Topical Metronidazole Formulations And Therapeutic Uses Thereof.

  • Published: Apr 6, 1994
  • Earliest Priority: Jan 15 1988
  • Family: 17
  • Cited Works: 1
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-- PatentLens OCR page0001.txt

111111111111111111111111111111111111111111111111111111111111111111111111111 

Europäisches Patentamt European Patent Office Office européen des brevets 

G Publication number: 

0355152 B1 

EUROPEAN PATENT SPECIFICATION 

@ Date of publication of patent specification: 06.04.94 @ Int. Cι,5 A61 K 31/78, A61 K 31/415 

@ Application number: 89902117.4 

@ Date of filing: 12.01.89 

@ International application number: 

PCT /US89/00116 

@ International publication number: 

WO 89/06537 (27.07.89 89/16) 

@ TOPICAL METRONIDAZOLE FORMULATIONS AND THERAPEUTIC USES THEREOF. 

@ Priority: 15.01.88 US 144252 

@) Proprietor: GALDERMA S.A. 

Sinserstrasse 47 CH-6330 Cham(CH) 

@ Date of publication of application: 28.02.90 Bulletin 90/09 

@ Publication of the grant of the patent: 06.04.94 Bulletin 94/14 

@ Inventor: BORGMAN, Robert, J. 1735 Victoria Road Mundelein, IL 60060(US) 

@ Designated Contracting States: 

AT BE CH DE FR GB IT LI LU NL SE 

@ Representative: Heath, Derek James et al BROMHEAD & CO. 

19 Buckingham Street London WC2N 6EF (GB) 

@ References cited: 

EP-A- O 320 254 WO-A-88/06888 DE-A- 3 340 872 

Physicians Desk Reference, 38th ed., 1984, Pub. Medical Ecanomis Co., Inc., USA, p. 1637 

British J. of Dermatology, vol. 109, 1983, pp. 63-65, Nielsen 

Jillison, Cutis, USA, vol. 34, Nov. 1984, pp. 457-458 

It) It) (V) 

O C. W 

Note: Within nine months from the publication of the mention of the grant of the European patent, any person may give notice to the European Patent Office of opposition to the European patent granted. Notice of opposition shall be filed in a written reasoned statement. It shall not be deemed to have been filed until the opposition fee has been paid (Art. 99(1) European patent convention). 

Rank Xerox (UK) Business Services 13 10/309/3331 

-- PatentLens OCR page0002.txt

EP O 355 152 B1 

Description 

This invention relates to novel topical compositions containing metronidazole. 

Metronidazole, 1-(2-hydroxyethyl)-2-methyl-5-nitroimidazole, is a drug known to be effective in treating a 

5 variety of disorders. For example, the drug has direct trichomonacidal and amebacidal activity against 

Trichomonas vaginalis and Entamoeba histolytica, and is useful in combatting infections caused by those microbial parasites. Metronidazole has also been reported to be effective (via both oral and topical application) in treating skin disorders such as rosacea, ulcers infected with anaerobic bacteria, including decubitus ulcers (bed or pressure sores), venous ulcers, and diabetic foot ulcers, and other anaerobic 

10 infections such as post operative sepsis. There have also been reports that metronidazole is effective against perioral dermatitis. 

Although oral administration of the drug has been employed for the treatment of certain disorders, longterm oral administration of the drug in cases of chronic disorders such as rosacea may be associated with certain unwanted side effects, and subjects all organ systems needlessly to high drug concentrations. Well15 known problems associated with systemic antibiotic therapy include gastro-intestinal intolerance and vaginitis. Thus, topical compositions are generally preferred for dermatological applications. See, for example, "Practical Advice Offered On Rosacea", Dermatology News, (April, 1985). 

When formulating topical compositions for application to diseased skin, different aspects, such as thermodynamic activity of the drug in the base material vehicle, i.e., the affinity of drug to the vehicle, the 

20 release rate of the drug from the vehicle, the type and status of the skin, and the sensitization and irritation potential of components, are factors that can affect the therapeutic effectiveness of topical dermatological preparations. In the case of non-diseased skin with its intact stratum corneum, cell membrane-controlled penetration of the drug occurs. Therefore, a high thermodynamic activity of the drug in the vehicle is desirable, i.e., the drug has a low affinity to the vehicle, and therefore has a high rate of cell membrane 

25 penetration to promote transfer of the drug across the epidermal cell membranes. With diseased skin, the release rate of the drug from the vehicle generally is rate-determining for penetration into a patient's cells. Therefore, vehicles which dissolve the drug and have a low diffusional resistance are preferred. In general, drug concentration in the vehicle, and thus the degree of saturation, is considered to be a key formulation factor when optimizing topical delivery for maximum bioavailability. 

30 Rosacea, formerly called Acne rosacea, is a chronic skin disease primarily affecting adults, with 

recurring symptoms that include erythema, papules, pustules, rhinophyma, and telangiectses, primarily in the region of the nose, cheeks, and forehead. In rosacea, other acneform conditions, and certain types of dermatitis, topical treatment compositions are usually applied to both unafflicted and diseased areas. It is therefore desirable that a treatment have a mitigating effect on the diseased tissue and a prophylactic effect 

35 to prevent extension of involvement to the unafflicted tissue. Therefore, the preferred vehicles, and hence compositions, to obtain these desirable effects should contain metronidazole in a high thermodynamic activity and with a fast rate of release from the vehicle. Aqueous compositions of metronidazole would appear to meet the above criteria. However, the low solubility of metronidazole in water and several other solvents inhibits the preparation of an aqueous compositions. This has resulted in the development of oil- 

40 based, rather than aqueous, metronidazole compositions. 

These current topical compositions generally are creams (oil in water emulsions) or ointments (petroleum jelly based compositions) with metronidazole being dissolved in the oil phase. The oils, certain surfactants and emulsifiers, and/or other ingredients utilized in the compositions have been found to be comedogenic, acnegenic, and/or irritating to the skin. See Fulton et aI., Amer. Acad. of Dermatology .!..Q(1)- 

45 :96-105, (Jan. 1984). Patients treated with such compositions therefore often experience skin problems which include irritation, uncomfortable drying of the skin, and "stinging" or "burning" sensations. In addition, the drug is generally dissolved or dispersed in the oil phase of such preparations, which reduces the specific activity of the drug due to inhibition of drug transfer across the cell membrane. See "Treatment Of Rosacea With 1% Metronidazole Cream. A Double-Blind Study", Nielsen, P., British J. of Dermatology 

50 108:327-332 (1983). 

Thus, a need remains for metronidazole-containing dermatological preparations suitable for topical use which avoid the problems of current compositions. Such dermatological preparations would be useful for treating skin disorders such as rosacea and certain types of dermatitis, including perioral dermatitis. 

In accordance with the present invention, the above need is met by the composition set forth in claim 1. 

55 Such compositions are single-phase aqueous gels that provide a relatively high specific activity of 

metronidazole as compared to prior art oil-based compositions and provide increased bioavailability of the metronidazole. The present compositions are constituted by substantially non-comedogenic, non-irritating ingredients and thus avoid problems associated with the use of prior art formulations in the treatment of 

2 

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EP O 355 152 B1 

skin diseases. 

The gel-form compositons of the present invention minimize "pooling" and "running" of the contained medication, e.g., pooling into facial creases, which sometimes occurs with dermatological cream preparations. The resulting local excesses of the creams may contribute to problematic erythema or stinging. The 

5 gel-form compositions of the present invention afford more control in application, and better maintenance of 

a uniform distribution of the drug over the area to be treated, than would generally be expected if the drug were applied as a cream or in an aqueous solution. 

The gel advantageously functions as a "sustained delivery" system for the metronidazole, in which the drug continuously is delivered to the cells at, or slightly above, a minimum therapeutically effective level 

10 which is sustained over a period of time. This mode of drug release from the vehicle is preferred over vehicles which release the drug at levels much higher than the necessary therapeutic level shortly after application to the skin, followed by a sharp decrease to a level which is not therapeutically effective. The aqueous gel compositions of the present invention function as sustained delivery systems, whereas prior art formulations generally do not provide sustained drug delivery at a relatively constant therapeutically 

15 effective level over a period of time. 

Compositions in accordance with the present invention therefore provide a means for the prophylactic or therapeutic treatment of humans afflicted with such skin disorders as rosacea, other acneform conditions, e.g., acne vulgaris, steroid acne, acne conglobata, or nodulocystic acne, or certain types of dermatitis, e.g., perioral dermatitis or seborrheic dermatitis. 

20 Numerous other advantages and features of the present invention will become readily apparent from the 

following description of the preferred embodiments of the invention, the accompanying examples, the drawings and the appended claims. 

In the figures forming a part of the disclosure; 

FIGURE 1 is a graph illustrating the in-vitro release of metronidazole from a gel composition (0.75 wt-% 

25 metronidazole; contains propylene glycol; pH 5.8) over a 60-minute time period. Data points for Trial One 

are designated by (o), for Trial Two (e) and for Trial Three by (x); 

FIGURE 2 is a graph illustrating the average release of metronidazole for the three trials shown in FIGURE 1; 

FIGURE 3 is a graph illustrating the in-vitro release of metronidazole from another gel composition (0.75 

30 wt-% metronidazole; no propylene glycol; pH 5.8) over a 60-minute time period. Data points for Trial One 

are designated by (o), for Trial Two by (e) and for Trial Three by (x); 

FIGURE 4 is a graph illustrating the average release of metronidazole for the three trials shown in FIGURE 3; 

FIGURE 5 is a graph illustrating the in-vitro release of metronidazole from a cream composition (1.0 wt- 

35 % metronidazole; pH 3.2) over a 60-minute time period. Data points for Trial One are designated by (o), 

for Trial Two by (e) and for Trial Three by (x); 

FIGURE 6 is a graph illustrating the average release of metronidazole for the tree trials shown in FIGURE 5; 

FIGURE 7 is a graph illustrating the average in-vitro release of metronidazole over a 60-minute time 

40 period. Data points for a gel composition (0.75 wt-% metronidazole containing propylene glycol; pH 5.8) 

are designated by (o), for another gel composition (0.75 wt-% metronidazole; no propylene glycol; pH 5.8) by (x) and for a cream composition (1.0 wt-% metronidazole; pH 3.2) by (e). 

While this invention is susceptible to embodiment in many different forms, there are shown in the drawings and will be described in detail, preferred embodiments of the invention. 

45 The drug 1-(2-hydroxyethyl)-2-methyl-5-nitroimidazole and varous derivatives thereof are described in 

U.S. Patent No. 2,944,061, to Jacob et al. 

The term "metronidazole" as used in this specification and claims is meant to include not only 1-(2hydroxyethyl)-2-methyl-5-nitroimidazole, but also those analogs and derivatives of metronidazole which are solubilized in the gel compositions described herein and which have therapeutic activity when topically 50 applied. 

Substantially oil-free, aqueous compositions of metronidazole, in which the drug is solubilized in a single-phase aqueous gel, are disclosed. The overall advantages of such aqueous compositions in treating skin disorders have been discussed above, and are presented in greater detail herein below. 

Metronidazole is employed in the compositions in a therapeutically effective amount. The actual 

55 concentration of metronidazole may vary, depending on the nature and degree of the disorders being treated, and whether the drug is being administered for therapeutic or prophylatic purposes. The compositions advantageously comprise at least 0.1 wt-% metronidazole, based on the total weight of the composition. Preferably metronidazole is present in an amount of 0.25% to 1.0%, and more preferably 0.75% by 

3 

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EP O 355 152 B1 

weight, based on the total weight of the composition. 

In the compositions of the present invention, metronidazole is dissolved in an aqueous solution of a high molecular weight polycarboxylated vinyl polymer. The polymer imparts a desirable viscous, gelled consistency to the composition when mixed with metronidazole and water. The gel compositions contain at least 

5 95% by weight water, based on the total weight of the composition, and have the requisite degree of 

metronidazole concentration, and hence thermodynamic activity, for effective topical delivery and bioavailability of metronidazole. The gel compositions of the present invention also have the requisite therapeutic activities as previously described. 

The gel-forming polymer useful in compounding the present compositions may be any suitable polymer 

10 which is hydrophilic and water-dispersible, has free carboxylic groups and relatively high base binding capacity, and forms a gel of substantially uniform consistency when neutralized with a base. Preferred polymers for use in the compositions of the invention are water-dispersible polycarboxylated vinyl polymers. Polyacrylic acid polymers are particularly preferred for the present purposes. The molecular weight of the polymer is desirably in the range of 1,250,000 to 4,000,000. Suitable polyacrylic acid polymers include 

15 polyacrylic acid polymers lightly crosslinked with a polyalkenyl polyether such as those commercially available from B.F. Goodrich, Cincinatti, Ohio, under the trademarks Carbo pol 934, 940, and 941. Carbo pol 940 ™ is a particularly preferred polymer for use in practicing this invention. 

The polymer is present in an amount sufficient to cause gelling of the composition and impart the desired viscous consistency to the topical formulation. The metronidazole compositions advantageously 20 comprise 0.2% to 7.0% by weight of the polymer, preferably 0.5% to 1.5%, and most preferably 0.6% by weight of the polymer based on the total weight of the composition. 

Aqueous solutions of these polymers form gels when neutralized with a base. Water-soluble bases which have been used to promote gelling of polymers such as Carbo pols ™ include inorganic bases such as an aqueous solution of ammonia, NaOH, and organic amines, e.g., alkylamines such as methylamine and 25 ethylamine, dialkylamines, trialkylamines, alkanolamines and dialkanolamines. The effective component of the compositions of the present invention, metronidazole, is sufficiently basic to partially neutralize the acidic polymer in aqueous solution to the desired degree and to promote gelling. 

Optionally, the composition may further include a "penetration enhancer", i.e., an agent that promotes penetration of the active drug into the patient's skin or tissues. Such penetration enhancers include but are 30 not limited to, dimethyl sulfoxide (DMSO) and propylene glycol, with the latter being preferred. The composition advantageously includes 1.0% to 50%, preferably 2% to 5%, and more preferably 3% by weight of said penetration enhancer, based on the total weight of the composition. 

Preservatives are incorporated into the compositions in an amount effective for inhibiting growth of microbes such as yeast and molds in the composition during storage. A mixture of methyl paraben and 35 propyl paraben has been found particularly effective as a preservative. Accordingly, the composition comprises 0.08% by weight of methyl paraben and 0.02% by weight of propyl paraben based on the total weight of the composition. 

Ethylenediaminetetraacetic acid (EDT A) or one of its salts is commonly added to dermatological preparations. EDTA chelates certain metals that may be present in the formulation, which is useful because 

40 some patients have adverse reactions to preparations containing metal impurities. The EDT A will also inhibit undesirable "browning" of the composition which may occur over time in compositions having a low pH value, e.g., a pH value of 3.5 to 5.4. Accordingly, the compositions of the invention further include 0.05% by weight of EDTA based on the total weight of the composition. 

The final pH value of the formulations of the invention may vary within a physiologically compatible 

45 range. Advantageously, the final pH value is a physiologically compatible, i.e., not harmful to biological tissue, acidic pH value. The pH value is preferably between 3 and 6.9, and most preferably between 4 and 5. Any suitable method of adjusting the pH value of aqueous solutions may be used. Advantageously, sodium hydroxide (NaOH) is added to the composition to bring the final pH value to the desired level. Gel compositions of the invention are more viscous at pH values that approach neutrality than at the more 

50 acidic pH values within the preferred range, i.e., viscosity increases as the polymer in the gel is neutralized to a greater degree, e.g., with NaOH. 

The ingredients listed above may be combined in any order and manner that produces a composition comprising metronidazole dissolved in, and evenly dispersed throughout, a one-phase aqueous gel of the desired consistency and pH value. One suitable method of preparing compositions of the invention involves 

55 preparation of an aqueous solution of the polymer, which will be called "Part A". Advantageously, this solution comprises the polymer in distilled water. A "Part B" is prepared comprising metronidazole. Mixing of Parts A and B results in gelling of the composition. The optional penetration enhancer and preservative(s) are preferably included in Part B. EDT A is preferably included in Part A. The pH value may then be 

4 

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EP O 355 152 B1 

adjusted to the desired level, e.g., by addition of NaOH. 

The resulting homogeneous gels possess the advantageous properties described above, including utilizing non-comedogenic, non-acneogenic, and non-irritating ingredients; higher specific activity of metronidazole due to increased diffusion across membranes and release from the vehicle which results in 

5 greater therapeutic effectiveness using smaller amounts of metronidazole; and a desirable consistency that 

prevents undesired pooling and spreading of metronidazole. High concentrations of skin-drying ingredients (e.g. alcohols and acetone), which are found in some dermatological preparations to promote drug solubility, are also avoided. Such ingredients at high concentration may excessively dry the patient's skin, causing undesirable flaking and discomfort. 

10 The therapeutic effectiveness of the metronidazole compositions of the present invention is dem- 

onstrated in the following examples. Additional ingredients such as coloring agents, and sunscreens, may be included in the compositions as long as the resulting composition retains the desirable properties, e.g., non-comedogenicity, and high specific activity, described above. 

15 EXAMPLE I 

A 30 kilogram batch of a composition of the present invention was prepared as follows. 180g of Carbo pol 940 ™ (0.6% by weight of the final weight of the composition) was dissolved in 16.5 liters of distilled water containing 15 g of ethylenediaminetetraacetic acid (EDT A) disodium dihydrate. Sufficient 

20 amount of 10 wt-% sodium hydroxide (NaOH) solution was added to bring the pH value to 5. This aqueous polymer solution was called "Part A". "Part B" was prepared by mixing 900 grams of propylene glycol (3% by weight of the final weight of the composition), 24 grams of methyl paraben (0.08% by weight of the final weight of the composition) and 6.0 g of propyl paraben (0.02% by weight of the final weight of the composition). The mixture was added to 225 g of metronidazole dispersed in 11.4 liters of distilled water 

25 maintained at 50 o C. Parts A and B were then mixed thoroughly and gelling of the composition resulted. A cold aqueous solution of NaOH was then used to adjust the final pH value to 5.25. Distilled water was then added to give the desired 30 kg final weight. The NaOH and water were thoroughly mixed into the viscous gel. 

A random, double blind, placebo controlled clinical trial was conducted to demonstrate the positive 

30 clinical efficacy of the aqueous metronidazole-containing gel composition prepared in Example I in treating rosacea. The study included patients who had received no prior treatment for rosacea, as well as patients who had been treated by conventional methods. Patients discontinued treatment, if any, at least 21 days prior to the start of this study. Each patient received metronidazole in the gel composition on one side of the face and the gel composition (placebo control) without metronidazole on the other side of the face. 

35 Therefore, in this study, each patient served as their own control. 

The effectiveness of the treatment was rated, at the time points indicated in the TABLES below, in six different categories, namely, reduction in inflammatory lesions (papules and pustules), erythema, stinging, burning, itching, and dryness. The data are shown in the TABLES below. 

TABLE I-A shows the percent reduction in inflammatory lesions (papules and pustules) from baseline 

40 values for active (i.e., metronidazole-treated) and placebo-treated sides. Inflammatory lesions were progressively reduced from 46.7% to 59.9% for active-treated sides while placebo-treated sides reflected an exacerbation. There was an 82.6% difference in inflammatory lesions at the end of drug treatment on the metronidazole versus placebo-treated sides. 

TABLE I-B shows mean erythema values for active and placebo-treated sides. Statistically significant 

45 differences were found at visits 2, 3, 4 and 5 for the active sides and at visits 3 and 4 for the placebo sides, when compared to baseline values. Active and placebo-side values were significantly different from each other at visits 3, 4 and 5. A concommitant improvement in reduction of erythema was seen at the same time point on the treated side and on the placebo side. 

Tables II-A, II-B, II-C, and 11-0 show an unexpected but dramatic improvement in local tolerance data. 

50 This data represents the patients' subjective assessments of stinging, burning, itching and dryness on each side of their faces before and during drug or placebo treatment. The data shows that there was a dramatic (highly statistically significant) improvement in the patients' perceptions of these attendant complications of the disease. Since both sides improved to the same degree, i.e., no statistically significant difference can be found, the improvement apparently comes from the gel composition per se. 

55 TABLE II-A shows mean stinging scores for active and placebo-treated sides. Statistically significant 

differences were found at visits 3, 4 and 5 for both the active and placebo sides, when compared to baseline values. Active and placebo-side values were not significantly different from one another. 

5 

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EP O 355 152 B1 

TABLE II-B shows mean burning scores for active and placebo-treated sides. Statistically significant differences were found at all visits (2, 3, 4, 5) for both the active and placebo sides, when compared to baseline values. Active and placebo-side values were not significantly different from one another. 

TABLE II-C shows mean itching scores for active and placebo-treated sides. Statistically significant 

5 differences were found at all visits (2, 3, 4, 5) for both the active and placebo sides, when Compared to 

baseline values. Active and placebo-side values were not significantly different from one another. 

TABLE 11-0 shows mean dryness scores for active and placebo-treated sides. Statistically significant differences were found at visits 3, 4 and 5 for active sides and at visits 4 and 5 for placebo sides, when compared to baseline values. Active and placebo-side values were not significantly different from one 10 another. 

This data confirms the effectiveness of metronidazole in the gel composition for treatment of rosacea and also demonstrates the unique therapeutic effects of the gel composition. 

15 

20 

25 

30 

35 

40 

45 

50 

55 

6 

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EP O 355 152 B1 

TABLE I-A 

5 

Inflammatory Lesions (Efficacy Data From 20 Subjects)     
    On Drug     Off Drug   
  Visit 2   Visit 3   Visit 4   Visit 5 Weeks   
  Weeks 3-5   Weeks 6-8   Weeks 9-11   12-17   
Active (Percent Reduction from Baseline)   46.7   55.1   59.9   41.6   
Placebo (Percent Reduction from Baseline)   -22.5   -4.2   -22.7   -46.8   
Difference (Active-Placebo Percent Difference)   69.2   59.3   82.6   88.4   10 

15 

TABLE I-B Erythema 

(Efficacy Data From 20 Subjects) 

20 

Visit 1 

On Drug Visit 2 Visit 3 

Off Drug Visit 4 Visit 5 

25 

Weeks 3-5 

Weeks 9-11 

Weeks 12-17 

Weeks 6-8 

Baseline 

30 

Active (Mean Values Placebo (Mean 

Values 3=Severe 2=Moderate l=Mild O=Absent 

2.10 

1.90 1.55*** 1.55*** 1.70 

2.10 

1.55**** 1.05*** 1.05*** 1.15*** 

35 

40 

45 *** p,O. 01 compared to 

baseline values. 

Active Versus 

50 

55 

Placebo Significant Differences 

(p values) None 

None 

p<0.02 

p.:.O.02 

~0.02 

7 

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EP O 355 152 B1 

TABLE II-A Stinging 

(Local Tolerance Data from 20 Subjects) 

5 

Visit 1 

10 

Baseline 

15 

Active (Mean Values 

0.70 

20 

Placebo (Mean 

Values 0.65 

3=Severe 2=Moderate l=Mild O=Absent 

25 

30 

Visit 2 Weeks 3-5 

0.25 

0.30 

* p~0.05 compared to baseline values. ** p<0.02 compared to 35 

baseline values 

*** p<O.Ol compared to baseline values 

40 Active 

Versus Placebo Significant Differences 

45 

(p values) None 

50 

55 

None 

On Drug Visit 3 Weeks 

6-8 

0.15** 

0.15* 

None 

8 

Visit 4 Weeks 9-11 

Off Drug Visit 5 Weeks 

12-17 

0.00*** 0.00*** 

0.20* 

None 

0.05*** 

None 

-- PatentLens OCR page0009.txt

5 

10 

Active (Mean Values Placebo (Mean Values 3=Severe 

~ 2=Moderate 

l=Mild O=Absent 

15 

20 

30 

EP O 355 152 B1 

TABLE 11-B 

Burning 

(Local Tolerance Data from 20 Subjects) 

Visit 1 

Baseline 

1.25 

1. 05 

Visit 2 Weeks 3-5 

0.30** 

On Drug Visit 3 Weeks 

6-8 

Visit 4 Weeks 9-11 

0.10*** 0.05*** 

0.30*** 0.05*** 0.10*** 

** ~0.02 compared to baseline values. *** p,O.Ol compared to baseline values Active 

Versus 

40 Placebo 

35 

45 

Significant Differences (p values) 

50 

55 

None 

None 

None 

9 

None 

Off Drug Visit 5 Weeks 

12-17 

0.05*** 

0.05*** 

None 

-- PatentLens OCR page0010.txt

5 

10 

20 

25 

30 

35 

40 

45 

50 

55 

EP O 355 152 B1 

TABLE II-C Itching 

(Local Tolerance Data from 20 Subjects) 

Visit 2 Weeks Baseline 3-5 

Visit 1 

1. 45 

0.55*** 

15 Active 

(Mean Values Placebo (Mean Values 3=Severe 

1. 40 

0.70*** 

2=Moderate l=Mild O=Absent 

*** p~O.Ol compared to 

baseline values Active 

Versus 

Placebo 

Significant Differences 

(p values) 

None 

None 

On Drug Visit 3 Weeks 6-8 

0.15*** 

0.25*** 

None 

10 

Visit 4 Weeks 9-11 

Off Druq Visit 5 Weeks 12-17 

0.20*** 0.10*** 

0.20*** 0.15*** 

None 

None 

-- PatentLens OCR page0011.txt

EP O 355 152 B1 

TABLE II-D 

5 

Dryness 

(Local Tolerance Data from 20 Subjects) 

Visit 1 

Visit 2 Weeks 3-5 

On Drug Visit 3 Weeks 6-8 

Visit 4 Weeks 9-11 

Off Drug Visit 5 Weeks 12-17 

10 

Baseline 

15 Active 

(Mean Values Placebo (Mean 

1. 45 

0.85 

0.50*** 

0.25*** 0.25*** 

20 

25 

Values 3=Severe 2=Moderate l=Mild O=Absent 

1. 40 

0.85 

0.75 

0.20*** 0.45*** 

30 

*** 

p<O.Ol compared to baseline values Active 

35 

40 

Versus Placebo Significant Differences (p values) 

None 

None 

None 

None 

None 

45 A study was conducted to determine differences in the in-vitro release characteristics of metronidazole 

from various topical compositions using the following experimental procedure. 

The metronidazole gel or cream was placed into a shallow well about 1 millimeter deep created by a Plexiglass ™ template placed on a round 5.2 centimeter Plexiglass ™ base. The diameter of the template into which the composition was placed was 3.0 centimeters. The composition was covered by a piece of 

50 Spectrapor ™ membrane (available from Spectrum Medical Industries, Inc., Los Angeles, CA 90054) having a molecular weight cutoff of between 12,000 and 14,000. The membrane had been soaked in a buffer having a pH value of 5.5 for 24 hours. A second template identical in size to the template forming the well was utilized to hold the membrane in place. The templates were secured by four nylon screws thereby creating a holder. 400 Cubic centimeters of an acetate buffer solution having a pH value of 5.5 was placed 

55 in a round bottom dissolution flask (available from Hanson Research Corporation, Northridge, CA 91324) and the temperature of the solution was equilibrated to 32 o C. A solid halogenated hydrocarbon polymercoated stirrer was lowered into a position 2.54 centimeters above the membrane surface. The solution was stirred at 50 RPM. Five cubic centimeter samples were removed at 5, 10, 15, 20, 30, 40, and 60 minutes. 

11 

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EP O 355 152 B1 

The volume of the sample was replaced each time with fresh solution. The samples were analyzed at 319 nanometers on a spectrophotometer (Model 8450A, Hewlett-Packard, Palo Alto, CA 94303). 

After absorbance was converted to concentration using a Beer's Law plot, the total milligrams of metronidazole released at each time point was calculated from the following equation: 

5 

[Concentration yAmg/cc)] X [400 

Metronidazole released (mg) = 

10 

[1000 micrograms/milligrams] 

Additional compositions that have been studied are shown in TABLE III, below. These compositions were prepared in substantially the same manner as described in Example I, above. 

15 

TABLE III 

20 

Compositions, in wt. %       
Components   C1   C2   C3   
Metronidazole   0.75   0.75   1.00   
Propylene Glycol   3.00   -   -   
Polyacrylic Acid Polymer 1   0.60   0.60   -   
Methyl Paraben   0.08   0.08   -   
Propyl Paraben   0.02   0.02   -   
Disodium EDT A   0.05   0.05   -   
Cetylane   -   -   5.00   
Cetyl Alcohol   -   -   15.00   
Sodium Lauryl Sulfate   -   -   1.50   
Lactic Acid   -   -   1.50   
Water, q.s. ad   100.00   100.00   100.00   25 

30 

1 Carbo pol 940 from B.F. Goodrich Company, a commercially available polyacrylic acid polymer. 

35 

Data from three trials for the release of metronidazole from C1, a gel composition, (0.75 wt-% metronidazole; pH value 5.8) are presented in TABLE IV and are plotted in FIGURE 1. In FIGURE 1, Trial One is denoted by (o), Trial Two by (e) and Trial Three by (x). The average data for the three trials is presented in TABLE VII and is plotted in FIGURE 2. Traditional linear plots for release of drugs from ointment bases are obtained by plotting amount released vs. the square root of time. 

40 

TABLE IV 

45 

Release of Metronidazole from C1 (mg)   
Time (Min)   Trial One   Trial Two   Trial Three   
O   O   O   O   
5   1.37   1.26   1.33   
10   2.09   2.14   2.14   
15   2.96   2.86   2.86   
20   3.54   3.47   3.44   
30   4.50   4.54   4.38   
40   5.19   5.34   5.10   
60   6.16   6.53   6.09   50 

55 

Data from three trials for the release of metronidazole from C2, another gel composition, (0.75 wt-% metronidazole, without propylene glycol; pH value 5.8) are presented in TABLE V and are plotted in 

12 

-- PatentLens OCR page0013.txt

EP O 355 152 B1 

FIGURE 3. In FIGURE 3, Trial One is denoted by (o), Trial Two by (e) and Trial Three by (x). The average data for the three trials is presented in TABLE VII and are plotted in FIGURE 4. Again, traditional linear plots for release of drugs from ointment bases are obtained by plotting amount released vs. the square root of time. 

5 

TABLE V 

10 

Release of Metronidazole from C2 (mg)   
Time (Min)   Trial One   Trial Two   Trial Three   
O   O   O   O   
5   1.21   1.27   1.39   
10   2.02   2.18   2.29   
15   2.70   2.95   3.04   
20   3.29   3.89   3.67   
30   4.30   4.62   4.75   
40   5.02   5.32   5.57   
60   6.15   6.41   6.69   15 

20 

Data from three trials for the release of the metronidazole from C3, a cream composition, (1.0 wt-% metronidazole; pH value 3.2) are presented in TABLE VI and are plotted in FIGURE 5. In FIGURE 5, Trial One is denoted by (o), Trial Two by (e) and Trial Three by (x). The average data for the three trials are presented in TABLE VII and are plotted in FIGURE 6. Again, traditional linear plots for release of drugs from 

25 ointment bases are obtained by plotting amount released vs. the square root of time. 

TABLE VI 

30 

Release of Metronidazole from C3 (mg)   
Time (Min)   Trial One   Trial Two   Trial Three   
O   O   O   O   
5   0.56   0.42   0.46   
10   0.78   0.67   0.66   
15   0.94   0.85   0.82   
20   1.09   0.98   -   
30   1.32   1.25   1.29   
40   1.53   1.54   1.63   
60   1.94   1.82   1.69   35 

40 

TABLE VII 

45 

Average Release of Metronidazole (mg)   
Time (Min)   C1   C2   C3   
O   O   O   O   
5   1.32 :t 0.06   1.29 :t 0.09   0.48:t 0.07   
10   2.12 :t 0.03   2.16 :t 0.14   0.70 :t 0.07   
15   2.89 :t 0.06   2.90 :t 0.18   0.87:t 0.06   
20   3.48:t 0.05   3.62 :t 0.30   1.04:t 0.08   
30   4.47:t 0.08   4.56 :t 0.23   1.29 :t 0.04   
40   5.21 :t 0.12   5.30 :t 0.28   1.57:t 0.06   
60   6.26 :t 0.24   6.42 :t 0.27   1.82 :t 0.13   50 

55 

13 

-- PatentLens OCR page0014.txt

EP O 355 152 B1 

TABLE VIII and FIGURE 7 show, for comparison Purposes, the average metronidazole released from C1 (o), C2 (x) and C3 (e). The large difference in the slopes of the plots indicate that the release rate of the gel compositions, i.e., C1 and C2, is about 3.7 times greater than that from the cream, i.e., C3. 

5 

TABLE VIII 

10 

Comparison of the Release Rates (Slopes) of the Three Compositions   
Composition   Release Rates (mg/min(1/2))   
C1   0.9166 :t 0.0492   
C2   0.9465 :t 0.0349   
C3   0.2505 :t 0.0071   15 The in-vitro release of metronidazole from the gel formulations with or without propylene glycol is either 

3.66 or 3.78 times faster, respectively, than that of the metronidazole from the cream formulation C3. 

Claims 

20 1. A composition in gel form for use in the treatment of skin disorders by topical administration, comprising : 

0.75 weight percent metronidazole; 

0.6 weight percent of a gelled, hydrophilic and water-dispersible polymer having free carboxylic groups; 

25 0.08 weight percent of methyl paraben; 

0.02 weight percent of propyl paraben; 

0.05 weight percent of disodium ethylene diamine tetraacetic acid; and water as solvent for the metronidazole. 

30 2. A composition as claimed in claim 1, wherein the skin disorder is rosacea. 

3. A composition as claimed in claim 1, wherein the skin disorder is acne vulgaris. 

4. A composition as claimed in claim 1, wherein the skin disorder is one from the group compnslng 

35 steroid acne, acne conglobata, nodulocystic acne, perioral dermatitis, and seborrheic dermatitis. 

5. A composition in gel form for use in the treatment of skin disorders by topical administration, comprising : 

0.75 weight percent metronidazole; 

40 0.6 weight percent of a gelled, hydrophilic and water-dispersible polymer having free carboxyl 

groups and having a molecular weight in the range of 1,250,000 to 4,000,000 daltons; 0.08 weight percent of methyl paraben; 

0.02 weight percent of propyl paraben; 

0.05 weight percent of disodium ethylene diamine tetraacetic acid; 

45 3 weight percent of propylene glycol; and 

water as solvent for the metronidazole. 

6. A composition as claimed in claim 5, wherein the skin disorder is rosacea. 

50 7. A composition as claimed in claim 5, wherein the skin disorder is acne vulgaris. 

8. A composition as claimed in claim 5, wherein the skin disorder is one from the group compnslng steroid acne, acne conglobata, nodulocystic acne, perioral dermatitis, and seborrheic dermatitis. 

55 Patentansprüche 

1. Zusammensetzung in Gelform zur Verwendung bei der Behandlung von Hauterkrankungen durch topische Verabreichung, umfassend: 

14 

-- PatentLens OCR page0015.txt

EP O 355 152 B1 

0,75 Gew.-5 Metronidazol, 

0,6 Gew.-% eines gelierten, hydrophilen und in Wasser dispergierbaren Polymers mit freien Carboxylgruppen, 

0,08 Gew.-% Methylparaben, 

5 0,02 Gew.-% Propylparaben, 

0,05 Gew.-% Dinatriumethylendiamintetraessigsäure und Wasser als Lösungsmittel für das Metronidazol. 

2. Zusammensetzung nach Anspruch 1, in der die Hauterkrankung Rosacea ist. 

10 

3. Zusammensetzung nach Anspruch 1, in der die Hauterkrankung Akne vulgaris ist. 

4. Zusammensetzung nach Anspruch 1, in der die Hauterkrankung eine solche aus der Gruppe ist, die Steroidakne, Akne conglobata, nodulocystische Akne, periorale Dermatitis und seborrhoeische Dermati- 

15 tis umfaBt. 

5. Zusammensetzung in Gelform zur Verwendung bei der Behandlung yon Hauterkrankungen durch topische Verabreichung, umfassend: 

0,75 Gew.-% Metronidazol, 

20 0,6 Gew.-% eines gelierten, hydrophilen und in Wasser dispergierbaren Polymers mit freien 

Carboxylgruppen und einem Molekulargewicht im Bereich von 1 250 000 bis 4 000 000 Dalton, 0,08 Gew.-% Methylparaben, 

0,02 Gew.-% Propylparaben, 

0,05 Gew.-% Dinatriumethylendiamintetraessigsäure, 

25 3 Gew.-% Propylenglykol und 

Wasser als Lösungsmittel für das Metronidazol. 

6. Zusammensetzung nach Anspruch 5, in der die Hauterkrankung Rosacea ist. 

30 7. Zusammensetzung nach Anspruch 5, in der die Hauterkrankung Akne vulgaris ist. 

8. Zusammensetzung nach Anspruch 5, in der die Hauterkrankung eine solche aus der Gruppe ist, die Steroidakne, Akne conglobata, nodulocystische Akne, periorale Dermatitis und seborrhoeische Dermatitis umfaBt. 

35 

Revendications 

1. Composition sous forme de gel pour être utilisée dans le traitement des affections cutanées par application topique comprenant: 

40 0,75 % en poids de métronidazole ; 

0,6 % en poids d'un polymère dispersible dans l'eau, d'hydrophile, capable de se gélifier et ayant des groupes carboxyles libres; 

0,08 % en poids de méthyle parabène ; 0,02 % en poids de propyle parabène ; 

45 0,05 % en poids d'acide tétracétique éthylènediamine disodique ; et 

de l'eau comme solvant pour le métronidazole. 

2. Composition selon la revendication 1, caractérisée par le fait que l'affection cutanée est la couperose. 

50 3. Composition selon la revendication 1, caractérisée par le fait que l'affection cutanée est l'acné. 

4. Composition selon la revendication 1, caractérisée par le fait que l'affection cutanée est l'une de celles du groupe comprenant l'acné stéro'läe, l'acné conglobata, l'acné nodulocystique, la dermatite périorale et la dermatite séborrhée. 

55 

5. Composition sous forme de gel pour être utilisée dans le traitement des affections cutanées par application topique comprenant: 

0,75 % en poids de métronidazole ; 

15 

-- PatentLens OCR page0016.txt

EP O 355 152 B1 

0,6 % en poids d'un polymère dispersible dans l'eau, hydrophile, capable de constituer un gel et ayant des groupes carboxyles libres et présentant un poids moléculaire compris entre 1.250.000 et 4.000.000 daltons ; 

0,08 % en poids de méthyle parabène ; 

5 0,02 % en poids de propyle parabène ; 

0,05 % en poids d'acide tétracétique éthylènediamine disodique ; 3 % en poids de propylène glycol ; et 

de l'eau comme solvant pour le métronidazole. 

10 6. Composition selon la revendication 5, caractérisée par le fait que l'affection cutanée est la couperose. 

7. Composition selon la revendication 5, caractérisée par le fait que l'affection cutanée est l'acné. 

8. Composition selon la revendication 5, caractérisée par le fait que l'affection cutanée est l'une de celles 

15 du groupe comprenant l'acné stéro'läe, l'acné conglobata, l'acné nodulocystique, la dermatite périorale 

et la dermatite séborrhée. 

20 

25 

30 

35 

40 

45 

50 

55 

16 

-- PatentLens OCR page0017.txt

  o                   
    o   2   :5   4   5   6   7   8   
      TIM E (aq. root of min)         
      -r- 7 9- 2_           
-   7                   
at                     
E                     
-   6                   
Q                   
1&1                     
(I)                     
et                     
1&1   5                   
rd                   
~                     
1&1   4                   
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Q                   
-                     
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O                     
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1&1                     
a                     
1&1                     
C!»                     
et                     
~                     
1&1   o                   
~     o   2   :5   4   5   6   7   8   
      TIM E (sq. root of min)         EP o 355 152 B1 

17 

-- PatentLens OCR page0018.txt

EP O 355 152 B1 

  o                   
    o   2   3   4   S   6   7   8   
      TIM E (sq. root of min)         
      -r: 7 9- 4.           
-   7                   
O'                     
E                     
-   6                   
Q                   
I&J                     
fi)                     
et                     
I&J   S                   
W                   
I&J   4                   
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et   3                   
e                   
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Ir                     
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11.1                     
2                     
11.1                     
C!)                     
et                     
Ir                     
I&J   O                   
>                   
CI:     O   2   3   4   S   6   7   8   
      TIME (Iq. root of min)         18 

-- PatentLens OCR page0019.txt

2   
-   
Ot   
E   
-   
Q   
\M   
e   
~   
a:::   
IIJ   
..I   
2   
e   
Q   
z   
o   
a:::   
ti   
:E   EP O 355 152 B1 

  O                   
    O   2   3   4   S   6   7   8   
      TIME ( 1(1. root of min.)         
      -F...:z 9_6_         
-   2                   
Ot                     
E                     
-                     
Q                     
W                     
~                     
IIJ                     
a:::                     
IIJ                     
.J                     
o                     
N                     
e                     
o                     
-                     
z                     
o                     
a:::                     
ti                     
:E                     
IIJ                     
a»                     
e                     
a:::                     
IIJ                     
>                     
e     O       4   5       e   
      TIME (Iq. root of min.)         19 

-- PatentLens OCR page0020.txt

EP O 355 152 B1 

20 

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