially cross-linked polymer of polyacrylic acid that is compatible with therapeutically effective compound, optionally, mixed with water, the solvent, optionally, a preservative, and water. The composition may include a solution of active compound or polymer. The lotion will also include pharmaceutically acceptable oil phase emulsified by one or more surface-active substances.

This composition is suitable for treatment of skin diseases such as acne and red acne or inflammatory skin diseases such as atopic dermatitis. This composition will include an active agent, which is only one compound or two or more compounds in combination. An active agent can be an antibiotic, corticosteroid is d, retinoid, imidazole anti-inflammatory, non-steroidal anti-inflammatory agent, or a combination.

The antibiotic is usually considered as a drug that inhibits the growth of unwanted microorganisms. Typical examples of antibiotics for topical use include lincomycin (e.g., clindamycin, erythromycin, minocycline and tetracycline, and their pharmaceutically acceptable salts, esters or prodrugs. Preferred is clindamycin phosphate.

“Retinoid” is a keratolytic drug, related to retinoic acid, and typically includes chemical substances such as retinol and its esters, and is closely related existing in the nature of a derivative that is close in structure to the synthetic analogues. This includes, for example, retinol, retinal, tretinoin (fully transretinoic acid), isotretinoin, adapalene (6-[3-(1-substituted)-4-methoxyphenyl]-2-naphthoic acid) and the like. Of these compounds of the tretinoin is preferred.

Usually corticosteroid for topical use is a compound that is a structural modification of hydrocortisone (also known as cortisol), and which exhibits a local anti-inflammatory effect. Typical examples include those represented by the table 65-1 page 1575 “Goodman & Gilman''s The Pharmacological Basis of Therapeutics, eighth edition, McGraw-Hill, Inc. (1993). Specific, non-limiting examples of corticosteroids for topical use include those described in “prior art” section of this application. Preferred corticosteroids, when used as the only active substance, include diflorasone diacetate, desonide, fluticasone propionate, halobetasol propionate or budesonide. Halobetasol propionate or desonide is most preferred when used as the sole active ingredient.

Non-steroidal anti-inflammatory drugs (NSAIDs) are compounds which inhibit the inflammatory reaction, when applied topically, through inhibition of prostaglandin synthesis or different mechanism of action. Examples can be found in Goodman and Gilman, Ibid. Typical examples include ibuprofen, indomethacin, diclofenac and naproxen, and their salts. It is preferable diclofenac.

Anti-inflammatory imidazole is an imidazole compound that inhibits local inflammation. Metronidazole is a typical imidazole compound suitable for the present invention.

When describing details of the present invention numeric intervals presented here are those quantities which provide the t functional results in this composition. Thus, the intervals are normally introduced by the term “about”to show some flexibility in the interval, i.e. ±10% or less when the lower and upper numerical limit.

As mentioned, the active agent may be present in one or in combination. For example, an antibiotic for topical use, such as clindamycin phosphate, can be combined with a corticosteroid for topical application.

When the drug is intended mainly for use on the face area, for example, for the treatment of acne, it is preferable to combine an antibiotic (e.g., clindamycin phosphate) with a less potent corticosteroid, such as desonide, hydrocortisone valerate, fluoqinolona acetonide, hydrocortisone butyrate or triamcinolone acetonide. Antibiotic for topical application can also be combined with a retinoid, such as clindamycin phosphate and tretinoin or adapalene.

The composition of this invention will contain a polymeric material that will be present in a quantity sufficient to impart a viscosity of the composition to no more than about 15000 SP, preferably between about 100 and about 12000 and more preferably between about 300 and about 10,000. The viscosity is measured at room temperature (20-25° (C) using a Brookfield viscometer model DV-I+, is terzani #27 at 12 revolutions per minute (rpm). If a specific viscosity of less than 4000 SP should be used pin #21 instead of #27. Maintaining viscosity below about 15000 SP achieved interesting cosmetic properties and easy precise application through improved expiry and fluidity.

Polymers, which has been found especially suitable for compositions of this invention are partially crosslinked polyacrylic acid polymers that are available from the company B.F. Goodrich under the trade name carbopol (CARBOPOL®). They are also called Carbonari. The polymers carbopol are hydrophilic polymers having in the basis of the structure of polyacrylic acid. For use in this invention is partially cross-linked polymers include carbopol 910, 941, 971 and 981 and carbopol D 2050.

Or carbopol 941 or 981 is particularly valuable for the present invention due to the fact that the viscosity of the gel on the basis of carbopol 941 or 981 is low relative to its concentration. This property is the result of a low degree of crosslinking in the polymer structure in neutralized water system. In contrast, polyacrylic acid polymers, which exhibit a high degree of crosslinking, such as carbopol 980 or R, give gels with higher viscosity at comparable concentrations.

0.5% Solution or carbopol 941 or 981 at pH 7.5 is set in the Scoti from 4000 to 11000 SP (Brookfield viscometer at 20 rpm) compared with the viscosity from 40000 to 60000 SP compared to 0.5% solution or carbopol 940 or 980 (source: B.F.Goodrich Product Guide Bulletin 2). This property viscosity lower level is partially crosslinked polyacrylic acid polymers such as carbopol 941 and 981 gives two advantages of the compositions of the present invention. Gel made from one of these partially cross-linked polymers, provides the best feeling on the skin and lubricity than comparable gel viscosity, made of longevity highly crosslinked polymer. Secondly, the gel with low viscosity may be dosed very accurately using a dropper or dispenser type dropper compared to other commercial products that are more dense gels that do not provide precise application.

Resin carbopol 941 NF and its sorusturma polymerized alternative, resin carbopol 981 NF, provide stable emulsions and suspensions with low viscosities. Gels produced from these resins have excellent transparency. In ionic systems, they are better than most other resins of carbopol and at concentrations below 1.5% in the solvent system. These polymers are available from the company B.F. Goodrich Specialty Chemicals, 9911 Brecksville Road, Cleveland, OH 44414-3247.

The carbopol resin are polymers of acrylic acid, crosslinked polyelectrolyte ethers or diphenylglycine. These polymers are flaky powder of core particles having an average diameter is the Tr of about 0.2 microns. Flocculent powders are agglomerates, averaging from 2 to 7 microns, which is defined by using the counter Coulter. These agglomerates cannot be broken down into basic (primary) particles, if they are already formed.

Each of the primary particle can be considered as a mesh (custom made) structure of polymer chains connected by cross links. Without cross-linking of the primary particle would be the accumulation of linear polymer chains, twisted, but not chemically related. These linear polymers are soluble in polar solvent such as water. They swell in water up to 1000 times their original volume (and ten times their original diameter) with the formation of the gel, especially when exposed to the environment with a pH above about 4-6. Since the pKa of these polymers is equal to 6,0±0.5, the carboxylate group of the main polymer chain are ionized, resulting in repulsion between the negatively charged particles that helps the swelling of the polymer. Longevity highly crosslinked polymers of this type do not dissolve in water, but rather they form gels by forming a homogeneous dispersion.

The glass transition temperature of the resin of carbopol equal 105°C (221° (F) in powder form. However, the glass transition temperature is greatly reduced when the resin is brought into contact with water. The polymer chains begin to bunch ivalsa spiral, and the radius of the circular collapse is becoming more and more. Macroscopically, this phenomenon manifests itself in the form of swelling.

The water composition of the present invention will optionally contain mixed with water, the solvent and preservative. Mixed with water, the solvent (i.e., the co-solvent) will be present, if necessary, to assist the dissolution of the active substance. The co-solvent may be a single component or mixture. Examples include those solvents that are mixed with water, such as ethanol, propylene glycol, glycerin, polyethylene glycol 400 and the like, Certain mixed with water solvents, such as glycerol or propylene glycol, and also add favorable moisturizing properties of the composition. Shipping drugs and penetration into the skin can be modified composition is mixed with water cosolvent.

Preservatives useful in this composition is a material that helps to provide stable compositions and/or prevents the growth of bacteria. Thus, the preservative may represent one or more of antioxidants, complexing agent, antibacterial agents or similar. Suitable preservatives include methylparaben, butylparaben, propylparaben, benzyl alcohol, Sarbinowo the acid, kidmuseinu, chimerical, propylgallate, BHA (BHA), BHT, citric acid, disubstituted edetate sodium, and the like. Another optional additive is a flavoring. Usually it will be present only in trace amounts and does not affect the action of the composition.

The preferred composition, in particular for the treatment of acne, will have a pH from about 3 to 9, preferably about 4-7, and most preferably about 5-6. Thus, the composition may also include a pH-regulating agent, when necessary, at this level, to bring the pH to the desired interval. These tools include many pharmaceutically acceptable organic or inorganic bases such as sodium hydroxide and tromethamine. The selected pH will partly depend on the pH tolerance for the active substance, selected for this composition. Examples are instructions for some of the compounds and suitable pH values for these compositions.

Another aspect of the present invention is embodied in the form of a cushioning means, i.e. liquid emulsion or lotion. This aspect of the present invention is a composition having internal oil phase, dispergirovannoyj with at least one surface-active substances (surfactants), such as emulsifier in the water. Approaching the s surfactants are well known in this field and include those which are anionic and non-ionic substances. They are described in Remington: The Science and Practice of Pharmacy, Nineteenth Edition, Vol. 1 on page 251. Typical examples of surfactants include Polysorbate 20, Polysorbate 40, Polysorbate 60, Polysorbate 80, sorbitan laurate, sorbitan the oleate, sorbitan stearate, polyoxyethylene stearate, sodium lauryl sulfate and Laureth-10. The components of the oil phase include those that are commonly used in this field, such as mineral oil, petrolatum, stearyl alcohol, cetyl alcohol, isopropylmyristate, diisopropylamide, stearic acid, white wax, and the like.

The following table illustrated and preferred ranges for the various components for the composition of the gel with the active ingredient, which may be a single compound or a combination of two or more compounds. The term “surfactant” means one or more surfactants, which include wetting agents and emulsifiers.

Table a
ComponentWeight %
 workpreferredmore preferred
The active ingredientof 0.005 to 10.0of 0.01 to 5.00,05-2,0
P is limer polyacrylic acid 0,05-3,00,05-1,00,1-0,5
The co-solvent0,0-70,00,0-40,00,0-25,0
Preservative0,0-3,00,01-1,00,05-0,25
Surfactant*0,0-8,00,0-5,00,0-3,5
The oil phase*0,0-50,00,0-25,0of 0.0 to 15.0
WaterQS to 100QS to 100QS to 100
BaseQS pHQS pHQS pH
* Presents for lotion
(QS to 100=a sufficient amount to 100
QS pH=sufficient amount for pH)

* Presents for lotion

(QS to 100 = a sufficient amount to 100

QS pH = sufficient amount for pH)

The following table presents workers, preferred and more preferred concentrations are typical examples of active ingredients that can beneficially be used in the practical implementation of the present invention or separately, or in combination. The exact number will be easily determined by the person skilled in the art by reference to standard guidelines, such as Pysician's Desk Reference or Goodman and Gilmann's, shown here previously.

TABLE
ComponentWeight %
 workpreferredmore preferred
Antibiotic0,1-5,00,5-2,00,5-1,0
Corticosteroidof 0.005 to 2.50,01-1,0the 0.05-0.1
Retinoid0,005-0,5the 0.05-0.10,025-0,05
The imidazole0,1-5,00,5-2,00,75-1,0
NSAIDs0,1-3,00,2-2,00,2-1,0

To produce a form of emulsion (i.e. lotion) of the present invention, as broadly shown in table A, in the composition include surfactants and oil phase component. The following table illustrates the way in which the composition is modified with the formation of lotion.

of 0.1 to 8.0
TABLE
ComponentWeight %
 workpreferredmore preferred
Surfactant0,5-5,01,0-3,5
The oil phasefrom 1.0 to 50.02,5-25,05,0-15,0

The preferred composition should be free from preservative or have a reduced level of preservatives in comparison with the material, which is commercially available. This is important because the presence of preservatives in the composition may cause irritation or allergic skin reaction. Reduce the possibility of skin irritation or allergic reactions to the composition provides a better product. With regard to compositions that contain clindamycin phosphate, the main product is gel cleocin So It is transparent viscous gel, tests have shown that it is not perceived as well as a less viscous material of the present invention, manufactured in accordance with partially crosslinked polymer. By adjusting the viscosity of the gel at a low level, it can be accurately dosed from transparent plastic crushed relentlessly bottle, not from a tube of ointment. The advantage is twofold. One is accurate dosing control through the use of smaller holes handpiece and improved product presentation for sale. In addition, tests showed that the less viscous material is cosmetically better and this drive is tons to more regular use.

Upon receipt of a composition of this invention will be used the main method of fabricating a drug known in the field of pharmaceutical science. See, for example, Remington: The Science and Practice of Pharmacy, Nineteenth Edition, Mack Publishing Company (1995). The manufacture of specific products can be found in the examples.

For the manufacture of the gel with two active ingredients, when one suspended, and the other is dissolved, first add insoluble active ingredient is mixed with water ingredient or part of the water with surfactants for dispersion. Separately dissolve another active substance or any of the other ingredients of preservatives in treated water. Dispersed gel-forming substance in an aqueous solution with appropriate mixing. Then add the variance of the first active ingredient to the gel and mixed well to obtain a mixture. And last, add a pH regulating substance in order to bring the pH to the desired interval. The manufacture of the gel, when both of the active ingredient is soluble, is similar, varying only in the first stage. First, add the active substance with low solubility in a solvent, solvent mixture or water. Mix to dissolve. Separately dissolve another active substance and any ingredient of preservatives in treated water. Dispersed of heliobar the respective substance in aqueous solution at the appropriate dilution. Then add a solution of the first active substance in the gel and mix well to obtain a mixture. And last, add a neutralizing substance to bring the pH to the desired interval.

As for the combination antibiotic, such as clindamycin phosphate with a retinoid such as tretinoin, can be used three approaches to the manufacture of the drug in relation to the composition of the present invention: 1) water-based gel formed gel-forming substance on the basis of partially cross-linked carbomer, dissolved clindamycin phosphate and suspended tretinoin; 2) emulsion oil-in-water with clindamycin phosphate, dissolved in water, thickened gel-forming substance on the basis of partially cross-linked carbomer, and tretinoin, dissolved in the internal liquid oil phase; and (3) a solution consisting of water and miscible with water and organic solvents both dissolved clindamycin phosphate and tretinoin.

The following compositions are given as representative examples of the types of compositions that are suitable in this invention.

When the composition contains only an antibiotic, such as clindamycin phosphate, the composition has a pH from about 4 to 7 and contains:

(a) from about 0.5% to 2% weight. clindamycin phosphate

(b) from about 0.1% to 0.4 wt%. polymer

(C) base to bring the pH,

(d) PR is approximately from of 15.0% to 25.0 wt%, mix with water solvent

(e) less than about 0.2% weight. preservative and

(g) QS purified water to 100% weight.

Preferably the composition has a pH of about 5-6, and contains:

(a) from 1.0% to 1.5% weight. clindamycin phosphate

(b) 0.2% weight. polymer

(C) base to bring the pH,

(d) 15,0% weight. propylene glycol and 5.0 wt%. polyethylene glycol 400,

(e) 0.1 to 0.15 wt%. the methylparaben and

(g) QS purified water to 100% weight.

The composition of the gel, where the antibiotic is clindamycin phosphate and retinoid is tretinoin, may contain:

(a) (i) from about 0.5% to about 2.0% weight. clindamycin phosphate and

(ii) from about 0.01% to about 0.05% weight. tretinoin;

(b) from about 0.1% to about 0.5% weight. polymer;

(C) base to bring the pH,

(d) from about 10% to about 30 wt%, mix with water solvent;

(e) less than about 0.2% of a preservative and

(g) QS purified water to 100% weight.

The composition of the lotion clindamycin phosphate and tretinoin will usually contain:

(a) (i) from about 0.5% to about 2.0% weight. clindamycin phosphate and

(ii) from about 0.01% to about 0.5% weight. tretinoin;

(b) from about 0.1% to about 0.5% weight. polymer;

(C) base to bring the pH;

(d) from about 5% to about 30 wt%, mix with water solvent;

(e) less than about 0.2% of a preservative;

(f) oil is ABC in combination with, at least one surfactant to form an emulsion and

(g) QS purified water to 100% weight.

Treatment

Another aspect of the present invention is a method of treatment of skin disease in humans, comprising applying the composition to the affected area of skin of a subject having such a disease, in the amount and within the period of time sufficient to improve the condition of skin disease, where the composition described in this patent application. Preferably the composition is applied once daily during the treatment period. Depending on the improvement of patient treatment may last for less than one week to two months or more. The speed improvement can be controlled by the patient or doctor.

Skin diseases that can be cured composition of this invention include common acne (acne vulgaris), red acne and various inflammatory conditions, including atopic dermatitis. Discussion of these conditions can be found in the Merck Manual. For example, acne vulgaris is an inflammatory disease that affects the hair follicles and sebaceous glands. Lesions are most common on the face, but also can affect the neck, chest, upper back and shoulders.

The affected area of skin of the subject can be located anywhere on the body that has skin C is bolovanje. The number of songs and time sufficient to improve the condition of skin disease will depend on the subject and condition the skin. Typically, a sufficient number will be squeezed out of the tip of the dropper crushed relentlessly bottle or eye dropper on the affected area and gently creep into the skin. Usually applied to the affected area will need no more than a few drops.

The product

Another aspect of the present invention is a product, which contains kompozitsiiu for the treatment of skin diseases, as described above, in a suitable container, preferably in a bottle with dropper, in conjunction with the accompanying instructions. Bottle with dropper can be made of any material, such as glass, hard plastic or elastic plastic. Other means of application are eye dropper or tube with a suitable tip with a hole of small size, the tube is drawn spout.

The composition of this invention can be, for example, placed and Packed in a compressible plastic bottle (i.e., 42 g). Suitable for this composition, the packaging system from sealed container described in table D.

TABLE D
Rated the local size Capacity up to overflowMaterial descriptionManufacturer
1 ounce46 cm2- The usual cylinder, round polypropylene bottle, polishing 15/415, Wheaton-21411Wheaton

Plastic

Products 1101,

Wheaton Avenue

Milvlle, NJ

08332

  - 15 ml dropper tube with a tip of white low-density polyethylene In Wheaton-11048
  Sealing means drawn with the tip of white polypropylene, Wheaton-15044

The accompanying instructions can be included in the form of leaflets, labels, affixed to the packaging or attached to the product packaging production.

The accompanying instructions are provided for applying compositions of the present invention to the affected area of skin of a subject having a skin disease, in the amount and within the period of time sufficient to improve the condition of skin disease. Printed accompanying instructions functionally related to the composition of the invention, as the instructions describe a method for the treatment of skin diseases. The accompanying instructions are an important aspect of the present invention in that before songs which I can be approved for any specific use, it must be approved for sale by the Department for quality control of food products and medicines of the United States. Part of this process includes providing labeling accompanying pharmaceutical composition, which ultimately will be sold. Although labeling will include the determination of the composition, and other topics such as clinical pharmacology, mechanism of action, drug resistance, pharmacokinetics, absorption, bioavailability, contraindications and the like, it will also be necessary dosage, application and instructions for use. Thus, the combination of the composition with the bottle with dropper and instructions for treatment, it is important for the correct use of drugs, when it goes on sale. In these instructions, the treatment will be described in the application in accordance with the method of treatment described previously.

Now that we have described in this invention, it will be better understood with reference to specific examples, which are included here only for purposes of illustration and are not intended to limit the present invention or any of its embodiments, if it is not specified.

In the following examples, the viscosity is determined at room temperature (20-25° (C) using a viscometer Bookfield model DV-I+, pin #27 at 12 revolutions per minute (rpm). If a specific viscosity of less than 4000 SP, instead of rod #27 should be used pin #21.

EXAMPLES

EXAMPLE 1

This example presents the composition is flowable gel of the present invention. The procedure presented in stages a-f provides a composition corresponding to table I. Composition is called “clindagel”. Application for the name “clindagel” (Clindagel) as a trademark was filed.

TABLE I
Component%weight
Clindamycin phosphate, US (USP) (equivalent to 1% clindamycin)1,19
Methylparaben0,15
The carbopol® 941 (or 981)0,20
Propylene glycol15,0
The polyethylene glycol 4005,0
Sodium hydroxide (10% solution)QS to pH of 5.3 to 5.7
Purified waterQS to 100.0

The viscosity of this composition is equal to about 1000 CP.

A. Measure approximately 90% of treated water in the boiler is stainless steel. Add the propylene glycol and polyethylene glycol 400. Stir propeller stirrer.

b. At room temperature add the methylparaben mixture to a hundred the AI a) with continuous stirring. Stir to dissolve.

C. With continued stirring, add clindamycin phosphate to the mixture from stage b). Stir to dissolve.

d. Continuing to mix, add carbopol® 981 or 941 to the mixture from stage (C), avoiding the formation of lumps. Vigorously stir at room temperature until, until a homogeneous, lump-free, dispersion.

that is, Under stirring add enough sodium hydroxide, 10% solution to achieve a pH of 5.3 to 5.7. Stir until smooth.

f. Add the remaining water to bring to 100%, and stir until smooth.

EXAMPLE II

This example shows the composition of a commercially available product containing clindamycin phosphate. This product sells Pharmacia in the form of a gel cleocin T®. Components and quantities, as determined by the analysis are as follows:

TABLE II
Component%weight
Clindamycin phosphate1,19
Carbomer 934 P0,8
Propylene glycola 4.9
The polyethylene glycol 40010,2
Sodium hydroxideQS to PH of 5.4
Methylparaben0,3
Allantoin 0,2
Purified waterQS to 100

The viscosity of this composition is equal to 20,000 CPS.

EXAMPLE III

Comparison of clindagel and gel cleocin-T®

This example presents clinical data showing the advantages of the compositions of this invention compared to known commercial composition.

Conducted blind clinical trial by researchers in many centres, comparing the composition of this invention (see example I) clindagel, once a day, and gel cleocin-T® (see example II), twice a day (in accordance with the manufacturer's instructions) when acne vulgaris. Three hundred and twenty-four patients, half in each group were treated for up to 12 weeks. The researcher was “blind” in the sense that she/he did not know what treatment the patient used before the researcher assesses the condition of the acne patient.

The assessment included the calculation of inflammatory lesions, total lesions, overall assessment of the doctor and is related to the skin side effects. Papules and pustules are considered inflammatory lesions. Defeat acne generally included blackheads and whiteheads in addition to inflammatory lesions. The overall score of the doctor was based on debatible scale. At the end of the study (12 weeks or last assessment was made Zack is Uchenie, that clindagel, applied once daily was equally effective to cleocin-T®applied twice a day, and clindagel had significantly fewer side effects. Data on the number of lesions are summarized in table III.

TABLE III
The improvement in the treatment of acne lesions at the end of the course: clindagel™ once a day compared with gel cleocin-T twice a day
DEFEAT ACNEClindagel™ once a dayGel cleocin-T® twice a day95% reliability, the lower border
The percentage change from baseline (standard deviation)
Inflammatory-50,90(2,62)-50,02(2,62)0,897
In General-37,27(2,44)-39,52(2,44)0,801

The overall score of the doctor are summarized in table IV.

TABLE IV
The total number of patients with improvement in two categories in comparison with the initial level, when assessing the overall severity of the doctor at the end of the treatment debatible
On the GENERAL ASSESSMENT of the DOCTOR Clindagel™ once a dayGel cleocin-T® twice a day95% reliability, the lower border
 The number of patients 
Improvement in two categories84840,833
The same or deterioration7273 
Only156157 

The frequency of side effects on the skin from clindagel™once a day, and from cleocin-T®twice a day, are summarized in table V.

EXAMPLE IV

This example presents the results of the test user preferences (with media (basics), not active substances), including composition of the present invention shown in example I (with carbopol® 981) with a commercially available composition of example II (Carbonera 934 P). Table VI presents the composition of drugs.

The study was performed in the group of normal subjects of the 10 patients, to assess the functional and cosmetic properties, using the plan drawing on half of my face, paired and symmetrical application.

Tested preparations (base gels) were defined who are blind identification code, preventing knowledge test patient characteristics of the tested drugs that will be applied. Each test pair was included tested preparations L in comparison with R, which is used on the left and right sides of the face, respectively. Tested preparations, codes marked L and R, were changed so that each trial medication on a random sample was evaluated on the localization test R and L and in order of application.

Subjects were grouped by sex. The average age of the group was 34-year interval age 25-44 years.

The following properties were evaluated during and after application: the ability to spreading, feeling/texture during application, ease of application, the ability to RUB the gel into the skin, drying time on the skin, the feeling on the skin after application, total cosmetic benefit and usability of the product. Each gel were evaluated for their functional and cosmetic properties on a scale of 1-6, where 1 means unacceptable, and 6 is excellent.

Of the nine subjects with a preference for one of the subjects of drugs, 67% preferred the basis of clindagel the basis of cleocin So the Degree of preference of clindagel towards cleocin T was estimated from “moderate” to “large” 100% of these subjects. The data summarized in table VII.

TABLE VII
Preference basis subject
Subject12345678910Only
Age26394442252842353326 
FloorWWmmWWmWmm 
Cleocin-T      pppNP3
ClindagelpPpppp   NP6
p=preferred NP=no preference

f=female m=male

The rating scale was significantly higher for the base of clindagel than for the base of the gel CL is ocin-T for four of specific properties, and no significant differences on two of these properties (table VIII). The basis of clindagel were assessed as “very good” in three of the six categories of properties and evaluation of “good” in the other three. The basis of gel cleocin-T was assessed as “very good” in one category, “good” in four categories and “satisfactory” in the same category.

Forty percent of subjects subjects independently explained that the basis of clindagel was “fluid” or “watery” when applying. This is also reflected in the “ease of application”, which cleocin-T had a slightly higher score. 50% of the test subjects independently commented on the feeling on the face as “sticky” after applying Foundation of cleocin-So 80% of the test subjects indicated that they would use the basis of clindagel as a therapeutic product for the face. Only 30% of these subjects indicated that they would use the basis of cleocin-T as a therapeutic product for the face.

EXAMPLE V.

The study of stability of clindagel™ clindamycin phosphate as the active ingredient.

This example presents laboratory data showing the stability of clindagel (example I) for at least 18 months at 25°s Clindagel experienced on the stability of the active ingredient clindamycin F. state, over time at a controlled room temperature (i.e. 25°C and 60% relative humidity). Showing the stability study using high-performance liquid chromatography was used to evaluate the continuing activity of clindamycin phosphate, which is expressed on clindamycin, in the course of the experiment. Based on the data presented in table IX, it is projected that clindagel has technical shelf life is approximately 24 months.

Estimated shelf life was calculated by the 95% credible interval approximation of the available data by the method of least squares. The predicted shelf life is the period over which the active drug reaches 90% specified on the label (as permitted by the USP). The program used for statistical analysis, called “SLIMStat+” and sold by the firm Metrics Inc., P.O. Box 4035, Greenville, NC 27836 phone 252-752-3800.

12 months
TABLE IX
Evaluation of the stability of the activity of clindamycin in clindagel™, 1%, at room temperature
 The percentage of clindamycin weight
 Source1 month2 months6 months18 months
Determination of clindamycin phosphate1,0281,017with 1.0091,0040,9830,959

EXAMPLE VI

Composition with a combination clindamycin phosphate tretinoin

Section 1

In this section, this example describes two compositions of the gels of the present invention, in which the active ingredient clindamycin phosphate and tretinoin.

Two fluid compositions of gels containing a combination of clindamycin phosphate and tretinoin were made in accordance with this invention. In the product And the gel has a pH of about 5.5 and a viscosity of about 6100 SP. The drug In the gel has a pH of about 4.7 and a viscosity of about 6000 SP. The quantitative composition, see table X. This example illustrates the applicability of the present invention for the manufacture of physically and chemically stable drug gel.

TABLE X
The quantitative composition of the two drugs gels with a combination clindamycin phosphate/tretinoin
ComponentAnd

%weight
In

%weight
Tretinoin0,0250,025
Clindamycin phosphate 1,211,21
Propylgallate-0,02
BGA0,02-
Citric acid-0,05
Dvuhkamernyi edetate sodium0,050,05
Polysorbate 805,00,08
Propylene glycol5,0-
PEG 40020,0-
Glycerin-10,0
Methylparaben0,10,15
The carbopol 9810,50,5
Tromethamine (10% in water)QS to pH 5.5QS to pH 4.5
Purified waterQS to 100QS to 100

Method of manufacturing: Drug And

A. Combine propylene glycol, polyethylene glycol 400 and Polysorbate 80. Add tretinoin and stir to dissolve.

b. In a separate container dissolve dvuhkamernyi edetate sodium, methylparaben and bottled hydroxyanisol in purified water.

C. Add clindamycin phosphate to the aqueous solution with phase b and stir to dissolve.

d. Dispersing the carbopol 981 in aqueous solution under high speed stirring.

E. Add drug phase tretinoin to aqueous dispersions of carbopol with stirring and then add tromethamine and stir till the formation of a homogeneous gel.

Method of manufacture of the drug In

A. Combine glycerin and Polysorbate 80. Add tretinoin and stir until the wetting and dispersion.

b. In a separate container dissolve propylgallate, citric acid, dvuhkamernyi edetate sodium, methylparaben and bottled hydroxyanisol in purified water.

C. Add clindamycin phosphate to the aqueous solution with phase b and stir to dissolve.

d. Dispersing the carbopol 981 in aqueous solution under high speed stirring.

E. Add tretinoin drug phase to aqueous dispersions of carbopol with stirring and then add tromethamine and stir till the formation of a homogeneous gel.

Section 2

In this section, this example describes two additional compositions that are slight modifications of drugs a and b, where preservatives are replaced or adjusted. The compositions presented below. Similar to a, And D similar to C.

In the manufacture of the drug With 0.1% preservative methylparaben in the formula And replaced with 1.0% benzyl alcohol. Part D as an additional preservative we use is and 0.03% propylparaben (as a combination of methyl paraben and propyl paraben sometimes is the best preservative system). Manufacturing methods:

The drug is made like a drug And, except that methylparaben on stage “b” should be omitted, and benzyl alcohol should be added at the stage of “a”.

Drug D is made like a drug; at the stage of “b” must be added propylparaben.

The gel composition has a pH of about 5.5 and a viscosity of about 9000 SP. The gel composition D has a pH of about 4.6 and a viscosity of about 4100 SP.

EXAMPLE VII

Evaluation of chemical stability of tretinoin in preparations a and b from example VI

This example presents laboratory data demonstrating the stability of tretinoin in two compositions of this invention in the test conditions for accelerated aging.

Tretinoin is known to be relatively unstable, therefore, the chemical stability of these combined drugs was evaluated in a 12-week study of stability in accelerated aging. The gels were Packed in receptacles of yellow glass, 8 grams each, and kept at 40°C. Research high-performance liquid chromatography was performed at the beginning and after 2, 4 weeks and 12 weeks using the method for tretinoin cream (USP 24, page 1684). Both compositions were found to retain its activity in this study on accelerated aging. In table XII summarizes the results of the chemical stability.

TABLE XII
Evaluation of stability of activity tretinoin in preparations a and b, example VI, at elevated temperature (40°)
 Time (in weeks)
The concentration of tretinoin (%, weight)02412
Drug And0,02100,02280,02360,0231
Drug0,02360,02310,02340,0234

EXAMPLE VIII

Composition of combined drug gel

In this example, instructions on how to modify known commercial composition of example II, to include tretinoin.

The drug combination of gel tretinoin 0.025% and clindamycin 1% was made by mixing spatula powder tretinoin and propylgallate (antioxidant to slow the loss tretinoin oxidation) with gel cleocin®T (example II). The quantitative composition shown in table XIII.

TABLE XIII
ComponentNumber
Tretinoin0,0074 g
Cut the Allat 0,0145 g
Gel cleocin®T28,0000 g
Only28,0219 g

Tretinoin and propylgallate accurately weighed, was placed on a glass plate and put in the gel cleocin®T with a spatula. During mixing with a spatula product is protected from light. The resulting product was a homogeneous, transparent light yellow gel with a pH of 5.7 and a viscosity of about 20,000 CPS.

EXAMPLE IX

The study of the physical stability of the compositions of example VI (preparation a) and example VIII

This example compares the composition of this invention (example VI preparation A) with a modified commercial composition (example VIII) in relation to crystal growth.

Physical stability of example VI preparation and example VIII were evaluated during a 4-week period at 5°S, 40°s and 50°C. Assessment of stability based on a thorough physical examination in the description at the beginning, and 2-week and 4-week period. At the end of the study, microscopic examination was performed to check on the precipitation tretinoin and crystal growth. As illustrated below (table XIV), modified commercial drug, gel cleocin®T, was physically unstable in comparison with the composition of this invention, example VI (product A).

TABLE XIV
 Description: clear light yellow gel
Example VI (drug A)Source2 weeks4 weeks
TransparentTransparentTransparent - no crystals
40°TransparentProzreniiTransparent - no crystals
50°TransparentTransparentTransparent - no crystals
Example VIIISource2 weeks4 weeks
TransparentSmokySmoky crystals up to 1200 microns
40°TransparentTranslucentSmoky crystals up to 1200 microns
50°TransparentTranslucentSmoky crystals up to 1200 microns

EXAMPLE X

This example presents the composition of the lotion of the present invention containing two active ingredients: an antibiotic, i.e. clindamycin phosphate, and retinoid, meaning tretinoin. Components for this lotion is presented in table XIV(a).

TABLE XIV(a)
Component%weight
Clindamycin phosphate1,21
Tretinoin0,025
Stearyl alcohol5,00
Diisopropylamide6,00
PEG-40 stearate (rj 52)2,00
Sorbitan stearate (Sn 60)2,00
Bottled hydroxytrol0,02
Propylene glycol5,00
Methylparaben0,15
Propylparaben0,03
Citric acid0,05
Dvuhkamernyi edetate sodium0,10
The carbopol 9810,10
Tromethamine (10%)qs to pH 5.5
Purified waterQs to 100

The viscosity of this composition is 7000 SP.

Method of delivery:

A. Combine propylene glycol and purified water. Add methylparaben, propylparaben, citric acid and dvuhkamernyi edetate sodium and stir to dissolve.

b. Add clindamycin phosphate to the mixture from stage a and stir to dissolve.

C. Add the carbopol 981 to the mixture from stage “b” and peremeci the AMB to the formation of homogeneous dispersion.

d. To heat the aqueous phase from step “C” to a temperature between 60°s and 70°C.

that is, to Combine stearyl alcohol, PEG-40 stearate, sorbitan stearate and bottled hydroxytoluene and heated to melt at a temperature between 60°s and 70°C.

f. Add tretinoin to diisopropylate and stir to dissolve.

g. Under high speed stirring, add the oil phase from step “e” and drug phase from step “f” sequentially to the aqueous phase with phase d and mix well.

h. Cooling the emulsion with continuous stirring.

i. Add tromethamine solution and stirred until formation of a homogeneous emulsion. Cool to room temperature with continuous stirring.

EXAMPLE XI

This example presents the composition is flowable gel of the present invention, and this gel contains a corticosteroid. Such a drug suitable for the treatment of inflammatory skin conditions such as atopic dermatitis.

12
TABLE XV
Componentweight%
Halobetasol propionate micronized0,05
The sodium docusinate0,10
The carbopol® 9810,3
Propylene glycol
Methylparaben0,1
Propylparaben0,02
TromethamineQS to pH 6.5
Purified waterQS to 100.00

The viscosity of this composition is approximately 6200 SP.

A. Dissolve the methylparaben and propylparaben in propylene glycol at room temperature using a propeller stirrer.

b. Weighing of 70% by weight of the preparation of purified water and slowly add the solution from step “a” under stirring propeller stirrer.

C. while Continuing to mix, slowly add the carbopol® 981 to the mixture from stage “b”. Stir at room temperature until, until you have a uniform and homogeneous dispersion.

d. To 10% by weight of the preparation water add sodium docusinate and stir until dissolved. To facilitate dissolution, the mixture can be heated to 40-50°and then cooling to room temperature, when dissolution is complete.

E. Dispersing fine halobetasol propionate in a mixture from step “d” by using a propeller stirrer or, preferably, a homogenizer of rotor-stator type.

f. Add the mixture from step “e” to the mixture from step C, using a propeller mixer to evenly atomized medicinal material.

g. The solution is to be tromethamine 10 times the amount of its weight in purified water. When mixing use tromethamine solution to bring the pH to thicken the gel. Continue increasing the add up until you reach a pH equal to 6.5.

h. Add water to obtain 100% of the download size and mix to homogeneity by using a propeller-type stirrer.

EXAMPLE XII

This example shows another composition flowable gel of the present invention. This product contains metronidazole for topical use on the skin area affected, for example, red eels.

TABLE XVI
Componentweight%
Metronidazole0,75
Methylparaben0,12
Propylparaben0,03
The carbopol® 9810,25
Glycerin5,00
TrollinQS to pH 8
Purified waterQS to 100.00

The viscosity of this composition is approximately 4700 SP.

A. Weigh 90% by weight of the preparation of purified water, metronidazole, glycerin, methylparaben and propylparaben in a suitable stainless steel container. Vigorously stir at room temperature until until all mponent will not dissolve. Particularly suitable stirrer propeller type.

b. Continuing to mix, slowly add the carbopol®. Stir until then, until the desired dispersion is obtained.

C. Mix of trolamine with an equal part of purified water. Use this solution to bring the pH to about 8 with increasing added under stirring.

d. Add the remaining purified water to obtain 100% and stir until then, until you have a homogeneous gel.

EXAMPLE XIII

This example presents the composition is flowable gel of the present invention, the gel contains a tool NSAIDs.

TABLE XVII
Componentweight%
Naproxen1,00
Octoxynol 90,10
The carbopol® 9810,30
Propylene glycol5,00
Glycerin5,00
Benzyl alcohol : 1,00
Sodium hydroxide, 10% solutionQS to pH of 3.0-3.5
Purified waterQS to 100.00

The viscosity of this composition is approximately 4200 SP.

A. Mix benzyl alcohol, glycerol and propylene glycol together at room temperature, the IP is by using a propeller stirrer.

b. Weighing of 70% by weight of the preparation of purified water and slowly add the solution from step “a” under stirring propeller stirrer.

C. while Continuing to mix, slowly add the carbopol® 981 to the mixture from stage “b”. Stir at room temperature until, until you have a uniform and homogeneous dispersion.

d. To 2-5% by weight of the preparation water add octoxynol 9 and stir it up until it is completely dissolved.

E. Dispersing naproxen in the mixture from step “d” by using a propeller stirrer or homogenizer.

f. Add the mixture from step “e” to the mixture from step C, using a propeller mixer to evenly atomized medicinal material.

g. When stirring, use a solution of sodium hydroxide to bring the pH. Continue adding increasing until, until you have a pH of 3.0-3.5.

h. Add water to obtain 100% of the download size and mix to homogeneity by using a propeller-type stirrer.

EXAMPLE XIV

This example presents the composition is flowable gel of the present invention. The procedure presented in stages a-f, gives the composition corresponding to table I. This composition is intended for use for sensitive skin and contains clindamycin phosphate as the active ingredient.

TABLE XVIII
Componentweight%
Clindamycin phosphate, US (equivalent to 1% clindamycin)1,19
Methylparaben0,15
The carbopol® 941 (or 981)0,20
The polyethylene glycol 4005,0
Sodium hydroxide (10% solution)QS to pH of 5.3 to 5.7
Purified waterQS to 100.0

The viscosity of this composition is approximately 1000 SP.

A. Weigh about 90% of the purified water in the boiler is stainless steel. Add polyethylene glycol 400. Stir propeller stirrer.

b. At room temperature add methylparaben to the mixture from stage a) with continuous stirring. Stir to dissolve.

C. while Continuing to mix, add clindamycin phosphate to the mixture from stage b). Stir to dissolve.

d. Continuing to mix, slowly add the carbopol® 981 or 941 to the mixture from stage (C), avoiding the formation of lumps. Vigorously stir at room temperature until, until a homogeneous, lump-free dispersion.

that is, While stirring, a sufficient amount of sodium hydroxide, 10% solution to obtain a pH of 5.3 to 5.7. Stir until smooth.

f. Add on the remaining water to obtain 100% and mix until smooth.

EXAMPLE XV

This example presents the composition is flowable gel of the present invention, and this gel contains a corticosteroid (desonide) as the sole active ingredient. Such a drug suitable for the treatment of inflammatory skin diseases such as atopic dermatitis.

TABLE XIX
Componentweight%
Desonide, fine0,05
The sodium docusinate0,10
The carbopol® 9810,3
Propylene glycol5,0
Methylparaben0,2
Propylparaben0,3
TromethamineQS to pH 5.5
Purified waterQS to 100.00

The viscosity of this composition is approximately 6200 SP.

A. Dissolve the methylparaben and propylparaben in propylene glycol at room temperature using a propeller stirrer.

b. Weighing of 70% by weight of the preparation of purified water and slowly add the solution from step “a” under stirring propeller stirrer.

C. while Continuing to mix, slowly add the carbopol® 981 to the mixture from stage “b”. Stir at room temperature the re as long until you have a uniform and homogeneous dispersion.

d. To 10% by weight of the preparation water add sodium docusinate and stir until dissolved. In order to facilitate the dissolution of the mixture can be heated to 40-50°and then cooling to room temperature, when dissolution is complete.

E. Dispersing fine desonide in the mixture from step “d” by using a propeller stirrer or, preferably, a homogenizer of rotor-stator type.

f. Add the mixture from step “e” to the mixture from step C, using a propeller mixer to evenly atomized medicinal material.

g. Dissolve tromethamine in ten times by weight the amount in purified water. When mixing use tromethamine solution to bring the pH and thickening gel. Continue increasing the add up until the pH reaches about 5.5.

h. Add water to obtain 100% of the download size and mix to homogeneity by a propeller-type stirrer.

All publications and patent applications mentioned in this specification, are included here by reference in the framework, as if a particular publication or patent application were specifically and separately for inclusion in the reference.

Now, after the invention is fully described, the specialist will be clear that it can be made in which were many changes and modifications without departing from the scope of the essence or scope of the attached claims.

1. Composition of water-based gel for topical application having a pH of 3-9 and a viscosity of less than 15,000 JV, for the treatment of skin disease in humans, containing

(a) a therapeutically effective amount of at least one compound suitable for the treatment of such diseases

(b) a hydrophilic, pharmaceutically acceptable polymeric material that is compatible with the connection,

(c) pharmaceutically acceptable base to bring the pH,

(d) optionally, mixed with water, the solvent,

(e) optionally, a preservative and

(f) water.

2. The composition according to claim 1 in which the polymeric material (b) is a partially cross-linked polymer of polyacrylic acid.

3. The composition according to claim 1 or 2, in which the compound is an antibiotic, an imidazole, a retinoid, steroid or non-steroidal anti-inflammatory drug (NSAID).

4. The composition according to claim 3, in which the connection is only antibiotic or antibiotic in combination with a corticosteroid, or a retinoid.

5. The composition according to claim 4, in which the antibiotic is clindamycin phosphate.

6. The composition according to claim 5 having a pH 4,0-7,0 containing

(a) 0.5 to 2.0 wt.% clindamycin phosphate

(b) 0.05 to 1.0 wt.% preferably 0.1 to 0.4 wt.% polymeric material

(c) base to bring the pH,

() 0.0 to 40 wt.% preferably 15,0-25,0 wt.%, mix with water solvent

(e) less than 0.2 wt.% preservative and

(g) QS to 100 wt.% purified water.

7. The composition according to claim 6, having a pH of 5.0-6.0, containing

(a) 1.0 to 1.5 wt.% clindamycin phosphate

(b) 0.1 to 0.4 wt.% polymer material, which is partially cross-linked polymer of polyacrylic acid,

(c) base to bring the pH,

(d) 3-10 wt.% polyethylene glycol 400,

(e) 0.1 to 0.15 wt%. of methylparaben,

(g) QS to 100 wt.% purified water.

8. The composition according to claim 4, in which the antibiotic is combined with a corticosteroid, an antibiotic is clindamycin phosphate and corticosteroid is desonide, hydrocortisone-valerate, fluoqinolona the acetonide, hydrocortisone-butyrate or triamcinolone the acetonide.

9. The composition according to p, 4, or 8, in which the corticosteroid is desonide present in an amount of 0.01-1.0 wt.%.

10. The composition according to claim 4, in which the antibiotic is combined with a retinoid, the antibiotic is clindamycin phosphate and retinoid is tretinoin, preferably clindamycin phosphate dissolved, and tretinoin is suspended.

11. The composition according to PP, 4 or 9, in which the corticosteroid is desonide present in amounts of 0.05-0.1 wt.% and the polymeric material is present in amounts of 0.05-1 wt.%.

12. The composition according to claim 3 or 4, in which Dirk the steroid is halobetasol propionate and the polymeric material is present in amounts of 0.05-1 wt.%.

13. The composition according to claim 11, having a pH of 4-7, and the composition is a gel containing

(a) (i) 0.5 to 2.0 wt.% clindamycin phosphate and

(ii) from 0.01 to 0.05 wt.% tretinoin;

(b) 0.05 to 1 wt.% preferably 0.1-0.5 wt.% polymeric material

(c) base to bring the pH,

(d) 0-40 wt.% preferably 10-30 wt.%, mix with water solvent

(e) less than 0.2 wt.% preservative

(g) QS to 100 wt.% purified water.

14. The composition according to claim 11, having a pH of 5-6, and the composition is a lotion containing

(a) (i) 0.5 to 2.0 wt.% clindamycin phosphate

(ii) from 0.01 to 0.05 wt.% tretinoin;

(b) 0.1-0.5 wt.% polymer

(c) base to bring the pH,

(d) 5-30 wt.% mix with water solvent

(e) less than 0.2% of a preservative,

(f) an oil phase in combination with at least one surface-active substance for the formation of emulsions,

(g) QS to 100 wt.% purified water.

15. The composition according to claim 1 or 2, in which the connection is a non-steroidal anti-inflammatory drug.

16. The composition according to item 15, in which the connection is naproxen, or diclofenac, or their pharmaceutically acceptable salt.

17. The composition according to claim 3, having a corticosteroid as the only active substance.

18. The composition according to 17, in which cortical rod is diflorasone the diacetate, desonide, fluticasone propionate, halobetasol propionate or budesonide.

19. The composition according to claim 3 or 18, having a pH 4,0-7,0, preferably 5-6, containing

(a) 0.01-0.1 wt.%, preferably 0,025-0,5 wt.% desonide,

(b) 0.1 to 0.4 wt.% polymer

(d) 3.0 to 10 wt.% mix with water solvent

(e) less than 0.25 wt.% preservative, preferably the methyl paraben and propyl paraben,

(g) QS to 100 wt.% purified water.

20. Composition according to any one of the preceding paragraphs, in combination with the container, which accurately dispenses to the patient a dose of the composition for local application.

21. The composition according to claim 20, in conjunction with the accompanying instructions for use in the treatment of skin diseases.

22. Composition according to any one of the preceding paragraphs, used for the manufacture of a medicinal product in the form of an aqueous gel with a viscosity of less than 15,000 JV for topical application for the treatment of skin diseases in humans.

23. A method of obtaining a composition according to any one of claims 1 to 22, including

(a) combining water with a therapeutically effective amount of at least one compound suitable for the treatment of skin disease in humans, and a polymer material,

(b) bringing the pH up to 3-9, preferably 4-7,

(c) optionally, combining mixed with water, solvent and to the sideboard for the formation of the composition.



 

Same patents:

FIELD: organic chemistry, medicine.

SUBSTANCE: invention proposes new compounds of the general formula (I):

wherein R1 means one or more similar or different substitutes taken among the group consisting of hydroxy-group, halogen atom including F, Cl, Br and J, (C1-C5)-alkyl, (C1-C5)-alkoxy-group under condition that when R1 means one substitute then it is in ortho-position and when R1 means above one substitute then at least one substitute at R1 is in ortho-position; R2 means halogen atom including F, Cl, Br and J, (C1-C5)-alkyl, (C1-C5)-alkoxy-group; R3 means halogen atom including F, Cl, Br and J; R6 means hydrogen atom or methyl; and its salts with pharmaceutically acceptable acids, hydrates or solvates. Compounds elicit activity against acne and acne-related diseases.

EFFECT: valuable medicinal properties of compounds.

7 cl, 4 tbl, 43 ex

The invention relates to medicine, cosmetology and can be used to treat acne

The invention relates to sunscreen compositions containing a derivative dibenzoylmethane (UV-a filter), such as 4-(1,1-dimethylethyl)-4'-methoxybenzoate and stabilizer derived dibenzoylmethane having the formula (I) or (II), or a mixture of

< / BR>
< / BR>
in which R1the same or different means, each alkyl group having 1-22 carbon atoms or a diol having the structure BUT R2HE or polyglycol, having a structure BUT R3-(-O-R2)mHE, and in which R2and R3identical or different, denote each alkylenes group with unbranched or branched chain, having 1 to 6 carbon atoms, m and n each is 1-100, or a mixture

The invention relates to new compounds of the formula (I)

< / BR>
where AG represents a radical selected from formulas (a) and (b) below:

< / BR>
R1represents a halogen atom, -CH3CH2OR SIG7, -OR SIG7, СОR8, R2and R3taken together form a 5 - or 6-membered ring, R4and R5represent H, a halogen atom, a C1-C10-alkyl, R7represents H, R8represents H orX represents the radical-Y-C-, r' and r" is H, C1-C10alkyl, phenyl, Y represents S(O)nor SE, n = 0, 1, or 2, and salts of compounds of formula (I)

The invention relates to the field of medicine and relates to a composition for local application on the skin to treat skin diseases such as acne, seborrhea, dandruff, etc

The invention relates to new triaromatic compounds of General formula I, characterized in p

FIELD: medicine.

SUBSTANCE: the present innovation deals with describing propofol solubilized in aqueous micellar preparations of poloxamers being stable in low concentration. The innovation proves that these preparations are being efficient forms of propofol introduction. Propofol formulas are easily prepared being non expensive and stable, moreover, they are easily sterilized.

EFFECT: higher efficiency.

14 cl, 4 dwg, 7 ex, 5 tbl

FIELD: medicine, pharmacy.

SUBSTANCE: invention describes sterile anesthetic composition for parenteral administration of propofol emulsified in water for injection. The composition comprise above 3 wt.-% but 6 wt.-% of less of solvent not mixing with water. Propofol is dissolved in indicated solvent. The composition is stabilized with 0.2-1.0 wt.-% of surface-active substance and has pH value level in the range 5.0-7.5. The composition with reduced pH value level allows preventing above 10-fold elevating growth of microorganisms for at least 24 h after random external pollution. Reduced fat content in composition also provides the stable analgetic effect for prolonged time and with reduced risk for the blood fat content exceeding.

EFFECT: improved and valuable properties of composition.

15 cl, 4 dwg, 4 tbl, 3 ex

The invention relates to the field of medicine and relates to a spontaneously dispersible pharmaceutical composition for oral administration comprising (2R,4S)-N-(1 -(3,5-bis(trifluoromethyl)benzoyl)-2-(4-Chlorobenzyl)-4-piperidinyl)quinoline-4-carboxamide as an antagonist of substance P and the carrier medium containing a hydrophilic component and a surfactant, and methods of treatment using the composition of CNS disorders, including depression and fear of society, and respiratory diseases, such as asthma and chronic bronchitis

The invention relates to medicine and colloid chemistry and can be used to obtain blood substitutes in the gas transport function based emulsions performancesin compounds (PFC)

The invention relates to chemical-pharmaceutical industry, in particular to the creation and production of tools for the treatment of skin diseases

The invention relates to the field of pharmaceutical industry and relates to medicines anticongestive actions

The invention relates to the field of medicine and relates to a composition in the form of pre-prepared emulsion or microemulsion concentrate, intended for oral administration and comprising a cyclosporin or macrolide and media, as well as a soft or hard gelatin capsules containing the specified composition, and method of reducing the variability of the bioavailability of cyclosporine or macrolide using the composition
The invention relates to the field of pharmaceutical industry and relates to a product for adaptogenic therapy and method of producing

The invention relates to the field of pharmaceutical industry and relates to nanodisperse in compositions for pharmaceutical use

The invention relates to the field of medicine and relates to a pharmaceutical for the treatment of skin diseases

FIELD: medicine, gynecology, pharmacology, pharmaceutical industry.

SUBSTANCE: invention proposes a preparation that comprises bacterial mass of live microorganisms as an active component, protecting medium and fat base. The preparation comprises lactobacilli as bacterial mass and one or some eubiotic microorganisms taken among the following group: bifidobacteria, streptococci and lactococci taken in the amount per a single dose. Also, the preparation comprises additionally an acceptable sorbent and a biologically active supplement. Also, invention relates to a method for preparing this preparation that involves preparing firstly lactobacilli bacterial mass and one or some genus of eubiotic microorganisms taken among the following group: bifidobacteria, streptococci and lactococci. Then the prepared bacterial mass of microorganisms is immobilized on sorbent used in medicine in its ratio to bacterial mass of microorganisms = (9-1):(1-9) followed by addition of the protecting medium and biologically active supplement to formed mass in the necessary amount. Also, invention describes a method for prophylaxis and treatment of bacterial vaginitis that involves intravaginal administration of the preparation described above in the amount 1-3 doses, 1-3 times per 24 h. The treatment course is prescribed individually. Invention provides expanding assortment of agents used for treatment of bacterial vaginitis. Invention can be used in obstetric-gynecological practice.

EFFECT: improved method for vaginitis treatment, valuable medicinal properties of preparation.

13 cl, 4 tbl, 1 ex

FIELD: medicine.

SUBSTANCE: the present innovation deals with medicinal preparation as an ointment for treating skin burns. The suggested preparation contains bee wax, propolis and vegetable oil. Thus, application of initially intact propolis and bee wax in combination with fatty foundation as vegetable oil enables to cheapen and simplify the technique to prepare the preparation, and optimally matched consistence provides prolonged safety of the preparation and accelerates healing of skin burns.

EFFECT: higher efficiency of therapy.

1 cl, 2 ex

FIELD: organic synthesis.

SUBSTANCE: invention provides a method for preparing water/glycerol complex of (2,3-dihydroxypropyl) ortho-titanate hydrochloride (chloride) having symbolic name "Ephtiderm", which is depicted by following empirical formula: Method consists in that glycerol is mixed with butyl ortho-titanate at molar ratio 12:1, whereupon butanol is distilled off in vacuum, residue is treated with water and aqueous hydrochloric acid to form reaction mass with pH 2.2-3.0, which is heated in vacuum. Method is characterized by that glycerol is mixed with low-grade butyl ortho-titanate and chloroform, reaction mass during the synthesis is maintained at temperature up to 100°C in vacuum 40-200 mm Hg, while chloroform is added at 40-50°C in amount corresponding to 1 L chloroform per 2 L low-grade butyl ortho-titanate.

EFFECT: reduced expenses due to use of low-grade butyl ortho-titanate and simplified technology.

1 tbl, 3 ex

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