KR920005648B1 - Dental applicable released composition containing antibiotics - Google Patents

Abstract

The dental composition for local prolonged administration is composed of 10-40 wt.% effective component (A) and a polymeric component (B) i.e. polyethylene vinylacetate (EVA), polycaprolactone (PCL) or PCL/polyethylene glycol (PEG). The component (A) is pref. tetracycline or minocycline. The EVA contains 15-30 wt.% vinylacetate, and the molecular wt. of PCL and PEG is 50000-100000 and 2000-30000, respectively. The composition has a local and prolonged release-control property for periodontal diseases.

Description

Dental topical, long-acting compositions of antibiotics

1 is a graph (a) showing the release ratio of minocycline from the polymer substrate for the first 24 hours in the polymer substrate prepared from the composition according to the present invention (Example 4), and the fraction of minocycline over time Graph (b) showing the emission ratio,

2 is a graph (a) showing the minocycline release ratio in the PCL film after the first 24 hours, as measured in Example 5 according to the present invention, and the release ratio for the 7 days 20% minocycline-containing PCL film Graph (b) shown,

3 is a graph showing the release ratio of tetracycline relative to the EVA polymer substrate (Example 8) prepared with the composition of the present invention,

4 is a graph showing the release ratio of minocycline relative to the EVA polymer substrate (Example 13) prepared with the composition of the present invention.

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to topical, topical, and sustained-release compositions containing antibiotic active ingredients, and more particularly, by mixing antimicrobial ingredients, such as tetracycline or minocycline, as active ingredients, with polymeric materials suitable for living being, particularly periodontal disease. A topical dosage composition having release control useful for the present invention.

In recent years, interest in the development of new drugs has been increasing, but since the development of enormous technology and cost is necessary, some have developed various dosage-release control compositions for enhancing the administration effect of the existing active ingredients. . Especially, it shows very good effect in the field of diabetes, hypertension and cancer treatment.

In the dental field, a release control method for reducing tooth decay by maintaining a constant concentration of fluorine in the oral cavity has been proposed. Recently, a topical administration method of antibiotics using a polymer has been developed.

Drugs used in these antibiotic topical administration methods include Tetracycline, Metronidazole, Chlorhexidine, and Minocycline, and hollow fiber, film, or gel may be used. have. In addition, poly (ethyl methacrylate), ethyl cellulose, polyethylene, EVA, polyurethane, and the like have been studied as polymers used as carriers (US Pat. Nos. 4764377, 4175326, and 3923939).

In Korea, the present inventors have studied microbial and immunological studies of the periodontal pathogens, and antibiotics research and treatment methods thereof [Korean Journal of Periodontal Science 17 (1), 11 (1987): 15 (1), 153 (1985)] . In particular, a method of incorporating tetracycline into a hydrophobic gel for topical application of antibiotics has been studied (Korean Journal of Microbiology 21,503 (1986)).

However, in these methods, the effect of the drug itself was shown, but since the persistence of the drug was less prominent, it was necessary to control the long-term drug release using a polymer. However, when antibiotics are administered systemically, since periodontal disease is a disease that occurs at a special anatomical location such as gingiva and periodontal sac, there is a problem that the drug does not penetrate well into the tissue area and the systemic side effects are large.

Therefore, in the present invention, unlike the prior art by combining an active ingredient such as tetracycline (TC) or minocycline (MC) with an active ingredient and a high-molecular polymer composition suitable for the living body, while having a local release control for periodontal disease, The purpose of the present invention is to provide a novel topical sustained composition useful for the treatment of periodontal disease, which enables the reduction of systemic toxicity, maximization of therapeutic effect, and economical administration.

Hereinafter, the present invention will be described in detail.

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a dental administration composition comprising an anti-bioactive component of tetracycline or minocycline as an active ingredient, wherein poly (ethylene vinyl acetate) (hereinafter abbreviated as "EVA") and polycaprolactone are used as the active ingredient and the polymer component. (Hereinafter, abbreviated as "PCL") and a mixture of PCL and polyethylene glycol (hereinafter abbreviated as "PEG"), wherein the active ingredient is contained in an amount of 20 to 30% by weight based on the polymer component. It is characterized by the composition for topical administration.

Referring to the present invention in more detail as follows.

The topical administration composition according to the present invention can be used in the form of a film or a peak containing a cyclocycline or minocycline active ingredient (Cone), wherein the thickness of the film or the peak is 100 ~ 400μm, preferably 150 ~ It is good that it is 250 micrometers. The polymer component used in the present invention serves to control the release of the carrier and the drug, the EVA polymer is preferably used that contains 10 to 40% by weight of vinyl acetate, more preferably the content is It is good that it is 15 to 35 weight%.

If the vinyl acetate contained in the 15% by weight or less in the EVA, there is a problem because there is too much flexibility, when using more than 35% by weight is not good because there is too much flow.

In addition, the PCL used in the present invention preferably has a molecular weight of 50,000 to 100,000, and preferably PEG to 2,000 to 30,000.

According to the present invention, the PCL is used alone, or the PCL and PEG are used in combination. When the PCL and PEG are used in combination, the weight ratio of 5 to 7: 5 to 3 is good. Mixed use is preferred because it increases the rate of drug release.

On the other hand, it is preferable to use the topical sustained-dose composition according to the present invention to 10 to 40% by weight based on the polymer component to which the antibiotic is added as an active ingredient. If it is too short and there is too much, it is economical and the said range is preferable.

In this case, as an active substance used as an active ingredient, for example, Tetracycline, Minocycline, Chlorhexidine, Sangyuinarine, Crindamycin, Augmentin, Augmentin , Ofloxacin, Metronidazole, or Fosfomycin may be used, in particular tetracycline or minocycline or hydrochloride thereof.

When described step by step as an embodiment to provide such a tablet until the topical administration composition of the present invention and the administration experiment as follows.

[Raw setting]

-Active ingredients

Tetracyclineminocycline hydrochloride

-High molecular weight

Poly (ethylene vinyl acetate): 15%, 30% content of vinyl acetate

Poly (ethylene glycol): molecular weight 2,000, 6,000, 20,000

Poly (ε-caprolactone): molecular weight 60,000

[Production of Polymer Strip]

The mixture of the active ingredient and CHCl ₃ was uniformly mixed in the polymer solution dissolved in 5 ml of solvent (CHCl ₃ ) per 1 g of the selected polymer for about 24 hours, and then a strip film was cast on the glass.

[Production of Polymer Membrane]

After dissolving at a rate of 5 ml of the polymer 1 g solvent (CHCl ₃ ), it was cast on a Teflon film.

[Drug Permeation Test on Polymer Membrane]

In the permeation test, a two chamber diffusion cell was used, in which the volume of the cell was 8 ml and the effective penetration area was 1.33 cm ² . In addition, the material of the cell is glass and the outside is surrounded by a water jacket (Water Jacket) to circulate the water to control the temperature. The Diffusion Console uses a Crown Glass Company product in the US and can run nine diffusion cells simultaneously.

For the permeation test, the prepared polymer membrane was sandwiched between two cells, and both sides of the polymer membrane were fixed with 0-rings. In the Donor Compartment, the drug was dissolved in distilled water in a supersaturated state, and the Receptor Compartment was filled with distilled water with 8m ^-4 , and the thermostat was controlled by circulating water at 36 to 38 ° C.

Each Cell Compartment was sampled from the sensitive compartment at regular time intervals while stirring with a magnetic stirrer. In addition, distilled water was added as much as the collected sample amount, and the sample amount was corrected at the time of data analysis.

Drug Release Experiment on Strip Film

In the release experiment of the drug as an active ingredient for the sprip film, a continuous diffusion device was used. The cell of this device is mounted so that the storage solution enters the inlet next to the cell and out of the upper outlet.The cell volume is about 500μl and the whole cell is placed in the jacket to keep the temperature around 37 ℃. Circulate At this time, distilled water was used as the storage solution, and the flow rate of distilled water was maintained at 3 to 4 ml / hr.

The strip film placed inside the cell was stirred by a magnetic bar at the bottom of the cell to mix the drug released from the strip film, allowing the bubbles inside the cell to easily escape to the outlet.

[Quantitative Analysis of Tetracycline and Minocycline]

Quantitative analysis of the drug tetracycline and minocycline as active ingredients in the present invention was carried out by UV / Visible Spectrophotometer (UV / Visible Spectrophotometer).

Tetracycline was fixed at pH 1.2 using 0.1 N HCl and analyzed at a wavelength of 268 nm. Minocycline was analyzed at a wavelength of 273 nm.

[Permeation Experiment of Tetracycline and Minocycline on Polymer Membrane]

When the active ingredient infiltrated into the polymer component is immersed in the tetracycline and minocycline solution at 37 ° C. by the solution depletion method and is in equilibrium with the bulk solution in the polymer component and the solution. The distribution coefficient of the active ingredient was measured, and the distribution coefficient, diffusion coefficient and permeability were calculated using the following equation.

Where Kd is the partition coefficient, Vs is the volume of drug solution, Vm is the volume of polymer, Co is the concentration of initial drug solution, and Cs is the concentration of drug in solution when equilibrium is reached.

Where P is the permeability, V receiver is the volume of the low compartment, A m is the permeation area, C donor is the drug concentration in the upper compartment, and C receiver is the drug concentration in the bottom compartment.

t = 1 ₂ / 6D

p = D kd / 1

Where t is the transmission delay time, D is the diffusion coefficient, P is the transmittance, and 1 is the thickness of the polymer membrane.

[Release Experiment of Tetracycline and Minocycline in Strip Film]

The release rate of tetracycline and minocycline from the strip film made by adding the amount of tetracycline and minocycline in 10% by weight, 20% by weight, 30% by weight and 40% by weight with respect to 1g of the polymer component, respectively, at a temperature of 37 ° C. per hour. Measured under conditions.

As a result, in the case of tetracycline, the initial burst effect increased as the amount of the active ingredient added compared to the polymer component increased, and after about 7-8 hours, the release rate was increased regardless of the amount of the active ingredient added. Appeared constantly. However, as the release rate is constant, the amount of the active ingredient released per hour is found to be somewhat smaller.

In addition, in case of Minocycline, the initial excess release phenomenon was observed, and the release rate slowly decreased with time, and the release rate of the active ingredient from 120 hours to 168 hours was 5 ± 1 to 10 ± 2 μg / cm. ^It was found to be ² / hr.

In particular, in the case of the polymer component mixed with PCL and PEG, the initial excess release phenomenon increased as the amount of the active ingredient increased, but after about 10 hours, a similar release rate appeared. The phenomenon was large.

From this, especially when the minocycline is used as the active ingredient in the composition range of the present invention, when PCL and PEG mixed components are used as the polymer component, when the content of the active ingredient is small, when the molecular weight of the polymer component is low The characteristic showed a tendency to be preferred.

As described above, the composition for topical administration according to the present invention can exhibit long-term efficacy by improving the release control by changing its composition, unlike the conventional, as well as reducing the systemic toxicity and maximizing the therapeutic effect and thereby economical administration effect. It represents.

Hereinafter, the present invention will be described in detail with reference to Examples.

Example 1-3

Preparation of Caprolactone Films Containing Minocycline

Poly (ε-caprolactone) (molecular weight 60,000: Interrox Chem. Ltd. alone) (Example 1) or the poly (ε-caprolactone) and 30% PEG (molecular weight 20,000: Wako Pure Chem. Ind. Ltd.) Each of the mixtures (Examples 2 and 3) was used to dissolve it in 10 ml of chloroform, and the minocycline powder (Sino pharmaceuticals, Korea) was dissolved in 5 ml of chloroform and stirred for 3 hours.

Each of the polymer solutions were then dropped into the solution and mixed for 24 hours. The mixed solution was dried at atmospheric pressure and room temperature, and then completely dried in a vacuum chamber for 3 hours to prepare a film having a thickness of 200 μm on a Teflon plate.

Example 4

Measurement of Minocycline Release Rate in Vitro

The film prepared in Example 2 was cut into a circular diameter of 20 mm (net weight 30 mg) and immersed in distilled water of a diffusion system. At this time, the volume of the system was 500 μl, and the system was stacked with a water jacket at 37 ° C., and the distilled water of the system was circulated rotationally at 3.5 ml / hr by a peristaltic pump.

The amount of minocycline released from the system was measured at 273 nm over time using a spectrophotometer (Shimadzu UV-240). The results are shown in the following Table 1 and Table 2, and the graphs are shown in FIG. 1 (a) and (b), respectively.

The amount of minocycline released from PCL or PCL and PEG (μg / cm ² / hr)

TABLE 1

* MC: Minocycline content in a film.

Fractional release ratio (%) of minocycline from PCL or PCL and PEG

TABLE 2

* MC: Minocycline content in a film.

Example 5

Antibiotics Measure

(1) Cultivation of experimental bacteria:

Bacteria used in this experiment were Bacillus Cereus KCTS 1012 (Korea Advanced Institute of Science and Technology), Bacteroides gingilvalis 381, Bacteroides intermidius NTCT 9336, Actinobacillus extinomy Setem Comitans (Actinobacilus actionmycetemcomitans Y4: Socransky), Olinella recta ATCC 33238, Actinomyces viscosus ATCC 19246, Capycytophaga gingivalis ATCC 33624 Terium nucleatum (Fusobacterium nucleatum ATCC 25586) and Emikenella corrodens ATCC 23834 were used.

Bacillus cereus was incubated in Nutrient broth (Difco Laboratories, Detroit, USA) at 37 ° C., 10% concentration. Actinobacillus actinomycetem comitans Y4 was inoculated in a medium consisting of NIH Thioglycollate boroth (Difco Research Institute) and incubated in a vacuum chamber (80% N ₂ , 10% H ₂ and 10% CO ₂ : 37 ° C) (Coy Institute product: An arbor.MI.USA).

Bacterial test bacteria and other periodontal bacteria include 2.5g yeast extract (Difco), 2.5g trypton (Difco), 2.5g tryptose (Difco), and 4.8g BHI (Difco) ), 10 ml of a slat solution, 1 ml of resazurine, 2.5 g of hemin, 0.5 g of menadione, and 0.25 g of cysteine HCl (Sigma) in 250 ml of distilled water. Inoculated and incubated at 37 ° C. for 2 days in a vacuum.

(2) Analysis of growth inhibitory activity by the disk diffusion method:

The inhibitory activity of the cast film against Bacterial cereus was measured by the disk diffusion method, and the diameter 1/3 containing 20% or 30% of minocycline released on the diffusion system for 1,3,5,7 days respectively. Four-inch circular PCL + PEG or PCL films were placed in a bacterial culture dish containing culture bacteria. At this time, the culture dish was incubated for 24 hours under CO ₂ gas condition at 37 ° C., and then the inhibition region was measured. The results are shown in Tables 3 and 4, respectively, and in particular, the results after 1 day (24 hours) and 9 days in Table 4 are shown as (a) and (b) in FIG.

Growth inhibition area by PCL + PEG sample disk containing 20% Minocycline (disc diameter 1/4 inch, thickness 200 ± 10μm)

TABLE 3

Growth inhibition zone (mm) by 20% and 30% Minocycline containing PCL sample discs

TABLE 4

(3) Analysis of growth inhibitory activity in the medium:

Antibiotic effect measurements of PCL films released on the test strains for 1, 3, 5 and 7 days in the diffusion system were performed by growth inhibition activity assay in batches. 30% Minocycline, released for 1, 3, 5 and 7 days, respectively, was immersed in bacteria-inoculated BHI medium containing PCL sample disks (1/4 inch diameter, 4 mg net weight).

Then, the inoculation medium without the PCL sample was cultured as a control bacterium. This was incubated for 48 hours in a vacuum system at 600nm at 37 ℃ using a spectrometer (Baush & Lomb) and then analyzed by measuring the turbidity of the medium composition, the results are shown in Table 5.

Density of media and control bacteria on minocycline containing or non-containing sample disks after 48 hours in vacuum chamber.

TABLE 5

* A. act: Actinobacillus Actinomycetem Comitans Y4

B. gin: Bacterolide Jinjivalis 381

B. int: Bacterial Intermedius NTCT 9336

W. rec: O'Nella Recta ATCC 33238

A. vis: Actinomyces Viscous ATCC 19246

F. nuc: Persobacterium nucleum ATCC 25586

E. cor: Akenella Corrodens ATCC 23834

C. gin: Caprositopaga Jinji Bally ATCC 33624

As can be seen from the above experimental results, 20% and 30% of minocycline released from minocycline-containing PCL or PCL + PEG strip showed 4-8 μg / ml / hr, and showed continuous antimicrobial activity after 7 days. .

Therefore, it can be seen that the composition of the present invention has excellent release control against periodontal disease.

[Examples 6 to 7]

Tetracycline Permeation Experiments on EVA Polymeric Membranes

Poly (ethylene vinyl acetate) (EVA) having a vinyl acetate (VA) content of 15% (Example 6) and 33% (Example 7) was used as a polymer component, and tetracycline was used as an anti-bioactive component. At this time, the distribution coefficient, the permeability and the diffusion coefficient of tetracycline for the EVA polymer film were calculated by the above formulas, and the results are shown in Table 6 below.

Distribution, Permeability, and Diffusion Coefficients of Tetracycline for EVA Polymers

TABLE 6

* VA content in EVA polymer

[Examples 8 to 10]

Experimental Release of Tetracycline on EVA Polymeric Strip Film.

Preparation of EVA polymer strip film in the same manner as in Examples 1 to 3, but the release of tetracycline from the strip film made by adding 10%, 20%, 30% of the amount of tetracycline to 1g of EVA polymer with a VA content of 30% The speed was measured in the same manner as in Example 4. The result obtained at this time is shown in the graph as shown in FIG.

[Examples 11 to 12]

Minocycline Permeation Experiments on EVA Polymeric Membranes.

The distribution coefficient of minocycline to the EVA polymer membrane, which is obtained by using an EVA polymer having a VA content of 15% (Example 11) and 33% (Example 12) as a polymer component and a minocycline as an anti-bioactive component, Permeability and diffusion coefficient were respectively calculated by the above formulas and the results are shown in Table 7 below.

Distribution, Permeability, and Diffusion Coefficients of Minocycline for EVA Polymers

TABLE 7

[Examples 13-15]

Release Test of Minocycline in EVA Polymeric Strip Film.

The release rate was measured in the same manner as in Examples 10 to 11 by performing a minocycline release experiment on an EVA polymer strip film.

The results are shown in the graph of FIG.

As can be seen from the results of Examples 6 to 15, as the amount of the active ingredient added to the polymer increases, the initial excess release phenomenon increased, and after 7 hours, the release rate was similar regardless of the amount of the added active ingredient. However, since the amount of the anti-bioactive component of the active ingredient released per hour was small, the EVA polymer was found to be somewhat lower than PCL or PCL + PEG according to the above embodiment.

Experimental Example

In the periodontal sac release experiment, a strip film containing 2.5% of minocycline in polycaprolactone was used (2.5 mm x 6 mm, net wt: 2 mg), which was released over time from the strip film inserted into the periodontal sac. The concentration of minocycline was determined according to bioanalysis. The concentration of minocycline in the periodontal sac of 5 mm or more in a periodontal sac was obtained by collecting gingival fibroblasts by using a Harco Periopaper over time. Until. Sampling time was 1, 2, 4, 8 hours after inserting the strip film, and again after the pulp bag, carried out for 7 days at intervals of 24 hours, the strip was dried until use and stored frozen at -20 ℃.

The concentration of minocycline in each strip was determined by culturing Bacillus cereus and measuring the diameter at the bacterial growth inhibitory site indicated by each strip. The method was cultivated Bacillus cereus KCTC 1012 (donated by KIST Genetic Engineering Center) in a 10 ml culture (Difco Lab. After sterilizing Mueller-Hinton broth (Difco Lab. Detroit, Michigan) added with 1.7% agar, cool to 50 ° C and add 2 ml of culture solution per 100 ml broth-agar to 7 ml on a 90 mm radius plate. After swelling and hardening, the strips collected from the standard strip and periodontal sac were cut to blue wire, placed on a plate medium, and incubated in a 37 ° C. carbon dioxide incubator for 24 hours. The standard strip was made by continuously diluting minocycline with distilled water to a concentration of 1,000 to 1 μg / ml, and absorbing the solution until the blue line of the strip was dried. After incubation, the diameter of the bacterial growth inhibitory site was measured using the vernier caliper up to 1 mm from the long axis and the short axis, and the average was calculated. In the relationship between the inhibitory diameter obtained from the standard strip and the concentration of minocycline, the log was taken from the concentration value and linear regression analysis was performed to generate a standard curve. The concentration of minocycline released into the periodontal sac was calculated according to the following equation. Can be.

log Y = A + BX

Where Y is the concentration of minocycline,

X means the diameter of the bacterial growth inhibitory site,

The value of A is -0.565218,

The value of B is 0.115161.

Free concentration of Minocycline over time calculated by linear regression analysis after inserting polycaprolactone containing 30% Minocycline into periodontal pocket

TABLE 8

The results of the in vitro release experiment (A ') and the concentration (B) in the in vivo release experiment compared with the size of polycaprolactone (2.5 mm x 6 mm) in the in vivo release test were compared in the in vitro release experiment. A concentration of 6.35 times greater than the amount of minocycline released per hour is detected (C).

TABLE 9

From the above results, the minocycline released from the polycaprolactone strip film containing 30% of the minocycline in the in vitro release experiment showed the same result as the release experiment in the film. ) And the rate of release decreases gradually. On days 6-7, more than 96% of minocycline was released, releasing 8-9 μg / cm ² every hour. As a result of in vivo release experiments, minocycline liberated in the periodontal sac from one polycaprolactone (2.5 mm × 6 mm, thickness 200 ± 10 μm) showed an initial maximum release at a concentration of 350 μm / ml at the initial 2 h. It gradually decreased over time and showed a concentration of 3.8 to 6.7 μg / ml at 6 and 7 days (see Table 8 and FIG. 5).

The concentration of minocycline liberated from polycaprolactone in the periodontal sac is similar to that of minocycline in in vitro release experiments (figure 5), which shows the amount of minocycline released over time in an in vitro release experiment. In comparison with the same size as the film in the in vivo experiment (2.5mm x 6mm), the concentration of minocycline extracted per hour in vivo is 6.35 ± 3.99 than the value in the release rate of minocycline in the in vitro release experiment. It was about twice as high (see Table 9).

As described above, in vitro and in vivo drug release experiments were carried out by incorporating 30% of minocycline into polycaprolactone for use in the treatment of periodontal disease according to the present invention.

First, the polycaprolactone (thickness 200 ± 10 μm) containing 30% of minocycline had a half-life of drug release in the in vitro release experiment for 16 hours, the highest release period for the first 2 hours, and an hourly release after 7 days of release experiments. The drug was released in an amount of 8 μm / cm ² .

Second, the release of drug into the periodontal sac from one polycaprolactone (2.5mm × 6mm, thickness 200 ± 10μm) containing 30% of minocycline showed a peak release of 350μg / ml in the first 2 hours, and gradually decreased 6, Day 7 showed concentrations of 3.8-6.7 g / ml.

Third, the concentration of minocycline extracted per hour in vivo shows a similar pattern to that of the release rate in the in vitro release experiment, and is 6.35 higher than the release rate of the minocycline in the in vitro release experiment released from the polycaprolactone film of the same size. A high value of ± 3.99 times is shown.

Therefore, according to the present invention, polycaprolactone film containing 30% of minocycline can continuously release the drug in the periodontal sac for 7 days and can be used as a release control agent for periodontal treatment.

Claims (5)

In the dental administration composition comprising the anti-bioactive component of tetracycline or minocycline, any one selected from poly (ethylene vinyl acetate), polycaprolactone, and a mixture of polycaprolactone and polyethylene glycol as the active ingredient and the polymer component A topical long-acting administration composition of an anti-bioactive component, wherein the active ingredient is contained in an amount of 10 to 40% by weight based on the polymer component. The topical sustained-dose composition according to claim 1, wherein the poly (ethylene vinyl acetate) has a vinylacetate content of 15 to 35% by weight. The topical sustained-dose composition according to claim 1, wherein the polycaprolactone and polyethylene glycol are mixed in a weight ratio of 5-7: 5-3. The topical sustained-dose composition according to claim 1 or 3, wherein the polycaprolactone has a molecular weight of 50,000 to 100,000, and polyethylene glycol has a molecular weight of 2,000 to 30,000. In a strip film containing a dental dosage composition containing the anti-bioactive component of tetracycline or minocycline as an active ingredient, poly (ethylene vinyl acetate), polycaprolactone and polycaprolactone and polyethylene glycol as the active ingredient and the polymer component Dentistry of the antimicrobial component containing any one selected from the mixture, by casting the composition containing 10 to 40% by weight of the active ingredient to the polymer component in a film or cone shape of 100 to 400μm thick A strip film containing a topical topical dosage composition.

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