AU651721B2 - Taste-masked medicaments and their preparation - Google Patents

Description

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PCT

ANNOUNCEMENT OF THE LATER PUBUCATION OF INTERNATIONAL SEARCH REPORT INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT) (51) International Patent Classification 5 (11) International Publication Number: WO 92/19209 A3 A61K 9/36 A (43) International Publication Date: 12 November 1992 (12.11.92) (21) International Application Number: PCT/US92/02692 (81) Designated States: AT (European patent), AU, BE (European patent), CA, CH (European patent), DE (Euro- (22) International Filing Date: 3 April 1992 (03.04.92) pean patent), DK (European patent), ES (European patent), FR (European patent), GB (European patent), GR (European patent), IT (European patent), JP, LU (Euro- Priority data: pean patent), MC (European patent), NL (European pa- 693,732 30 April 1991 (30.04.91) US tent), NO, SE (European patent).

(71) Applicant: FMC CORPORATION [US/US]; 1735 Market Street, Philadelphia, PA 19103 Published With international search report.

(72) Inventors: WHEATLEY, Thomas, A. 70 Beth Drive, Richboro, PA 18954 ERKOBONI, David, Frank 731 President Avenue, Lawrenceville, NJ 08648 (US).

(74) Agent: FELLOWS, Charles, FMC Corporation, 1735 (88) Date of publication of the international search report: Market Street, Philadelphia, PA 19103 7 January 1993 (07.01.93) 17 21 (54)Title: TASTE-MASKED MEDICAMENTS AND THEIR PREPARATION (57) Abstract A taste-masked solid medicament such as an aspirin tablet or the like in which the taste-masking means is a thin cellulose ester film formed of the dried coating of an aqueous plasticized cellulose ester dispersion, The film constitutes no more than about 1 part percent of the film coated medicament.

Ir- j WO 92/19209 PCT/US92/02692 -1- TASTE-MASKED MEDICAMENTS AND THEIR PREPARATION This invention relates to taste-masking of solid medicaments, particularly by enveloping them in a tastemasking polymer film coating.

Therapeutic formulations designed for oral administration 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 appra=,'h is to include a flavoring agent in the formulati-. to overpower the taste of the offending component. Both solid and liquid medicaments can be tastemasked 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 swallowing of the medicament. More recently, the pharmaceutical industry has focused its attention on coatings produced 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 medicament 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 medication. 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 ,1 i WO 92/19209 PCT/US92/02692 -2release 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 dissclution rate of APAP in simulated gastric fluid at a coating level of 17.5% by weight and which the percent of .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 solvents tend to be toxic and/or flammable thereby posing a hazard to personnel and operators. Also, organic solvents are pollutants, necessitating the installation of expensive and complex solvent recovery systems to meet environmental regulations. Furthermore, traces of residual 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% WO 92/19209 PCT/US92/02692 -3have 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 CA Latex, 5 Min.

CA Latex, 10 Min.

Figure 2 is a graph of percent dissolution versus time for ASA tablets coated with the ultra-thin cellulose ester films of the invention, for ASA tablets similarly coated with the cellulose ester/PVP blend of U. S.

Patent No. 4,851,226 to Julian et al., and for the.uncoated core control.

In Figure 2 the symbols have the following meaning: 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 chemical entity. Commonly referred to as a cellulose ester latex, it is prepared by dissolving the polymer in a suitable organic solvent, dispersing the resulting solution in an aqueous phase, homogenizing, and evaporating the solvent. To the resulting latex is added an appropriate plasticizer.

Cellulose ester latex systems have previously been RiTTI TF S H 1 ET WO 92/19209 PCT/US92/02692 -3a-

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jt 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 delivery membranes, see Bindschaedler et al. Proceed.

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

Illustrative of the cellulose ester latexes suitable for producing the ultra-thin coatings of the invention are latexes made from cellulose acetate, cellulose acetate butyrate and cellulose acetate phthalate.

SUBSTITUTE SHEET WO 92/19209 PCT/US92/02692 -4- Cellulose ester polymers are manufactured and sold com- Smercially by a number of suppliers of industrial chemicals, for example, the Eastman Kodak Company, Kingsport, Ii Tenn.

Examples of suitable plasticizers for cellulose i aqueous dispersions include triacetin, diacetin and triethylcitrate.

As understood herein, medicament can be, for example, granules, tablets including tablets of the com- 10 pressed coated granules of drugs such as aspirin (ASA), acetaminophen, and ibuprofen.

The ultra-thin, taste-masking films of the invention are conveniently produced by coating the solid medicament substrate with an aqueous cellulose acetate dispersion in which the preferred plasticizer is triacetin. 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 cellulose 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 coating formulation plus plasticizer is in the neighborhood of from about by weight 10% to about 30%, preferably to 20%. In the final dried coating, the amount of plasticizer present in the film coating ranges by weight from about 30% to about As previously pointed out, effective taste-masking of standard pharmaceutical tablets such as an aspirin I j WO 92/19209 PCT/US92/02692 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 tastemasking.

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 Formula #1 Incredients Cellulose acetate latex (29.0%'solids)** Triacetin Water Formula #2 Ingredients Cellulose acetate latex (29.0% solids) Triacetin Polyvinylpyrrolidone Water Wet* 25.86 7.50 66.64 100.00 in Dry Film 50.0 50.0 100.0 Wet* in Dry Film 21.98 6.38 2.25 69.39 100.00 42.5 42.5 15.0 100.0 15 solids concentration in coating CA398-10, FMC Corporation ***KolidonR 30, BASF formulation WO 92/19209 1

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PCrI US92/02692 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 0

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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 CA latex) Actual Inlet Temp. (OC) 63 67 Exhaust Temp. (OC) 37 43 Bed Temp. (OC) 34 42 Batch #2 (ASA 325 mg coated with coating solution CA latex with PVP Actual Inlet Temp. (OC) 62 66 Exhaust Temp. (OC) 38 41 Bed Temp. (oC) 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 tablets 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 tablets without PVP in the film relative to WO 92/19209 PCT/US92/02692 -7the 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 provide release of the drug acetaminophen from granules/tablets coated with cellulose acetate applied from a I 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 tablets coated with cellulose acetate applied from an aqueous latex dispersion. The dissolution testing was performed using USP Apparatus 1 (Basket) .at 50 rpm with S00 ml of 0.05M acetate buffer, pH 4.5. The samples were analyzed on a Beckman DU-7 UV/Vis spectrophotometer.

i' 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 Set al. Moreover, it was found that ASA tablets coated with CA latex without PVP exhibited superior taste-masking compared to tablets coated with CA latex/PVP blend at approximately identical coating levels.

Clearly, there is no advantage in using PVP to provide 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 Thickness (mm, N=10) Dis. Time (sec, USP XXII for uncoated tabs) Weight Variation (N=4 00) 5 4.27 Average wt. (mg) St. Dev. (mq) 0O Coeff. of Wt. Var.() Maximum wt. (rig) Minimum wt. (mg) -368.0 4.1 1.12 -378 -357 Coated ASA Tablets (Dost drvinr. 35 0 C/30 min) Batch 41 (ASA 325 mg tablets coatr-±d with coating solution CA latex) Physical Properties Thickness (mm, N1=3) Dis. Time (sec, N1=3, USP XXII for uncoated tabs) Init.

4. 27 min 4.25 -25 mhin 4.30 48 min 369.9 4.0 1.07 378 361 min 4.29 Weight Variation (N1=25) Average wt. (mg) St. Dev. (mg) Coeff. of Wt. Var.() Maximum wt. (mg) Minimum wt. (mg) Init.

36-i'.6 3.3 0.89 375 360 mhin 369.1 2.6 0.71 375 364 Tin 371.2 3.4 0.92 375 363 0 TABLET- Continued TABLET PROPERTIES: Batch #2 (ASA 325 mg tablets coated with coating solution CA latex with PVP) Physical Properties Thickness (mm, N=3) Dis. Time (sec, N=3, USP XXII for uncoated tabs) Weight Variation (N=25) Average wt. (mg-) St. Dev. (mg) Coeff. of Wt. Var.() Maximum wt. (mg) Minimum wt. (mg) Init.

4.27 Min 4.29 25 Init.

367.6 3.3 0.89 375 360 min 369.0 4.4 1.19 378 361 min 4.27 25 10 min 368.6 3.6 0.99 378 364 min 4.28 38 m in 370.3 4.3 1.15 378 363 WO 92/19209 WO 9219209PCr/US92/02692 TABLE II Dissolution Profile of Coated Aspirin Tablets Taste Masking Study Mean Aspirin in Solution S.D.

Cellulose Acetate Latex Coatina (Batch :lj.

Ai Time (min) 15 cores (n=18) 21 5.2 46 9.5 66 10.7 94 5.7 Cellulose Acetate min CA Latex (n31 22 6.4 42 12.5 61 14.2 91 12.1 10 min CA Latex _Ln 39 11.0 62 15.6 78 14.2 96 Latex With PVP LBatch 2) Time (mhin) Cores (n=18) 21 5.2 46 9.5 66 10.7 94 5.7 Latex W/ PVP (n=3) 13 0.6 27 3 .2 47 9.0 74 10.5 CA Latex W/ PVP (n=3) 30 8.1 55 6.1 77 4.7 100 1.2

Claims (8)

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 release of active ingredients from the medicament, the said film characterized by the dried residue of an aqueous plasticized dispersion of a cellulose ester and 0'3 constituting D-5-1.0 weight percent of the film coated medicament, said plasticizer being present in an amount of 30-60 weight percent of said film coating.

2. The medicament of claim 1 characterized in that the film envelopment constitutes 0.3 weight percent of the medicament.

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

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

A taste-masked disagreeable solid medicament enveloped in a cellulose acetate film characterized by the dried coating of an aqueous cellulose acetate dispersion, the said film containing by weight from 33% to 60% of triacetin plasticizer and consttuting 0.3-1.0 weight percent of the film coated medicament.

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

7, The composition of claim 5 characterized in that the disagreeable tasting medicament is selected from the class consisting of aspirin, acetaminophen and ibuprofen, c! )TPIP-~ i'- -11a-

8. The composition of claim 7 characterized in that the medicament is in the form of granules, tablets or compressed coated granules. js ;i [I i r r