EP0583399A1

EP0583399A1 - Taste-masked medicaments and their preparation

Info

Publication number: EP0583399A1
Application number: EP92912798A
Authority: EP
Inventors: Thomas A. Wheatley; David Frank Erkoboni
Original assignee: FMC Corp
Current assignee: FMC Corp
Priority date: 1991-04-30
Filing date: 1992-04-03
Publication date: 1994-02-23
Also published as: WO1992019209A2; EP0583399A4; NO933920D0; NO933920L; AU651721B2; JP2538491B2; WO1992019209A3; AU2167392A; CA2107229A1; CA2107229C; JPH06501027A

Abstract

Médicament solide au goût déguisé, tel qu'un comprimé d'aspirine ou analogue, dans lequel l'élément déguisant le goût est une mince pellicule d'ester de cellulose composée d'une couche séchée d'une dispersion aqueuse d'un ester de cellulose plastifié. La pellicule ne constitue pas plus d'un pourcent du médicament enrobé d'une pellicule.Solid drug with a disguised taste, such as an aspirin tablet or the like, in which the taste-disguising element is a thin film of cellulose ester composed of a dried layer of an aqueous dispersion of an ester of plasticized cellulose. The film does not constitute more than one percent of the drug coated with a film.

Description

TASTE-MASKED MEDICAMENTS AND THEIR PREPARATION

This invention relates to taste-masking of solid medicaments, particularly by enveloping them in a tasta- masking polymer film coating. Therapeutic formulations designed for oral adminis¬ tration often contain active ingredients which have an unpleasant taste. For instance, many drugs produce a bitter or acrid sensation when taken by mouth.

Various techniques are known for counteracting the disagreeable taste of medicinal products. Perhaps the. oldest a proc-i- is to include a flavoring agent in the formulati_.. -_o overpower the taste of the offending com¬ ponent. Both solid and liquid medicaments can be taste- masked in this manner. In the case of a solid medicament, taste-masking is commonly effected by coating the medicament with a taste blocking layer. This can be something as simple as a sugar coating which dissolves to provide a pleasant taste during the interval between ingestion and swallow- ing of the medicament. More recently, the pharmaceuti¬ cal industry has focused its attention on coatings pro¬ duced from film-forming polymers and considerable effort has been devoted and continues to be devoted along this line of approach for taste-masking of solid dosage forms.

A new development in polymeric taste-masking films is disclosed in U. S. Patent No. 4,851,226 to Julian et al. These films are formed of a blend of a cellulose ester and polyvinylpyrrolidone (PVP) applied to a me- dicament such as acetyl-p-aminophenol (acetaminophen or APAP) from an organic solvent solution of the polymers. The purpose of the PVP, which is water soluble, is to temper the hydrophobic character of the cellulose ester and thereby control the drug release rate of the medi- cation. According to the patent, a film coating may be designed so that the medicine is released relatively rapidly or in a sustained released mode. When rapid release is desired, the proportion of PVP in the film coating is from about 12% to 20% by weight. If used alone, however, the patentees found that the cellulose ester coating would not provide adequate bioavailability of the active ingredient at the specified coating levels of 5% to 20% by weight. This is clearly evident from Figure 1 of the patent depicting in graphic form the dissolution rate of APAP in simulated gastric fluid at a coating level of 17.5% by weight and which the percent o-f PVP in the coating blend varied from 0% to 25% 'by weight. As will be noted, at 0% PVP in the film coating drug release amounted to only 40% after 40 minutes.

The chief problem with the coatings of the Julian et al. patent is that they are applied from an organic solvent solution of the film-forming resin. Such sol¬ vents tend to be toxic and/or flammable thereby posing a hazard to personnel and operators. Also, organic sol¬ vents are pollutants, necessitating the installation of expensive and complex solvent recovery systems to meet environmental regulations. Furthermore, traces of re¬ sidual solvent may remain in the treated medicament giving use to a potential health threat.

In accordance with the present invention solid medicaments can be effectively taste-masked with a film envelope consisting essentially of a cellulose ester applied from a latex dispersion of the ester, while maintaining rapid release of active ingredients. The provision of such taste-masked medicaments constitutes the main advantage and purpose of the invention. Other advantages and purposes will become apparent in the ensuing description.

The advantages and purposes aforesaid are realized by employing as the source of the cellulose ester film envelope, an ultra-thin coating formed of the dried residue of an aqueous plasticized dispersion of the cellulose ester. Remarkably, taste-masking of aspirin tablets at coating levels significantly below about 0.4% have been realized while also exhibiting dissolution profiles similar to uncoated controls.

Figure 1 is a graph of percent dissolution versus time for aspirin tablets (acetylsalicylic acid - ASA) coated with the ultra-thin cellulose ester films made in accordance with the invention and the uncoated core control.

In Figure 1 the symbols have the following meaning:

—|— Uncoated Cores

-Φ- CA Latex, 5 Min. -*K- CA Latex, 10 Min.

Figure 2 is a graph of percent dissolution versus time for ASA tablets coated with the ultra-thin cellu¬ lose ester films of the invention, for ASA tablets simi¬ larly coated with the cellulose ester/PVP blend of U. S. Patent No. 4,851,226 to Julian et al., and for the.un- coated core control.

In Figure 2 the symbols have the following meaning:

—ι Uncoated Cores -£- CA/PVP Latex, 5 Min. -*- CA/PVP Latex, 10 Min

The aqueous plasticized cellulose ester dispersion used in the practice of the invention is a known chemi- cal entity. Commonly referred to as a cellulose ester latex, it is prepared by dissolving the polymer in a suitable organic solvent, dispersing the resulting solu¬ tion in an aqueous phase, homogenizing, and evaporating the solvent. To the resulting latex is added an appro- priate plasticizer.

Cellulose ester latex systems have previously been -3a-

investigated as a film coating material for controlled release drug products. So far as is known, however, there has been no recognition or appreciation by the pharmaceutical community that cellulose ester latex dispersions would have application to taste-masking using the ultra-thin coating technique as set forth herein.

For a brief description of cellulose ester latex and its use in the fabrication of controlled drug de- livery membranes, see Bindschaedler et al. Proceed.

Intern. Symp. Control. Rel. Bioact. Mater 12, (1985).

Illustrative of the cellulose ester latexes suita¬ ble for producing the ultra-thin coatings of the in¬ vention are latexes made from cellulose acetate, cellu- lose acetate butyrate and cellulose acetate phthalate.

-4-

Cellulose ester polymers are manufactured and sold com¬ mercially by a number of suppliers of industrial chemi¬ cals, for example, the Eastman Kodak Company, Kingsport, Tenn. Examples of suitable plasticizers for cellulose aqueous dispersions include triacetin, diacetin and triethylcitrate.

As understood herein, medicament can be, for ex¬ ample, granules, tablets including tablets of the co - pressed coated granules of drugs such as aspirin (ASA) , acetaminophen, and ibuprofen.

The ultra-thin, taste-masking films of the in¬ vention are conveniently produced by coating the solid medicament substrate with an aqueous cellulose acetate dispersion in which the preferred plasticizer is tri¬ acetin. The triacetin is added to the dispersion and the mixture thoroughly mixed. In general, the amount of plasticizer ranges by weight from about 50% to about 150%, preferably from about '30% to 120%, optimally about 100% of the solids content of the dispersion. A cellu¬ lose acetate aqueous dispersion having a solids content of by weight of from about 28% to 32% is available from the FMC Corporation under the designation CA398-10 latex dispersion. The ultra-thin, taste-masking cellulose films of the invention are applied to the solid medicament in a known manner and with standard pharmaceutical coating equipment. Coating is normally carried out by spraying in a pan or in a fluidized bed. Solids content of the aqueous cellulose ester coat¬ ing formulation plus plasticizer is in the neighborhood of from about by weight 10% to about 30%, preferably 15% to 20%. In the final dried coating, the amount of plas¬ ticizer present in the film coating ranges by weight from about 30% to about 60%.

As previously pointed out, effective taste-masking ^' of standard pharmaceutical tablets such as an aspirin -5-

can be realized with the ultra-thin cellulose ester film coatings of the invention at coating levels of about 0.4% by weight based on total solid dosage form weight. Other types of solid dosage forms such as granules may require somewhat higher coating levels. So far as has been determined, overall coating levels will vary from about 0.3% to about 1.0% by weight for effective taste- masking.

The amount of coating applied to the substrate can be controlled in known manner such as solids content of the coating dispersion and contact times.

The following examples, that is, procedures and test data tables illustrate the invention in further detail. Throughout this specification and claims, all parts and percentages are by weight unless otherwise indicated.

COATING FORMULATIONS

* 15 % solids concentration in coating formulation ** CA398-10, FMC Corporation ***Kolidon^R 30, BASF -6-

COATING CONDITIONS: Constant Conditions:

The following conditions were held constant for both batches. Coating Equipment AccelaCota 24 inch pan

Batch Size 10 kg ASA cores

Inlet Temperature Set 170 - 175°F

Pump Type Peristaltic

Nozzle Size 1.0 mm Atomizing Pressure 25 psi

Spray Rate 16 ml/min/gun

Batch #1 (ASA 325 mg coated with coating solution #1: CA latex) Actual Inlet Temp. (°C) 63 - 67 Exhaust Temp. (°C) 37 - 43

Bed Temp. (°C) 34 - 42

Batch #2 (ASA 325 mg coated with coating solution #2: CA latex with PVP

Actual Inlet Temp. (°C) 62 - 66 Exhaust Temp. (°C) 38 - 41

Bed Temp. (°C) 36 - 42 Uncoated aspirin (ASA) cores and coated ASA tablet physical properties data are presented in Table I. It can be seen from the table that after five minutes of coating, ASA tablets coated with CA latex without PVP are exhibiting a 0.41% weight gain as compared to the 0.38% weight gain for the ASA tablets coated with CA latex with PVP. No detectable film could be measured at five minutes for coated ASA tablets without PVP, whereas a film (thickness) of 0.01 mm was measured for ASA tab¬ lets coated with CA latex with PVP. When the coated tablets were tasted after only five minutes coating, the masking_^of the acid taste of aspirin was clearly better for the ASA ta-blets without PVP in the film relative to -7-

the ASA tablets with PVP in the film.

Julian et al. in U.S. Patent No. 4,851,226 state that PVP, a water-soluble polymer, is required to pro¬ vide release of the drug acetaminophen from granules/- tablets coated with cellulose acetate applied from a solvent system. Dissolution analysis was performed on the coated tablets of this invention to determine if PVP was required to facilitate release of aspirin from tab¬ lets coated with cellulose acetate applied from an aque- ous latex dispersion. The dissolution testing was per¬ formed using USP Apparatus 1 (Basket) .at 50 rpm with 500 ml of 0.05M acetate buffer, pH 4.5. The samples we_e analyzed on a Beckman DU-7 UV/Vis spectrophotomete . The dissolution analysis results are presented in Table II and Figures 1 and 2.

Turning to the drawing, it can be seen from Figure 1 that the dissolution profile of ASA tablets coated with ultra-thin CA latex are essentially identical to the control ASA cores and that ASA release as depicted in Figure 2 was faster than for tablets coated with the CA latex/PVP blends of U.S. Patent 4,851,226 to Julian et al. Moreover, it was found that ASA tablets coated with CA latex without PVP exhibited superior taste-mask¬ ing compared to tablets coated with CA latex/PVP blend at approximately identical coating levels.

Clearly, there is no advantage in using PVP to pro¬ vide water solubility as claimed by Julian et al. since:

1. More effective taste-masking is realized at lower coating levels using CA latex without PVP relative to CA latex with PVP.

2. Dissolution analysis (ASA release) was more rapid for aspirin tablets coated solely with CA latex than with the CA latex/PVP blend.

TABLE I

TABLET PROPERTIES:

Uncoated ASA Cores

Physical Properties Weight Variation (N=400) Thickness (mm, N=10) 4.27 Average wt. (mg) -368.0 Dis. Time (sec, USP XXII St. Dev. (m ) - 4.1 for uncoated tabs) 50 Coeff. of Wt. Var. (%) - 1.12

Maximum wt. (mg) -378

Minimum wt. (mg) -357

Coated ASA Tablets (post drying, 35°C/30 min) Batch #1 (ASA 325 mg tablets coated with coating solution #1: CA latex) I

C I

10 15

Physical Properties Init. min min Thickness (mm, N=3) 4.27 4.30 4.29 Dis. Time (sec, N=3, USP XXII for uncoated tabs) -25 48 63

Weight Variation (N=25) Init.

Average wt. (mg)

St. Dev. (mg)

Coeff. of Wt. Var. (%)

Maximum wt. (mg)

Minimum wt. ( g)

TABLE I - Continued

TABLET PROPERTIES: Batch #2 (ASA 325 g tablets coated with coating solution #2: CA latex with PVP)

5

Physical Properties Init. min

Thickness (mm, N=3) - 4.27 4.29 Dis. Time (sec, N=3, USP XXII for uncoated tabs) - 25 33 25 38

Weight Variation (N=25) Init.

Average wt. (mg) - 367.6

St. Dev. (mg) 3.3 I

Coeff. of Wt. Var. (%) 0.89 I

Maximum wt. (mg) - 375

Minimum wt. (mg) - 360

-10-

TABLE II Dissolution Profile of Coated Aspirin Tablets Taste Masking Study

Mean % Aspirin in Solution + S.D.

Cellulose Acetate Latex Coating (Batch 1

Claims

-11-CLAIMS :

1. A taste-masked, solid medicament in which the taste-masking agent is a cellulose ester film enveloping the medicament, and of sufficient thickness to act as a taste-masking barrier without interfering with the re¬ lease of active ingredients from the medicament, the said film characterized by the dried residue of an aque¬ ous plasticized cellulose ester and constituting no more than 1.0 weight percent of the film coated medicament.

2. The medicament of claim 1 characterized in that the film envelopment constitutes no more than 0.3 weight percent of the medicament.

3. The medicament of claim 1 characterized in that the plasticizer is present in the fxlm in an amount of 33% weight percent to 60%.

4. The medicament of claim 1 characterized in that the plasticizer is triacetin.

5. A taste-masked disagreeable solid medicament enveloped in a cellulose acetate film characterized by the dried coating of an aqueous cellulose acetate dis¬ persion, ^'the said film containing by weight from 33% to 60% of triacetin plasticizer.

6. The composition of claim 5 characterized in that the amount of plasticizer is by weight 50%.

7. The composition of claim 5 characterized in that the disagreeable tasting medicament is selected from the class consisting of aspirin, acetaminophen and ibuprofen.

8. The composition of claim 7 characterized in that the medicament is in the form of granules, tablets or compressed coated granules.