Application of adapalene and benzoyl peroxide for long-term treatment of acne vulgaris

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to field of pharmaceutics and represents application of composition, including adapalene and benzoyl peroxide, in preparation of local medication, intended for application by patient who requires it to provide long-term treatment of acne vulgaris, where scheme of application of local medication includes application of therapeutically efficient quantity of composition for, at least, 9 months.

EFFECT: invention ensures achievement of stable positive effect in long-term treatment of acne with composition, including adapalene and benzoyl peroxide, as well as absence of side effects.

19 cl, 1 ex, 3 dwg

 

The invention relates to the use of a composition comprising adapalene and benzoyl peroxide (BPO), in the preparation of local medicinal product intended for administration to the needy in this patient to ensure the long-term treatment of acne vulgaris, and the invention proposes a method long-term treatment of acne with ordinary use of the composition comprising adapalene and BPO.

Acne ordinary represent a widespread skin disorder which is caused by 20% of the references to dermatologists and which affects the majority of the teenage population. Acne treatment is questioned especially when considering the chronic course of the disease and variability in response to treatment.

The treatment of acne ordinary often requires combination therapy and long-lasting therapeutic strategies (e.g., Thiboutot D. New treatments and therapeutic strategies for acne. Arch Family Med 2000; 9: 179-187; Gollnick H1 Cunliffe W, Berson D, et al. Management of acne, a report from a Global Alliance to Improve Outcomes in Acne. J Am Acad Dermatol. 2003;49 (suppl 1):S1-S37). Supportive therapy is necessary for many patients with acne, because it has been shown that damage in the form of acne recur after discontinuation regimens (Gollnick H, Cunliffe W, Berson D, et al. Management of acne, a report from a Global Alliance to Improve Outcomes in Acne. J Am Acad Dermatol. 2003;49 (suppl 1):S1-S37; Thielitz A, Helmdach M, Ropke E-M, Gollnick H. Lpid analysis of follicular casts from cyanoacrylate strips as a new method for studying therapeutic effects of antiacne agents. Br J Dermatol. 2001; 145: 19-27). Prolonged therapy is necessary for many patients with acne to achieve the target of reducing damage in the form of acne, as well as to increase the likelihood of maintaining short-term improvements often recurrent state (Tenaud I, et al., In vitro modulation of TLR-2, CD1d and IL-10 by adapalene on normal human skin and acne inflammatory lesions Exp. Dermatol. 2007 Jun;16(6):500-6; and Thiboutot DM et al. Treatment considerations for inflammatory acne: clinical evidence for adapalene 0.1% in combination therapies, J Drugs Dermatol. 2006 Sep;5(8):785-94. Review. Erratum in: J Drugs Dermatol. 2007 Jan; 6(1): the table of contents).

Despite the variety of drugs available for the treatment of acute acne, there are few studies regarding the safety and efficacy of long-term treatment of patients with acne ordinary.

Currently, the most effective comedolytic agents are isotretinoin oral administration and retinoids topical application (Cunliffe WJ, Holland DB, Clark SM, Stables, Gl. Comedogenesis: some new aetiological, clinical and therapeutic strategies. Br J Dermatol. 2000;142:1084-1091). Isotretinoin oral administration is an impractical option for long-term therapy because of its toxic and teratogenic potential. Medicines for local use against acne, such as retinoids, can be associated with increased irritative skin, thus, re is usemost potential maintenance therapy should be subjected to scrutiny. Skin side effects can reduce the probability of correct adherence to treatment, especially when treating asymptomatic state (Koo J. How do you foster medication adherence for better acne vulgaris management SKINmed. 2003; 2:229-33; and Haider A, Shaw JC. Treatment of acne vulgaris. JAMA. 2004;292:726-735).

Available for local and systemic therapy for the treatment of acne include retinoids, benzoyl peroxide (BPO), antibiotics and hormone therapy. Because acne ordinary include a variety of etiological factors, including follicular hyperkeratosis, increased production of sebum, the proliferation of P. acnes and inflammation, (Thiboutot DM et al. Treatment considerations for inflammatory acne: clinical evidence for adapalene 0.1% in combination therapies, J Drugs Dermatol. 2006 Sep;5(8):785-94. Review. Erratum in: J Drugs Dermatol. 2007 Jan;6(1): table of contents; Pariser DM, Westmoreland P, Morris A, Gold MH, Liu Y, Graeber M. Long-term safety and efficacy of a new fixed-dose combination of adapalene 0.1% and benzoyl peroxide 2.5% for the treatment of acne vulgaris. J Drugs Dermatol. 2007; 6(9):899-905; Thiboutot DM, Bucko A, Eichenfield L, et al. Adapalene-benzoyl peroxide, a new fixed-dose combination for the treatment of acne vulgaris: results of a randomized, multi-centre, double-blind, controlled study. J Am Acad Dermatol. doi:10.1016/j.jaad.2007.06.006. Published online July 24, 2007), as long therapeutic strategies used combination therapy using agents with complementary mechanisms, such as retinoid topical application and an antimicrobial agent.

This manual is recommended early initiation of combination t is rapie using retinoids topical application and use of antimicrobial agents for all cases of acne, but for the most severe cases with subsequent support retinoid therapy topical application together with benzoyl peroxide (BPO) or in its absence (Thiboutot DM, et al., J Drugs Dermatol. 2006 Sep;5(8):785-94. Review. Erratum in: J Drugs Dermatol. 2007 Jan;6(1): the table of contents). Although the use of additional agents increases the complexity of treatment regimens, combination therapy is effective when applied to acne multilateral pathophysiological nature. Combined products with a fixed dose can help patients and doctors to reduce the complexity of the treatment of acne by reducing the number of medicines that the patient should remember to take daily, whereby potentially improving adherence to treatment. Despite the potential advantages, there are relatively few products combined with a fixed dose available for the treatment of acne. Several combinations BPO-antibiotic available in addition to the product that unites retinoid topical application and local antibiotic application (Harkaway KS, McGinley KJ, Foglia AN et al. Antibiotic resistance patterns in coagulase-negative susceptible after treatment with topical erythromycin, benzoyl peroxide, and combination therapy. Br J Dermatol. 1992; 126(6):586-90; Thielitz A, Krautheim A, Gollnick H. Update in retinoid therapy of acne. Dermatol Ther. 2006; 19(5):272-9; Adapalene-benzoyl peroxide, a new once-daily fixed-dose combination for the treatment of acne vulgaris: a radomized, bilateral (split-face), dose-assessment study of cutaneous tolerability in healthy subjects. Cutis. Submitted).

However, currently there is not a combination product containing BPO and retinoid topical application, a combination that is both compatible with the recommendations of the guidelines for short-term and long-term treatment of acne.

Thus, there is a need in the emergence of effective and safe drugs that would meet at the same time short-term and long-term treatment of acne.

The present invention offers a safe and effective composition that includes adapalene and benzoyl peroxide used for long-term treatment of acne ordinary.

Thus, the first embodiment of the present invention is a use of a composition, which in the preferred embodiment is a combination with a fixed dose, including adapalene and BPO, in the preparation of local medicinal product intended for administration to the needy in this patient to ensure the long-term treatment of acne vulgaris, where the scheme of local administration of drugs includes the introduction of a therapeutically effective amount of the composition for at least 4 months, preferably for at least the least 6 months, more preferably for at least 9 months, most preferably for at least 12 months. Local medicinal product is administered daily and preferably once a day. In another embodiment of the local medicinal product is administered every two days, and preferably once a day.

In both cases, local medicinal product is administered in the evening after cleansing the skin procedure.

In the preferred embodiment of the local medicinal product is a gel composition.

Local drug includes at least about 0.001% adapalene by weight relative to the total weight of the composition, preferably includes 0,01%-2% adapalene by weight, preferably includes at 0.01%and 0.5% by weight, most preferably 0,1%-0,3% adapalene by weight relative to the total weight of the composition. The drug also includes 0,025%-20% BPO by weight, preferably includes a 0.5%-10% BPO by weight, most preferably 2%-10%, most preferably of 2.5%-5% BPO by weight relative to the total weight of the composition.

Another embodiment of the invention is a use of a composition comprising adapalene and BPO, in the preparation of local medicinal product intended for administration to the patient to maintain its biological response in the treatment of acne vulgaris, where CX is the mA of local administration of medicines involves applying to the affected skin adapalene in number, which is in the range of 0.01%and 0.5% by weight, and BPO in the number that is in the range of 2%-10% by weight relative to the total mass of the composition for at least 4 months, preferably for at least 6 months, more preferably for at least 9 months, preferably for at least 12 months. Specifically, one embodiment of the invention is a use of a composition comprising adapalene and BPO, in the preparation of local medicinal product intended for administration to the patient to maintain its biological response in the treatment of acne vulgaris, where the scheme of local administration of medicines involves applying to the affected skin adapalene in the amount of 0.1% by mass, and BPO in the amount of 2.5% by weight, once a day, every day for at least 6 months, preferably for at least 9 months, more preferably for at least 12 months.

According to these embodiments, the local drug is applied to the affected skin, which contains preferably 20-100 nevospalennyh damage and/or 20 to 50 inflammatory lesions, and does not contain active nodules or cysts, and in a preferred embodiment the composition is a gel composition. In another voploshennaia the invention concerns a method of providing long-term treatment of acne ordinary we need in this patient, including topical application to the affected skin an effective amount of a composition comprising adapalene and benzoyl peroxide in a pharmaceutically acceptable carrier. The composition is applied topically for at least 4 months, preferably used for at least 6 months, preferably for at least 9 months, more preferably for at least 12 months.

The term "pharmaceutically acceptable carrier" means a carrier that is compatible with the skin, mucous membrane shell and the outer cover.

The term "fixed combination" should be understood as a symbol combination, whose active ingredients are combined in fixed doses in the same filler/carrier (formula one), which brings them together at the point of application. Preferably the pharmaceutical composition is in the form of a fixed combination represents the gel; in this case, two of the active component in the process of getting dispersed and well mixed in the same filler, which performs joint delivery during gel application.

More specifically, the present invention is described to evaluate the clinical characteristics of long-term action of this combination with a fixed dose using 12-month study evaluating b is opasnosti and effectiveness of gel combination adapalene-BPO fixed-dose daily use once a day for the treatment of subjects, having acne is common, when used daily, once a day for up to 12 months.

Also in the present invention have been efforts to develop effective compositions for dermatological diseases, allowing for daily use once a day, and convenient use for the patient.

However, the composition including BPO and retinoids, presents difficulties. First of all, the effectiveness of BPO related to its disintegration in contact with skin. Indeed, with the collapse of the oxidative properties of free radicals provide the target effect. With regard to optimum efficiency BPO, it, therefore, is critical to prevent its collapse during storage. In addition, BPO is an unstable compound, which hardly include part of the combined products.

The solubility and stability of BPO were investigated Chellquist et al. in ethanol, propylene glycol and mixtures of polyethylene glycol 400 (PEG 400) and water (Chellquist E. M. Gorman et W. G., Pharm. Res., 1992, Vol.9: 1341-1346). The authors noted that BPO in solution degrades to a greater or lesser extent according to the solvent and its concentration.

Time degradation BPO in PEG 400 (0.5 mg/g), in ethanol and propylene glycol, respectively 14, 29 and 53 days at 40°C. This degradation is not compatible with kommercializirovannyh products. Other technical PR the problem, you want to allow to obtain a composition containing both adapalene and BPO, is a chemical and physical compatibility of these compounds within a single structure, provided that the usual retinoids are sensitive to natural oxidation, to a visible light and ultraviolet, and BPO is a strong oxidizing agent.

Indeed, BPO triggers rapid degradation of sensitive natural oxidation of retinoids: 50% of retinoin degrades within 2 hours, and 95% degraded within 24 hours. On the contrary, taking into account the composition according to the invention, where adapalene is a retinoid, no degradation adapalene not detected within 24 hours. In the context of the present invention BPO can be used in free or encapsulated form, for example in adsorbed form BPO or absorbed form within any porous substrate. He may represent, for example, encapsulated BPO in the polymer system consisting of porous microspheres, such microgram sold under the trademark Microsponges P009A benzoyl peroxide from Cardinal Health.

Adapalene (6-[3-(1-substituted)-4-methoxyphenyl]-2-naphthoic acid) is a derivative of naphthoic acid with potential retinoid and anti-inflammatory properties. Daalen was developed for the topical treatment of acne and other ordinary sensitive to retinoids dermatosis, including a variety of disorders of keratinization, proliferation and differentiation. Adapalen operates mainly through the regulation of differentiation of keratinocytes (comedolytics effect and preventing the formation of new comedones), but also has anti-inflammatory activity. In particular, adapalene is a highly portable retinoid topical application. Adapalen sold under the trademark Differin® with the mass concentration of component 0.1%, in the form of a solution in the form of "alcohol lotion, in the form of water-soluble gel and cream form. These compositions are intended for the treatment of acne.

The present invention also includes salts adapalene. Under salt adapalene indicated salts formed with pharmaceutically acceptable base, especially with mineral bases such as sodium hydroxide, potassium hydroxide and ammonium or organic bases such as lysine, arginine or N-methylglucamine. The term "salt adapalene" also refers to salts formed with fatty amines, such as dioctylamine and stearylamine.

In addition, the patent application WO 03/055472 describes a stable pharmaceutical composition comprising adapalene and benzoyl peroxide (BPO).

Published minor adverse effects associated with adapalene include usually the s signs and symptoms of local irritative reactions (erythema, peeling, dry skin, itching, burning and stinging), rare cases of local allergic reactions (edema at the application site, contact eczema, or dermatitis, or other skin and nasal disorders (very rare cases of hypopigmentation and hyperpigmentation, photosensitive reactions, thinning hair, hair growth, erosion of the skin after any facial). However, adapalen and other effective retinoids have been studied only with short-term clinical trials (12 weeks). Thus, there is a need to develop a safe and effective method of long-term treatment of acne vulgaris, and, in addition, without inducing bacterial resistance. BPO is a well-studied antimicrobial agent which is more effective in suppressing P acnes than antibiotics topical application, with no signs of resistance to him microorganisms.

Because retinoids do not create selective pressure for resistance, it is expected that this combination will reduce the occurrence of epidermal resistance of bacteria against antibiotics.

In addition, as shown in the example, the composition of the present invention, which is a combination adapalene and benzoyl peroxide (BPO) with a fixed dose found in the current a lengthy study is AI good tolerability, security and type of endurance, like monotherapy adapalene.

Mostly this composition includes BPO in number, which is in the range of 0.0001 to 20% by weight, and adapalen, in an amount which is in the range of 0.0001 to 20% by weight relative to the total weight of the composition; preferably respectively BPO of 0.025-10% by weight, adapalen 0.01 to 2% by weight relative to the total weight of the composition.

Preferably and as an example, in compositions intended for the treatment of acne, BPO is used in concentrations which are in the range of 2-10% by weight and preferably in the range of 2.5 to 5% by weight relative to the total weight of the composition. In this type of composition, adapalene is used in a concentration that is in the range of 0.01-1% by weight and preferably in the range of 0.01 to 0.5%, most preferably 0.1 to 0.3% by weight relative to the total weight of the composition. Mainly particles adapalene and BPO have a size such that at least 80% of the particles and preferably at least 90% of the particles have a diameter less than 25 microns and at least 99% of particles have a diameter less than 100 microns.

The aim of the present invention is to offer an effective way to treat acne ordinary on a continuous basis using a composition that combines adapalene and BPO. Another goal of the infusion is his invention is to offer long-term treatment of acne with ordinary high efficiency and comparable tolerability using high efficiency adapalene and BPO compared to short-term research. The invention also relates to a method of treatment of a patient affected by the disease in the form of acne vulgaris, and the method comprises topical application to the affected skin area of the patient local medicines (which here is a dermatological preparation), includes the introduction of a therapeutically effective amount of a composition comprising adapalene and BPO at least every two days, preferably at least once every two days. More preferably, the composition is injected daily, preferably once daily for at least 6 months, more preferably once daily for at least 12 months. Local medicinal product, which is a dermatological preparation can be applied to the affected area of the skin in the evening after cleansing skin treatments, preferably once daily.

More specifically, the present invention proposes the use of adapalene and BPO in the preparation of local medicinal product intended for administration to the patient to maintain its biological response in the treatment of acne vulgaris, where the scheme of local administration of drugs includes the introduction of adapalene in the amount of 0.1 mass% and BPO in number, amounting to 2,% by weight, once daily for more than 3 months, preferably for at least 4 months, more preferably for at least 6 months, more preferably for at least 9 months, most preferably for at least 12 months.

The invention also relates to a method long-term treatment of acne vulgaris, comprising the topical application to the affected skin of the patient local medicines, including adapalene in the amount of 0.1% by mass, and BPO in the amount of 2.5% by weight, once daily for more than 3 months, preferably for at least 4 months, more preferably for at least 6 months, more preferably for at least 9 months, most preferably for at least 12 months.

Local medicinal product is presented in a form that is compatible with the local introduction and, in particular, in the form of a gel, cream, lotion, emulsion, suspension.

Preferably local medicinal product is a gel composition, and more preferably is a water-soluble gel composition, comprising adapalene in the amount of 0.1% by mass, and BPO in the amount of 2.5% by weight, and applied to the affected the auger for at least 4 months more preferably for at least 6 months, most preferably for at least 9 months, preferably for at least 12 months. Local drug is particularly effective when the affected skin contains 20-100 nevospalennyh damage 20-50 inflamed lesions and does not contain active nodules and cysts. For a better understanding of the invention, used his advantages and the specific objectives attained through its use, must be referenced on the drawing and text material, in which are illustrated and described preferred embodiments of the invention.

In the drawings:

Figure 1 shows the time dependence of the average relative change in the number of injuries. The mean Relative Change in the Number of Lesions (ITT population, Observed Data, and Month 12 LOCF) Expected outcome: the latest available data observed during the study. Used original value, if the data after the initial point of the survey were not available.

Figure 2 shows the time dependence of the local skin irritation (higher than the data at the starting point of the study, the observed data and the score of the last data). The percentage of subjects with grade rating higher than at the starting point of research in each mo is UNT of time together with the expected result.

Figure 3: shows the local Tolerability display marks the Latest Data and Scoring Data Deterioration (Population Security)

"Last data" refers to the latest available data observed during the period after the starting point of the study.

Data "Deterioration" refers to the observed data the greatest severity in the period after the starting point of the study.

In the present invention proposes a method long-term treatment of acne ordinary by applying a gel composition containing adapalene in the amount of 0.1% by mass, and benzoyl peroxide in the amount of 2.5% by weight. This product is described in a patent application WO03/055472. Next is described a study that clearly demonstrates the clinical benefit of long-term treatment of acne using the above composition.

ExampleClinical test long-term treatment of acne ordinary using gel combination with a fixed dose containing adapalene in the amount of 0.1%and BPO in the amount of 2.5% by weight relative to the total weight of the composition.

Study design and subjects

The safety and efficacy of prolonged treatment with gel combination adapalene-BPO with fixed the bathtub dose was evaluated in a multicenter, open, no comparative study conducted at 28 centers in the United States.

Subjects with disease in the form of acne vulgaris, applied to the face once a day every day adapalene-BPO for up to 12 months.

Evaluation of safety and effectiveness conducted at the origin, at 1 week, 2 week, and months 1, 2, 4, 6, 8, 10, and 12. Urine test for pregnancy is required for all women of childbearing potential at the origin, and when viewed in the latter study. The subjects were free to withdraw from the study at any time and for any reason. State actors have not completed the whole study could be assessed, when possible.

In General was involved 452 subject in 28 research centers in the United States. All 452 subject has used an investigational drug at least once and were analyzed simultaneously in populations the safety and efficacy (ITT). The study involved subjects men and women aged 12 years or older, with 30-100 nevospalennyh facial injuries 20-50 inflamed facial lesions and no active nodules or cysts. Certain periods of neutralization was required for subjects who are taking certain local and systemic treatment. Exclusion criteria prevented the inclusion of subjects with serious the Loy acne, requiring therapy with isotretinoin, or subjects with other dermatological conditions requiring counter treatment. Women were excluded if they were pregnant, nursing, or planning pregnancy, as well as men with facial hair, which would preclude assessment.

TABLE 1
Summarizing the DEMOGRAPHIC DATA ABOUT the SUBJECTS AND baseline CHARACTERISTICS (ITT POPULATION)
Total (N=452)
Gender
Men222 (49,1%)
Women230 (50,9%)
Only452 (100,0%)
Age (Years)
N452
Value18,3
The standard Deviation6,62
Average16,0
Min, Max 12,50
Age category (Years)
12-17299 (66,2%)
18-64153 cases (33.8%)
65 and above0
Only452 (100,0%)
Race
Caucasian345 (76,3%)
Black53 (11,7%)
Mongoloid10 (2,2%)
Americanada31 (6,9%)
Other13 (2,9%)
Only452 (100,0%)
Photo Skin Type
I12 (2,7%)
II105 (23,2%)
III162 (35,8%)
IV87 (19,2%)
V61 (13,5%)
VI 25 (5,5%)
Only452 (100,0%)

Assess the safety and efficacy

Safety and tolerability were assessed through surveys of local facial tolerability and side effects. At each visit, the researcher assessed erythema, peeling, dryness, burning/burn on a scale from 0 (absent) to 3 (severe manifestations). Side effects were assessed at each visit. Normal laboratory data (Hematology, chemical analysis of blood and urine analysis) were collected for screening at 6 month and 12 month. Efficacy parameter was the percentage decrease in the number of injuries relative to the origin of the study (all, inflamed, nevospalennyh), and assessed the condition of acne entity (on a scale from 0 [improvement] to 5 [deterioration]). The number of lesions were evaluated only on the face except for the nose.

The parameters of efficacy and safety

Table 2 represents the scheme of assessment measurements during the study.

TABLE 2
The SCHEME of MEASUREMENTS of EFFICACY AND SAFETY
ScreeningThe starting point of the research the project Weeks. 1 and 2Months. 1, 2 and 4Months. 6Months. 8Months. 10Months. 12/inspection for terminations
Efficiency
The number of lesionsXXXXXXXX
Assessment of acne subjectXX
Security
Local tolerabilityXXXXXXX
Side effects XXXXXXX
The blood and urine testsXXX
Weeks. = Week
Months. = Month

The researcher (or responsible person) assessed the effectiveness, consisting of counting the number nevospalennyh lesions (open and closed comedones) and counting the number of inflamed lesions (papules and pustules and nodules/cysts. Counting the number of lesions was performed only on the face. Assessment of acne subject also documented.

The number nevospalennyh and inflamed lesions were counted on the forehead, on the left and right cheeks and chin above the jaw bone (except the nose). The total number of injuries was calculated using the sponsor. Used the following definitions:

Nevospalennyh damage

- Open comedo: weight of fatty material compacted for open follicularis hole (eels).

- Indoor Comed is n, the weight of the fatty material, sealed behind closed follicularis hole (white eels).

Inflamed damage

- Papule: a small hard swelling with a diameter of less than one centimeter.

- The pustule: a Small limited swelling of the skin, which contains a yellow-white exudate.

Nodule/Cyst: a Limited swollen damage in diameter, usually more than 1 cm

Subjects rated their facial acne on 6 month and 12 month/inspection for terminations compared to inspection at the starting point of the study according to the following scale:

TABLE 3
1A noticeable Improvement
2The average Improvement
3The minimum Improvement
4Unchanged
5Deterioration

Evaluate the security settings were: local tolerability (erythema, scaling, dryness, stinging/burn), side effects (PE), and standard laboratory data (Hematology, chemical analysis of blood and urine analysis). Side effects, expected the during treatment with retinoids topical application, include erythema, scaling, dryness, stinging/burning. During the study a number of these events were assessed as local tolerability.

Erythema, scaling, dryness, stinging/burn evaluated on the following scale:

TABLE 4
ERYTHEMA: ABNORMAL redness of the SKIN
No0Erythema no
Small1There is easy rotatet
Average2Some redness, identifiable
Severe manifestations3Intense redness

TABLE 5
PEELING: ABNORMAL LOSS of the stratum corneum
No0No peeling
Small1A barely noticeable loss, visible only when light scratching or friction
Average2Regular, but not excessive loss
Severe manifestations3Process strong exfoliation

TABLE 6
DRYNESS: a SENSE of FRAGILITY AND/OR RETRACTION
No0Dryness is missing
Small1Easy, but a certain roughness
Average2The average roughness
Severe manifestations3Noticeable irregularity

TABLE 7
BURNING/BURNS: the TINGLING SENSATION IMMEDIATELY AFTER DOSE
(Within 5 MINUTES)
No0No burning/burns
Small1Average2A certain feeling of warmth, tingling/burning sensation that causes anxiety
Severe manifestations3The sensation of heat, tingling/stinging, which cause some discomfort

Erythema, desquamation and dryness were evaluated with the help of the researcher. Burning/burn evaluating with the Researcher after discussion with the subject.

Indicators of local tolerability signs and symptoms of irritation of the skin suggested the presence of side effects only if the severity of the expected signs and symptoms was this that led to the termination of participation of the subject in the study at his/her request or at the discretion of the researcher. The modified scheme doses (such as the introduction of a day) for the treatment of irritation is not anticipated termination of participation of the subject in the study.

Side effects (PE)

PE was defined as any unwanted or unintended sign, symptom, or disease temporarily associated with the use of drugs (research) of the product, associated or not with research is their product. Any new sign or symptom of a disease or clinically significant increase in the intensity of an existing sign, symptom or disease is considered as a PE. This includes any new signs or symptoms, which suffers from the subject after accidental or intentional overdose or misuse. The lack of efficacy of the investigational medicinal product does not require any PE until then, until it leads to unwanted medical manifestations. However, clinically significant worsening of the disease, plunge treatment, suspected PE. Pregnancy did not assume the presence of PE, but was an important event from a medical point of view.

The severity of PE was assessed as small, medium, or heavy. Link PE with the investigational medicinal product has been evaluated as: related (possibly, probably or definitely related, or not related (unlikely or definitely not related).

Severe side effects (TPE)

TPE was defined as any adverse medical manifestation of that at any dose:

- has resulted in death, was life-threatening (i.e. the subject was exposed to the risk of death during the manifestation of this effect, but no such effect, which hypothetically can cause death if it is more tan elem);

- required admission to hospital or prolongation of existing hospitalization (do not create TPE hospitalization solely for carrying out diagnostic tests, even if they are associated with side effect of elective hospitalization for any intervention before the subject has been accepted for participation in the study or treatment center day care);

- has resulted in persistent or significant disability/incapacity, or

- has resulted in hereditary anomalies/appearance of the defect, or

- other important health effects that jeopardize the subject or may require intervention to prevent one of the consequences listed above.

Conventional lab tests

The blood and urine samples were obtained according to the plan described in the study design Table 1. Evaluated the following parameters chemical analysis of blood protein, albumin, globulin ratio (A/G, bilirubin (total), the alanine transaminase (ALT), the aspartate transaminase (AST), alkaline phosphates, gamma glutamyltransferase GGT, lactic acid dehydrogenase (LDH), urea nitrogen, blood (BUN), creatinine, uric acid, cholesterol (total), triglycerides and glucose.

Evaluated the following hematological parameters: hematocrit, hemoglobin, the number is on erythrocytes, the average volume of erythrocytes (MCV), mean hemoglobin in the red blood cell (MCH), the average concentration of hemoglobin in the red blood cell (MCHC), leukocyte counts, and platelet count.

Performed regular analysis of urine for the following parameters: color, clarity, specific gravity, pH of urine, glucose, protein (qualitative analysis), ketones, occult blood, bilirubin, nitrite and leukocytes.

Statistical analysis

Because this study was an open, conducting presentations only descriptive data. Not tested formal statistical hypotheses. Descriptive statistics were used to summarize all the data. For continuous variables, the number of subjects (N), mean value, standard deviation (SD), mean, minimum and maximum values for the data collected at each visit, and presents changes/percentage changes relative to the original point of the study at each visit after the initial point of the study. For categorical variables presents the frequency and percentage of each category.

All summation characteristics of the subject and effectiveness data were carried out on the basis of population, formed in accordance with the assigned intervention (ITT), (this population consists of all involved subjects for whom intended the right investigational medicinal product). All safety information is based on population security (all subjects who received the investigational drug at least once).

Analytical examinations were performed according to the algorithm for summarizing data on the duration of treatment. If there were multiple measurements within the same interval, then used for the analysis dimension, the near-to-day case studies. If two measurements are made with equal differences in the schedule compared to the target of the day, for the analysis used data obtained from the nominal number of inspections (recorded in individual registration card). For example, if the measurements were collected at Day 360 Day and 367, the data collected at Day 360, used for analysis of Month 12, whereas the data collected in Day 367, used for analysis of the end point of the study. Although used for the analysis all the data obtained during the inspection, some of the data used for analysis due to multiple observations within the interval between checks.

Data subjects for all treated subjects summarized in four blocks of research: "the starting point of the research - <3 month, 3 months <6 months" "6 months - <9 months, and 9 months - 1 year. Was tabulirovanie the number of subjects, Podgorze who were at increased risk in each period (i.e. the subjects available at the beginning of each period). The number of subjects at risk is determined on the basis of the duration of treatment of each subject. For these calculations it was assumed that each month contains 30 days, and used 7-day intervals between examinations. Thus, the starting point of the research - <3 months" represents the interval from Day 1 to Day 82, "3 months - <6 months" represents the interval from Day 83 to Day 172, "6 months to <9 months" represents the interval from the Day 173 until the Day 262, "9 months - 1 year" represents the interval from Day 263 until the Day 352, and "1 year and over" represents the interval from the Day 353 and more.

On the same principle were aggregated information about subjects that completed/terminated the study, number of subjects and within four blocks. The extent of the termination of the study for each quarter was calculated as the number of subjects who discontinued the study during this period divided by the number of subjects at risk at this time. Planned security settings, which should be analyzed, represented as follows:

1. Evaluation of local tolerability (erythema, peeling, dryness, burning/burn) had to assess the starting point of the study and at each visit after the similar point of the study on a scale from "0" (=No) to "3" (=Severe manifestations).

2. PE should be assessed at each visit.

3. Normal laboratory data (Hematology, chemical analysis of blood, urine) should be collected at screening, month 6 and month 12/inspection in case of early termination of the study.

Planned performance parameters that should be considered, were:

1. Percentage change relative to the origin of the study the number of facial inflammatory lesions, nevospalennyh facial damage and total Damage in the prescribed examinations after the initial point of the study.

2. Assessment of acne subjects on a scale of "5" (Deterioration) to "0" (improvement) in month 6 and month 12/inspection in case of early termination of the study.

The number nevospalennyh damage was the sum of open comedo and closed comedones. The number of inflamed lesions represented the sum of papules and pustules. A number of other damage was the sum of nodules and cysts. The total amount of damages was the amount of inflamed, nevospalennyh and other damage. Assessment of acne entity was evaluated on a scale from 5 (Deterioration) to 0 (Complete improvement).

Population, formed in accordance with the assigned intervention (ITT), was defined as all involved in the investigated the e subjects, which is a drug. Population security was defined as all involved in the study, the subjects who used the investigational medicinal product at least once. Was tabulirovanie the number of subjects for which there were deviations from the conditions of the main Protocol. For this study did not define the population (PP) to meet the requirements of the Protocol and completed the study violence.

All data analyses were conducted according to a predetermined plan analysis. Sample average of 450, was chosen to ensure that approximately 300 subjects will be exposed to adapalene-BPO for at least 6 months, and 100 will be exposed to during the period of 1 year. All safety data were summarized on the basis of population security. Side effects were tabulirovanie in the form of tables of distribution and summarized by quarter to evaluate the side effect profile over time. Parameters tolerability (erythema, peeling, dryness, burning/burn) summarized using a scoring force in these processes. The table shifts to laboratory data for screening against the last inspection in the period after the starting point of the study was tabulirovanie for each laboratory parameter. All performance data summarized on the Nove ITT population. Summarized data on the amount of damage collected at each visit, as well as changes and percentage changes relative to the original point of research when examining the period after the starting point of the study. Was tabulirovanie assessment of acne subjects. Used descriptive statistics to summarize the data. Not tested formal statistical hypotheses.

Population security was defined as all patients randomized and treated at least once. Population, formed in accordance with the assigned intervention (ITT)included all randomized subjects who approved the investigational medicinal product. In each moment of time evaluating the effectiveness was evaluated using the observed data and methodology using a prolongation of the last observation (LOCF). Was tabulirovanie the number of subjects for which there were deviations from the underlying Protocol. For this study did not define the population (PP) to meet the requirements of the Protocol and completed the study violence.

RESULTS

Disposition of subjects and characteristics of the source point of the study

Only 452 of the subject involved in the study (table 1). All 452 subject has used an investigational drug at least about the in time, and were analysed in the ITT population and in the population security. 397 (87,8%) of the subjects were assessed for 3 months or more, 366 (81%) were evaluated for 6 months or more, and 334 (73,9%) were evaluated for 9 months or more. In total, 327 (72,3%) subjects completed the 12-month study. Average length (±SD) exposure was 294,6 days (±117,7). No single actor has discontinued the study due to the lack of efficiency, and the percentage of termination due to adverse effects was low (2%). The characteristics of the original point of the study ITT population are summarized in Table I.

Evaluation of effectiveness

The results of the percentage change of the number of injuries in the ITT population is shown in figure 1 and in table 8.

The total number of lesions
TABLE 8
SUMMATION INFLAMED, NEVOSPALENNYH AND TOTAL DAMAGE: AVERAGE NUMBER AT the starting POINT of the STUDY AND the AVERAGE PERCENTAGE CHANGE RELATIVE to the INITIAL POINT of the STUDY AT EACH visit AND AT MONTH 12 LOCF (ITT POPULATION)
TimeNThe number of inflamed lesionsNThe number nevospalennyh damageN
The number at the starting point of research45227,045242,045272,0
Week 1423-21,9%423-19,3%423-19,4%
Week 2429-32,1%429-31,7%429-31,0%
Month 1415-42,5%415-43,3%415-43,2%
Month 2426-53,7%426-54,0%426-53,7%
Month 4390-69,3%390-64,8% 390-65,4%
Month 6361-69,4%361-61,9%361-64,8%
Month 8341-74,1%341-70,6%341-70,1%
Month 1329-74,4%329-68,8%329-69,4%
Month 10327-76,0%327-70,0%327-70,8%
Month 12 LOCF452-69,5%452-65,7%452-64,9%

For 327 subjects who remained in the study until its examination in Month 12 (completed cases), the percentage reduction in General, the number of inflamed the nevospalennyh damage amounted to 70.8%, 76% and 70%, respectively. When I examined the data for the ITT LOCF, the average percentage reduction relative to the original point of the study in General, the number of inflamed and nevospalennyh damage amounted to 64.9%, respectively, of 69.5%, and 65.7% in month 12, respectively. Reduce inflamed, nevospalennyh and total damage was observed already in week 1. For patients remaining in the study, the number of injuries continued to decline during the first 4 months of the study, and the decrease continued throughout the time of the study.

Evaluation of the subjects showed clinical improvement during treatment with adapalene-BPO within 12 months. At the end of the study, 330 subjects (330/411, 80.3 per cent) reported average, significant or complete improvement of 45 subjects (45/411, 10,9%) reported minimal improvement and 36 subjects (36/411, 8,8%) reported no change or worsening. The results were similar regardless of age, gender or race.

Figure 1 illustrates the effect of combined therapy with adapalene-BPO on facial acne within a 12-month course of the study.

TABLE 9
SUMMARIZATION EVALUATION of ACNE SUBJECTS (ITT POPULATION, 12 MONTH OBSERVED DATA, AND MONTH 12 LOCF)
Assessment of acne entitiesMonth 6Month 12Month 12 LOCF
0 = Complete improvement17 (4,7%)40 (12,2%)43 (10,5%)
1 = marked improvement149 (41,5%)164 (50,2%)193 (47,0%)
2 = Average improvement147 (40,9%)77 (23,5%)94 (22.9 per cent)
3 = Minimal improvement31 (8,6%)37 (11.3 per cent)45 (10,9%)
4 = No change11 (3,1%)6 (1,8%)20 (4,9%)
5 = Worsening4 (1,1%)3 (0,9%)16 (3,9%)
Only359 (100,0%)327 (100,0%)411 (100,0%)
Month 12 LOCF: last available data during the extension study. The value of the similar point of research used in the case if the data in period after starting points of the study were not available.

Safety assessment

Evaluation of local tolerability

The parameters of the local tolerability (erythema, scaling, dryness, stinging/burn) summarized using scoring at each visit, the strength of these processes on a scale of 4 points (from 0=absent to 3=severe manifestations). Each score of the subject corresponding to the "Deterioration" and "Last data", summarized, where "Impairment" meets the highest scoring, and "Last data" corresponds to the last observation in the time period after the starting point of the study.

At each visit in the period after the starting point of the study was tabulirovanie the number of subjects whose data local tolerability were worse (higher score than the score at the starting point of the study. Scoring for each subject was tabulirovanie in excess of the point estimates, corresponding to the "Deterioration" and "Last data", on point estimates at the starting point of the study.

In General, the treatment of subjects with disease in the form of acne, using adapalene-BPO was safe and well-tolerated when used for up to 12 months. Scoring on the power of erythema, peeling, dryness, GIE the Oia/burn analyzed after treatment are summarized in figure 2. Local skin tolerability of the investigational treatment was good throughout the study, where all secondary scoring portability for erythema, peeling, dryness, burning/burn was less than 1 (slight symptoms) at each visit during the study period. Average values for the worst score of all subjects were associated with a small irritating. The average values of the highest score of the skin were recorded during the first visit, after the initial point of the study (week 1), and then decreased to levels similar point estimates at the starting point of the study.

Erythema, scaling, dryness, stinging/burn distributed when viewed at the starting point of the study and at each visit after the initial point of the study on a scale from "0" (=No) to "3" (=Severe symptoms). For each of the signs and symptoms and the results were similar. The worst scoring the severity of the match, usually small or medium-sized displays, and rarely severe. Using estimates of local tolerability in Table 10 for the subjects represented by the summation of the score, which is worse than the starting point of the study. Frequency score local tolerability, corresponding to severe manifestations, ranged from 0.4% to 3.3% for all signs and symptoms.

TABLE 10
SUMMARIZING DATA ON estimates of the LOCAL TOLERABILITY - PERCENTAGE of SUBJECTS WITH POINT ESTIMATES is WORSE THAN the starting POINT of the STUDY (POPULATION SECURITY)TimeNErythemaNPeelingNDrynessNBurning/burnsWeek 1 (completed)42329,3%42340,2%42345,2%42350,8%Week 2 (completed)42919,8%42929,4%42931,5%42924,0%Month 1 (completed)41516,1%41520,5%415 25,5%41519,3%Month 2 (completed)42613,4%42616,4%42621,6%42611,5%Month 4 (completed)3894,6%3898,0%38911,8%3895,9%Month 6 (completed)3617,8%3617,8%3619,1%3616,4%Month 8 (completed)3417,9%34110,0%34113,8%3418,2Month 10 (completed)329 7,0%3299,1%32911,9%3297,3%Month 12 (completed)3275,5%3274,6%3279,2%3275,8%The latest data4487,4%4489,4%44814,1%4488,5%Maximum deterioration44848,0%44861,8%44865,2%44866,1%Recent findings: the Latest available data, observed in the period after the starting point of the study.
Deterioration: the Observed data with the highest severity in the period after the starting point of the research is of.

During the first week of treatment with a gel containing adapalene/benzoyl peroxide, have been reported in the majority of point estimates corresponding to the estimated local tolerability, which were worse than scoring at the starting point of the study, namely, about 29.3% of subjects with symptoms of erythema, 40.2 per cent, signs of peeling, 45.2% of symptoms of dryness and 50.8%, signs of burning/burn (table 10). However, manifestations of erythema, peeling and burning/burn quickly decreased to 4 months was reported about 10% of the subjects or less with these manifestations. Symptoms of dryness was less than 12% to 4 months, and after 4 months ranged from 9% to 14% for the remaining study subjects. The expected signs and symptoms of local skin irritation ranged in severity from small to medium.

Very few subjects had scoring corresponding to severe manifestations. (Table 11).

TABLE 11
SUMMARIZING DATA ON estimates of the LOCAL TOLERABILITY, WHICH WERE WORSE THAN AT the starting POINT of the RESEARCH IS SCORING DETERIORATION (POPULATION SECURITY)
Local tolerability worse than in the original stockexpert - the worst scorea(N=448)b
The number of subjectsThe worst score of the severity of these entities
Small
N (%)
Average
N (%)
Severe manifestations, N (%)
Erythema215 (48,0%)151 (33,7%)61 (13,6%)3 (0,7%)
Peeling277 (61,8%)225 (50,2%)50 (11,2%)2 (0,4%)
Dryness292 (65,2%)230 (51,3%)57 (12,7%)5 (1,1%)
Burning/burns296 (66,1%)185 (41,3%)96 (21,4%)15 (3,3%)
aThe observed data corresponding higher Stepni of gravity in the period after the starting point of the study, for subjects with data worse than the starting point of the study.
bN = 448 represents the number of su whom yackov, data about the local tolerability of which were available at the starting point of the study and at least once after the Initial point of the study.

Side effects

All PE recorded in individual registration cards (CRF), shown in listings data.

Data about PE were also summarized for all subjects. Subjects were considered only once on the system of accounting subjects, even if reported more than one case, and only once on the system COSTART (Coding Symbols for a Glossary of Terms Adverse Reactions), even if reported more than one case.

The manifestation of PE quarterly summarized for the periods starting point of the research - <3 month, 3 months <6 months" "6 months - <9 months and 9 months - 1 year. The manifestation of PE for each period was calculated as the number of subjects with data on the manifestation of PE in a given period, divided by the number of subjects at risk in this period. Tables summarizing data about PE is given in terms of the Statistical Analysis (PSA).

Summarizing data about side effects during the entire course of the study are shown in Table 12. Just 288 subjects (63.7 per cent) experienced side effects during the study. Only 147 subjects (32.5 per cent) were associated with treatment side effects (i.e. connection side effe is the one with the investigational medicinal product has been evaluated as "possible", "probable" or "definite link"). The most common associated with treatment side effect was dry skin (17.3 percent) (table 13). Most side effects were small or moderate in severity. Most side effects were encountered in the first three months of therapy, and their expression was decreased in subsequent examinations. Only 19 subjects (4,2%) had severe side effects, and of these, 10 subjects (2,2%) had severe side effects, recognized at least possibly related to study treatment. During the 12-month course of the study, only 9 subjects had 10 side effects that led to discontinuation of the study. Of these 10 side effects 7 were related to the investigational treatment.

TABLE 12
The TOTAL SUMMATION of DATA ABOUT SIDE EFFECTS
(POPULATION SECURITY)
CategoryStarting point - <3 month
(N+=452)
Month 3 - <a 6 month
(N+=397)
Month 6 - <month 9
(N+=366)
Month 9 - year
(N+=334)
Just
(N=452)
Subjects with at least one PE195 (43,1%) 79 (19.9 per cent)83 (22,7%)82 (24,6%)288
(63,7%)
Dermatological PE104 (23,0%)13 (3,3%)12 (3,3%)11 (3,3%)131 (29,0%)
Not Dermatological PE139 (30,8%)72 (18.1 per cent)77 (21,0%)78 (23,4%)243 (53,8%)
Subjects with at least one PE associated with the investigational medicinal product127
(28,1%)
16 (4,0%)11 (3,0%)5 (1,5%)147
(32,5%)
Dermatological PE94 (20,8%)8 (2,0%)8 (2,2%)4 (1,2%)110 (24,3%)
Not Dermatological PE66 (14,6%)8 (2,0%)4 (1,1%)2 (0,6%)78 (17.3 per cent)
Sub the projects, having at least one TPE1 (0,2%)2 (0,5%)1 (0,3%)1 (0,3%)5 (1,1%)
Dermatological PE00000
Not Dermatological PE1 (0,2%)2 (0,5%)1 (0,3%)1 (0,3%)5 (1,1%)
Subjects with at least one PE, leading to discomfort7 (1,5%)1 (0,3%)01 (0,3%)9 (2,0%)
Dermatological PE6 (1,3%)1 (0,3%)007 (1,5%)
Not Dermatological PE1 (0,2%)001 (0,3%)2 (0,4%)
Subjects could be taken into account twice, once in the dermatology category and once in determatologist categories for the presence of more than one PE.
Associated with the investigational medicinal product indicates that the connection PE with the investigational drug was assessed as 'possible', 'probable' or 'definite connection'.
Subjects could account for more than one period, due to multiple PE.
PE with incomplete date of onset or date of onset prior to first use, only included in the Final column.
N+=N at risk, the number of subjects at the beginning of each period.

TABLE 13
The MOST COMMON SIDE EFFECTS REPORTED by AT LEAST 1% of SUBJECTS USING the system-ORGAN CLASSES AND PREFERRED TERMS of USE (POPULATION SECURITY)
System organ class/preferred term of use*Starting point - <3 month
(N+=452)
Month 3 - <a 6 month
(N+=397)
Month 6 - <month 9
(N+=366)
A 9 month - 1 year
(N+=334)
Just
(N=452)
The total number PE405113125108766
The total number of subjects with PE195 (43,1%)79 (19.9 per cent)83 (22,7%)82 (24,6%)288 (63,7%)
Infections and infestations48 (10,6%)33 (8,3%)39 (10,7%)49 (14,7%)135 (29,9%)
The common cold14 (3,1%)7 (1,8%)9 (2,5%)8 (2,4%)30 (6,6%)
Infection of the upper respiratory tract7 (1,5%)011 (3,0%)9 (2,7%)26 (5,8%)
Flu4 (0,9%)2 (0,5%)2 (0,5%)10 (3,0%)18 (4,0%)
Sinusit 6 (1,3%)3 (0,8%)3 (0,8%)5 (1,5%)15 (3,3%)
Streptococcal pharyngitis5 (1,1%)2 (0,5%)3 (0,8%)3 (0,9%)13 (2,9%)
A urinary tract infection1 (0,2%)3 (0,8%)04 (1,2%)8 (1,8%)
Viral gastroenteritis2 (0,4%)1 (0,3%)2 (0,5%)3 (0,9%)7 (1,5%)
Bronchitis03 (0,8%)1 (0,3%)3 (0,9%)7 (1,5%)
Skin and subcutaneous tissue disorders104 (23,0%)13 (3,3%)12 (3,3%)11 (3,3%)131 (29,0%)
Dry skin71 (15,7%)5 (1,3) 6 (1,6%)3 (0,9%)80 (17,7%)
Erythema22 (4,9%)1 (0,3%)2 (0,5%)1 (0,3%)25 (5,5%)
Desquamation of the skin22 (4,9%)01 (0,3%)023 (5,1%)
Contact dermatitis12 (2,7%)1 (0,3%)2 (0,5%)2 (0,6%)17 (3,8%)
Pruritis4 (0,9%)02 (0,5%)1 (0,3%)7 (1,5%)
Acne3 (0,7%)2 (0,5%)005 (1,1%)
Swelling face4 (0,9%)01 (0,3%)1 (0,3%)5 (1,1%)
The discomfort of the skin5 (1,1%)0005 (1,1%)
General disorders and States in the introduction63 (13.9 per cent)5 (1,3%)7 (1,9%)2 (0,6%)74 (16,4%)
Burn the introduction57 (12,6%)3 (0,8%)4 (1,1%)1 (0,3%)64 (14,2%)
Irritate place of introduction16 (3,5%)1 (0,3%)01 (0,3%)18 (4,0%)

Complications related to injury, poisoning and procedural points21 (4,6%)18 (4,5%)5 (1,4%)4 (1,2%)47 (10,4%)
Sunburn11 (2,4%)8 (2,0%) 1 (0,3%)2 (0,6%)21 (4,6%)
Tensile joint2 (0,4%)1 (0,3%)01 (0,3%)5 (1,1%)
Respiratory, thoracic and mediastinal disorders9 (2,0%)6 (1,5%)13 (3,6%)3 (0,9%)29 (6,4%)
Paralingual pain4 (0,9%)4 (1,0%)5 (1,4%)1 (0,3%)14 (3,1%)
It's congestion nasal1 (0,2%)1 (0,3%)2 (0,5%)1 (0,3%)5 (1,1%)
Gastrointestinal disorders14 (3,1%)8 (2,0%)6 (1,6%)4 (1,2%)28 (6,2%)
Vomiting4 (0,9%)1 (0,3%)2 (0,5%) 06 (1,3%)
Nausea1 (0,2%)1 (0,3%)3 (0,8%)1 (0,3%)6 (1,3%)
Disorders of the nervous system16 (3,5%)5 (1,3%)1 (0,3%)5 (1,5%)25 (5,5%)
Headache16 (3,5%)4 (1,0%)1 (0,3%)3 (0,9%)21 (4,6%)
*Multiple occurrence in the System organ Class (SOC) were treated by the subject only once on JUICE
Multiple occurrence of the term preferred use of the subject was counted only once for the system of the preferred terms of use.
The subject was taken into account once, even if a subject experienced more than one PE during the study.
The entities could be considered for more than one period due to multiple PE.
PE with incomplete date of onset or date of onset prior to first use, only included in the Final column.
N+=N, under ariannah risk the number of subjects at the beginning of each period.

Five subjects (5/452, 1,1%) had a total of 6 serious side effects (depression, staphylococcal infection, fracture of clavicle, fainting, bipolar disorder and drug dependence), which was not a dermatological and were not related to the investigational medicinal product. During the study, were no deaths and not met confirmed cases of sensitization. During the course of a period of one year did not observe clinically relevant related drug changes in standard laboratory parameters (clinical biochemistry, Hematology and urinalysis). Ten subjects (10/452, 2,2%) had clinically significant laboratory evaluation in the form of side effects in the period after the starting point of the study, although they were not considered related to treatment.

This study represents the first extensive clinical evaluation of the safety and efficacy of a unique combination of retinoid (adapalene 0.1%) and BPO 2.5% of the fixed dose. This disposable combination is addressed to multiple pathogenic factors of acne, providing rapid and sustained efficacy in the absence of the risk of antibiotic resistance. In General, the results of the study support the safe and effective use is their gel combination adapalene and BPO with fixed dose for long-term treatment of subjects, with the disease in the form of ordinary acne. As for security, most of the side effects and symptoms of irritation of the skin was a manifestation with the severity from small to medium, which met early in the study and were temporary. Use a daily moisturizer in the beginning of therapy can help to avoid the most common side effects like dryness of the skin. It is important, that there was a low level abort research caused side effects (2%), and subjects continued research in the absence of efficiency. Observed decrease in the number of clinically significant inflamed and nevospalennyh damage already at week 1, which was maintained for up to 1 year. Eighty percent (80%) of the subjects reported an average visible or complete improvement in their acne. The results of this study are consistent with the previous 12-week controlled study with double anonymity, which showed that the combination of adapalene-BPO produced significantly more reduction of damage and had a more rapid manifestation of the action in relation to the relevant monotherapies, and had comparable with adapalene the security profile.

Since acne is a chronic the disease definition, its treatment often requires prolonged therapeutic strategies to control acne and maintain improvements. For all cases of acne, but especially for the most severe cases, you should use combination therapy using agents with complementary mechanisms of action as early as possible, and then apply subsequent maintenance therapy. As was observed in this study, using a combination of adapalene-BPO fixed-dose can be used for both initial and long-term therapy for acne with severity from moderate to severe. Previous studies have shown that the use of combination therapy using gel containing 0.1% adapalene may be more portable, and is associated with less side effects compared to other retinoids for topical use. According to these previous experiments, adapalen, when combined with BPO in the composition of fixed-dose was well tolerated during the pre-clinical studies in large controlled clinical study with double anonymity and present long-term study with the profile of safety and tolerability similar to the profile in monotherapy adapalene. In addition, well what about the portable combination therapy with fixed-dose can also be more convenient and may simplify the treatment of acne, whereby potentially improving compliance with treatment.

The results of this study comparable with recently published reports of research supporting the treatment of acne. It was shown that damage for acne return after cessation of schema therapy and, thus, prolonged therapy is necessary for many patients with the disease in the form of acne. In this study, damage for acne continued to decrease from the starting point of the study until about month 4, and therapeutic effect was maintained throughout the year. There are several published studies demonstrating the value of long-term treatment following the successful initial therapy, helping to limit the development of subclinical mikrokomedony, and whereby, to prevent the return of the disease after initial improvement. For example, Thiboutot et al. appreciated to support the effect of the gel containing 0.1% adapalene, relative to the gel containing media, 253 subjects successfully treated using a previous investigational combination therapy using adapalene-doxycycline. This 16-week study demonstrated a significant clinical benefit of long-term treatment with p the power gel, containing 0.1% adapalene, in relation to the media. Although future studies need to be properly evaluating the use of adapalene-BPO as a maintenance therapy, the results of this study on the safety and efficacy of prolonged treatment suggest that expanding the set of tools and medicines available for the treatment of acne, will provide greater flexibility for implementation at the same time short-term and long-term treatment.

1. The use of a composition comprising adapalene and benzoyl peroxide, in the preparation of local medicinal product intended for application to the needy in this patient to ensure the long-term treatment of acne vulgaris, where the scheme of local medicinal product includes applying a therapeutically effective amount of the composition for at least 9 months.

2. The use according to claim 1, where the composition includes adapalene and benzoyl peroxide, is a combination with a fixed dose.

3. The use according to claim 1, where the local drug used for at least 12 months.

4. The use according to any one of claims 1 to 3, where the local drug used daily and preferably once a day.

5. The use according to any one of claims 1 to 3, where the local Lek is rstone tool is applied every two days.

6. The use according to any one of claims 1 to 3, where the drug is applied in the evening after cleansing the skin procedure.

7. The use according to any one of claims 1 to 3, where the local medicinal product is a gel composition.

8. The use according to claim 1 or 2, where the local drug includes at least about 0.001% adapalene by weight relative to the total weight of the composition.

9. The use according to claim 1, where the local drug comprises 0.01 to 2% adapalene by weight, preferably includes 0.01 to 0.5% by weight, most preferably 0.1 to 0.3% adapalene by weight, relative to the total weight of the composition.

10. The use of claim 8, where the local drug includes 0,025-20% of benzoyl peroxide by weight, preferably comprises 2-10% of benzoyl peroxide by weight, most preferably 2.5 to 5% benzoyl peroxide by weight, relative to the total weight of the composition.

11. The use according to claim 9, where the local drug includes 0,025-20% of benzoyl peroxide by weight, preferably comprises 2-10% of benzoyl peroxide by weight, most preferably 2.5 to 5% benzoyl peroxide by weight relative to the total weight of the composition.

12. The use of a composition comprising adapalene and benzoyl peroxide in the preparation of local medicinal product intended for application to the patient to maintain rivate its biological response in the treatment of acne vulgaris, where the scheme of local medicines involves applying to the affected skin adapalene in an amount which is in the range of 0.01 to 0.5% by weight, and benzoyl peroxide in an amount which is in the range of 2-10% by weight relative to the total weight of the composition, for at least 9 months.

13. The application indicated in paragraph 12, where the local medicinal product is administered for at least 12 months.

14. The use of a composition comprising adapalene and benzoyl peroxide, in the preparation of local medicinal product intended for application to the patient to maintain its biological response in the treatment of acne vulgaris, where the scheme of local medicines involves applying to the affected skin adapalene in the amount of 0.1% by mass, and benzoyl peroxide in the amount of 2.5% by weight, once a day, every day for at least 9 months.

15. The application 14, where the drug is applied to the affected skin for at least 12 months.

16. The use according to any one of p-15, where the affected skin contains 20-100 nevospalennyh damage, 20 to 50 inflammatory lesions, and does not contain active nodules or cysts.

17. The use according to any one of claims 1 to 3, 9-15, where the composition is a gel com is ositio.

18. The way to ensure long-term treatment of acne ordinary we need in this patient, comprising the topical application to the affected skin an effective amount of a composition comprising adapalene and benzoyl peroxide, in an acceptable pharmaceutical carrier for at least 9 months.

19. The method according to p, where the composition is applied topically for at least 12 months.



 

Same patents:

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to field of dermatology and represents application of 1-aminoalkylcyclohexane derivative, selected from neramexane and its pharmaceutically acceptable salts for treatment or prevention of inflammatory skin diseases, which represent acne, irritant dermatitis, impetigo and atopic dermatitis.

EFFECT: invention ensures extension of arsenal of medications for treatment of inflammatory skin diseases.

39 cl, 7 ex, 35 tbl, 5 dwg

FIELD: medicine.

SUBSTANCE: invention relates to medicine, particularly to dermatology, more specifically to methods of treating pyoinflammatory skin diseases, particularly furunculosis and acne. The method of treating the patients suffering pustular skin disorders, according to the invention, consists in the fact that the affected and surrounding skin areas are prepared with warm weak antiseptic, dried and further processed with an ointment prepared by thorough mixing on a water bath until smooth: zinc-salicylic paste, Lorinden C, gioxizone, streptocide liniment, synthomycin liniment and retinol acetate in the ratio of 3÷1÷1÷1÷0.8÷0.1 with skin treatment produced 2 times a day. The weak antiseptic is sodium bicarbonate or chamomile infusion at temperature 40-45°C. Besides, water bath temperature is to be 40-50°C, and the ointment is to be prepared is a glass or ceramic container. Face acne requires the affected area to be warmed with a vapour bath before finally applying the ointment. To prevent accidental wipe-out of ointment from the ointment treated skin, it is covered with the napkins attached to healthy skin. To enhance the effect of the ointment applications, the affected skin is exposed to UV lamp and/or sunlight for 10-30 minutes.

EFFECT: method enables faster treatment and prevented the recurrent disease, and also ensures the prevention of side effects and provides outpatient treatment.

6 cl, 7 dwg

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to cosmetology and dermatology and represents a composition for treating dermatological disorders containing in a physiologically acceptable medium, at least: (i) peroxide benzoyl, (ii) a naphthoic acid derivative specified in 6-[3-(1-adamantyl)-4-methoxyphenyl]-2-naphthoic acid, 6- [3-(1-adamantyl)-4-hydroxyphenyl]-2-naphthoic acid, 6-[3-(1-adamantyl)-4-decyloxyphenyl]-2-naphthoic acid and 6-[3-(1-adamantyl)-4-hexyloxyphenyl]-2-naphthoic acid and (iii) a compound of polyurethane polymer representing a polyol pre-polymer with said naphthoic acid derivative and said benzoyl peroxide being found in the dispersed form in said composition.

EFFECT: invention provides producing a non-irritant stable composition.

25 cl, 8 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to chemical-pharmaceutical industry, and concerns preparing an agent for treating various dermatopathies: psoriasis, eczema, atopic dermatitis, ulcers incl. trophic and other diseases accompanied by inflammation or skin flaking. According to the first version, the composition contains ethoxylated alcohol, glycerol monostearate, higher fatty alcohols C16-C18 and cocoglycerides, as well as glycerol, olive oil and water. According to the other versions, it contains naphthalan oil or pentoxifylline or urea. All the versions provide a liposomal form of the composition improving healing, soothing and trophic effects.

EFFECT: composition is hypoallergic, easy-to-use.

12 cl, 8 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to new benzimidazole derivatives of general formula (I) or to its pharmacologically acceptable salts wherein R1 represents a C6-aryl group which can be substituted by 1-3 groups optionally specified in a group of substitutes (a), or a heterocyclic group which represents pyridyl, dihydrobenzofuranyl, 1,3-benzodioxolyl, tetrahydropyranyl, tetrahydrofuranyl which can be substituted by 1-3 groups optionally specified in a group of substitutes (a), R2 represents a C1-C6 alkyl group, R3 represents a C6-aryl group which can be substituted by 1-2 groups optionally specified in a group of substitutes (a), Q represents a group represented by formula =CH-, or a nitrogen atom and a group of substitutes (a) represents a group consisting of a halogen atom, a C1-C6 alkyl group, a C1-C6 halogenated alkyl group, a carboxyl group, a C2-C7 alkylcarbonyl group, a C2-C7 alkoxycarbonyl group, a C1-C6 alkoxy group, a C1-C6 halogenated alkoxy group, an amino group, a 4-morpholinyl group and a di-C1-C6 alkyl)amino group. Also, the invention refers to a pharmaceutical composition based on a compound of formula (I), to a PPARγ activator/modulator based on the compound of formula (I), to using the compound of formula (I), to a method of reducing blood glucose, to a method of activating PPARγ, a method of treating and/or preventing said pathological conditions.

EFFECT: there are produced new benzimidazole derivatives showing PPARγ modulatory activity.

41 cl, 2 dwg, 6 tbl, 76 ex

FIELD: medicine.

SUBSTANCE: invention refers to medicine, specifically dermatology, and may be used for treating the acne. A standard drug-induced therapy is prescribed. From the first day of treatment, it is added with 10 sessions of subcutaneous puncture of morphological acne elements with an ozone-oxygen mixture with the ozone concentration of 3500 mcg/ml. The sessions are performed every second day. The volume of the injected ozone-oxygen mixture per each puncture makes 0.2 ml to 0,6 ml. Besides, the preparation Imunorix 800 mg is prescribed in the morning and in the evening orally between meals for the first 14 days of the therapy. Then, for the following 14 days, Imunorix is dosed 400 mg according to the previous regimen.

EFFECT: method allows 29% higher clinical effectiveness in severe and moderate acne, including in patients with accompanying cardiovascular pathologies and with aggravated inflammatory diseases, due to lower intensity of inflammation processes and normalised immune status.

2 ex

FIELD: medicine.

SUBSTANCE: invention refers to cosmetology and represents a dermatological agent for acne and psoriasis, containing Vaseline and mineral powder Belemnit, characterised by the fact that it additionally contains polyethylene glycol 200 and salicylic acid with the ingredients in the agent taken in certain proportions, wt %.

EFFECT: invention provides eliminated cosmetic defects caused by clinical manifestations of psoriasis and acne.

3 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: there are presented a pharmaceutical composition containing calcipotriene - at least one compound of vitamin D, at least one compound of corticosteroids (betamethasone dipropionate), paraffin, mineral oil, tocopherol and a solvent specified in a list: triglyceride, sorbitan, fatty sorbitan ester, cetearyl glucoside, polyethylene glycol-p-sorbitan stearate, an acrylamide and sodium acryloyldimethyltaurate copolymer, and their mixture, a method for making and applying it for preparing a drug for treating psoriasis. What is shown is the fact that: paraffin provides resistance to anhydrous calcipotriene in the composition with the corticosteroid betamethasone dipropionate.

EFFECT: composition of calcipotriene and betamethasone dipropionate increases the compliance of the patient suffering psoriasis.

13 cl, 3 tbl, 2 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to dermatology and represents using lysate of strains Actinomyces R/3.88, L/1.89 or their mixtures for preparing dermatics for treating acne, as well as a method for treating acne characterised by the fact that actinomycetes lysate according to cl.1 is applied on skin of a patient in need thereof.

EFFECT: invention provides higher bioavailability of actinomycetes lysate, effective local concentration of the drug in focus of disease, reduced side effects.

2 cl, 5 ex, 2 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to cosmetology and represents application of a protein fraction of milk whey containing 50 to 98 wt % of lactoferrin for making an oral composition for treating acne which is applied without adjunctive local treatment and wherein the protein fraction of milk whey is introduced in dose 40 to 800 mg per a patient a day.

EFFECT: invention provides higher clinical effectiveness in acne.

7 cl, 4 ex, 2 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to cosmetology and dermatology and represents a composition for treating dermatological disorders containing in a physiologically acceptable medium, at least: (i) peroxide benzoyl, (ii) a naphthoic acid derivative specified in 6-[3-(1-adamantyl)-4-methoxyphenyl]-2-naphthoic acid, 6- [3-(1-adamantyl)-4-hydroxyphenyl]-2-naphthoic acid, 6-[3-(1-adamantyl)-4-decyloxyphenyl]-2-naphthoic acid and 6-[3-(1-adamantyl)-4-hexyloxyphenyl]-2-naphthoic acid and (iii) a compound of polyurethane polymer representing a polyol pre-polymer with said naphthoic acid derivative and said benzoyl peroxide being found in the dispersed form in said composition.

EFFECT: invention provides producing a non-irritant stable composition.

25 cl, 8 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to field of cosmetics and represents composition for treatment of dermatologic disorders characterised by the fact that it has form of cream-gel and contains in physiologically acceptable medium: from 0.0001 to 20% of dispersed benzoyl peroxide, from 0.0001 to 20% of at least one retinoid, at least one lipophilic compound, which contains fatty phase, and from 0.001 to 15% of at least one pH-independent gelling agent.

EFFECT: invention ensures homogeneity, physical and chemical stability of active composition ingredients.

18 cl, 4 ex

FIELD: medicine.

SUBSTANCE: invention refers to dermatology and cosmetology, and represents a composition for prevention or treatment of dermatological diseases associated with disturbed cell differentiation and/or proliferation and/or keratinisation, containing at least one retinoid representing adapalene, and dispersed benzoyl peroxide, differing by the fact that it is presented in the form of an emulsion, and in addition to retinoid and benzoyl peroxide it contains at least one hydrophilic phase, at least one fatty phase, at least one emulsifier.

EFFECT: invention provides high stability of the composition.

19 cl, 5 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to medicine, in particular to ophthalmology. The invention discloses an ophthalmic composition containing ketotifen and a hydrogen peroxide source supplying hydrogen peroxide in the amount approximately from 0.001 to approximately 0.1% (wt %) with pH making 4 to 5.3. What is also disclosed is a method of treating and preventing allergic conjunctivitis with using said composition.

EFFECT: invention provides minimum adverse side effects in treating and preventing conjunctivitis.

16 cl, 4 tbl, 1 ex

FIELD: ophthalmology.

SUBSTANCE: main composition contains: (a) ketotifen fumarate to the concentration in calculation to free ketotifen from approx. 0.01 mas. % to approx. 0.1 mas.%;(b) source of hydrogen peroxide ensuring presence of hydrogen peroxide with trace quantities amounting from approximately 0.001 to approximately 0.1% (mas./vol.); (c) one or several stabilizers of hydrogen peroxide compatible with eyes; (d) hypromellose to the concentration from approximately 0.005 mas% to approximately 0.5 mas.%; and (e) sodium carboxymethyl cellulose to the concentration from approx. 0.005 mas.% to approx 0.5 mas.%. At this the value of composition pH amounts to approximately from 4.0 to 5.3.

EFFECT: invention is a method of treatment and prevention of allergic conjunctivitis which is ensured with application locally in the effective quantity of the mentioned eye composition to person with allergic conjunctivitis or sensitive to it.

13 cl, 15 tbl, 4 ex

FIELD: medicine.

SUBSTANCE: invention relates to medicine, namely to dermatology, and can be applied for treatment of acne vulgaris. For this purpose, complex treatment is performed. On the places of appearance of skin rash additionally applied is propolis powder in form of mask with 3% hydrogen peroxide in ratio 2.0 g per 2 ml of peroxide. Treatment course consists of 10 daily procedures.

EFFECT: method is efficient with absence of side effects, as well as simple in application, is not toxic and economically beneficial.

FIELD: medicine.

SUBSTANCE: invention is related to composition containing water-swellable, water-insoluble polymer, mixed hydrophilic polymer and complementary oligomer capable to form hydrogen bridges and electrostatic couplings with said hydrophilic polymer, and a substrate. The invention is also applied to the method for teeth wigthening.

EFFECT: tooth hypersensitisation minimal or not observed.

58 cl, 3 ex

FIELD: medicine, dermatology, pharmacy.

SUBSTANCE: invention relates to a composition containing at least retinoid, dispersed benzoyl peroxide in physiologically acceptable medium and at least one pH-independent gel-forming substance chosen from polyacrylamides, acrylic polymers with hydrophobic chains, modified starches and their mixtures. Also, invention relates to a method for preparing such composition and its using in dermatology for treatment of differentiation and proliferation of cells or keratinization, and to using in treatment of common acnes. Proposed composition shows high effectiveness in treatment of common acnes, erythematosa acnes and folliculitis. The composition shows a homogenous dispersion of both active substances and physical stability, and good chemical stability of retinoid and benzoyl peroxide.

EFFECT: improved and valuable properties of gel.

19 cl, 6 ex

FIELD: medicine, disinfecting and washing agents.

SUBSTANCE: invention relates to agents for disinfecting and washing of medicine articles such as hemodialysis equipment and dialysers. Claimed agent contains citric acid and water.

EFFECT: agent of increased activity and oxidative properties.

3 tbl, 3 ex

Disinfectant // 2286145

FIELD: medicine, in particular preparation for disinfecting agents for disinfections of surfaces, medicine tools, etc.

SUBSTANCE: claimed agent contains alkyldimethylbenzammonium chloride, benzotriazole, glutaric anhydride, monovalent alcohol, hydrogen peroxide and water in specific component ratio.

EFFECT: agent with high bactericide, antiviral and fungicide activity against wide spectrum of pathogens at relatively low concentration and prolonged storage time.

3 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: claimed invention relates to fizzy therapeutic form of ibuprofen, which includes (a) granule, which contains active ingredient, containing water-soluble ibuprofen salt and main filling agent, and (b) fizzy granule, which contains sour component and component, which forms carbon dioxide. Said fizzy therapeutic form is selected from fizzy tablet, having weight from 1000 to 1500 mg per 200 mg of ibuprofen, or drinkable granules, whose single dose has weight from 500 to 950 mg per 200 mg of ibuprofen.

EFFECT: claimed invention ensures obtaining fizzy therapeutic forms of ibuprofen with reduced relative weight per a single dose, pleasant taste and dissolving in water with formation of transparent solution.

13 cl, 9 ex

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