JP2538491B2 - Taste-masked drugs and their manufacturing method - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to taste masking, in particular by encapsulating a solid dosage form in a taste masking polymer film coating.

BACKGROUND OF THE INVENTION Therapeutic formulations designed for oral administration often contain active ingredients which have an unpleasant taste. For example, many medicines
Causes a bitter or sour sensation when placed in the mouth.

Various techniques are known for counteracting the unpleasant taste of pharmaceutical products. Probably the oldest solution is to include a seasoning in the formulation to defeat the taste of the offending ingredient. Both solid and liquid drugs can mask their taste in this way.

In the case of solid formulations, taste masking is usually done by coating the drug with a taste blocking layer. This is as easy a method as a coating of sugar that dissolves to give a pleasing taste between ingestion and swallowing. More recently, the pharmaceutical industry has focused its attention on coatings resulting from film-forming polymers, and considerable efforts have been made to continue pursuing this solution for taste masking solid dosage forms. There is.

A new development in polymeric taste-masking films is disclosed in Julian et al., US Pat. No. 4,851,226. These films are formed from a blend of a cellulose ester and polyvinylpyrrolidone (PVP) applied to a drug such as acetyl-p-aminophenol (acetaminophen or APAP) from an organic solvent solution of the polymer. The purpose of PVP, which is water soluble, is to soften the hydrophobicity of the cellulose ester and thereby control the drug release rate of the formulation. According to this patent, the film coating can be devised such that the drug is released in a relatively fast or sustained manner. When rapid release is desired, the percentage of PVP in the film coating is
It is about 12-20% by weight. However, it has been found that the cellulose ester coating, if used alone, does not provide adequate bioavailability of the active ingredient at a particular coating level of 5-20% by weight. This is quite clear from Figure 1 of the patent,
It shows in graph form the dissolution rate of APAP in gastric fluid simulated at a coating level of 17.5% by weight,
The% PVP in the coating blend varied from 0-25% by weight. As you can see, PVP during film coating
At 0%, the drug release reached only 40% after 40 minutes.

The main problem with the coatings of the Julian et al. Patent is that they are applied from organic solvent solutions of film-forming resins. These solvents are toxic and / or flammable and prone, which is harmful to personnel and operators. In addition, organic solvents are pollutants and require installation of an expensive and complicated solvent recovery system in order to meet environmental regulations. Moreover, traces of residual solvent remain in the treated drug and pose a health hazard to its use.

DISCLOSURE OF THE INVENTION According to the present invention, solid dosage forms can be effectively taste masked by a film wrap consisting mainly of a cellulose ester applied from a latex dispersion of the ester while maintaining a rapid release of the active ingredient. Providing these taste-masked formulations constitutes a major advantage and purpose of the present invention. Other advantages and objectives will be apparent from the description below.

The above advantages and objectives are realized by using an ultra-thin coating formed from the dried residue of an aqueous plasticized dispersion of cellulose ester as a source of cellulose ester film wrap. . Surprisingly, taste masking of the asbilin tablets at coating levels well below about 0.4% was achieved, also showing a dissolution profile similar to the uncoated control.

FIG. 1 is a graph of% Dissolution vs. Time for a control of asubilin tablets (acetylsalicylic acid-ASA) coated with an ultrathin cellulose ester film made in accordance with the present invention and an uncoated core.

In FIG. 1, the symbols have the following meanings. +: Uncoated core, ◇ is CA latex, 5 minutes, * is
CA latex, 10 minutes.

FIG. 2 is a graph of% Dissolution vs. Time for ASA tablets similarly coated with the cellulose ester / PVP blend of Julian et al., US Pat. No. 4,851,226, and an uncoated core control.

In FIG. 2, the symbols have the following meanings. ＋ is uncoated core, ◇ is CA / PCP latex,
5 minutes, * is CA / PVP latex, 10 minutes.

The aqueous plasticized cellulose ester dispersions used in the practice of this invention are well known chemicals. What is commonly called cellulose ester latex is
It is prepared by dissolving the polymer in a suitable organic solvent, dispersing the resulting solution in the aqueous phase, homogenizing and evaporating the solution. In the obtained latex,
Add the appropriate plasticizer.

Cellulose ester latex systems have been previously studied as film coating materials for sustained release formulation products. However, to the best of our knowledge, it is not recognized or recognized by the pharmaceutical industry that cellulose ester latex dispersions have application in taste masking using the ultra-thin coating techniques described herein. That is not done.

For a brief description of cellulose ester latex and its use in forming controlled drug delivery membranes, Bindschaedler et al., Proceed.Intern.Symp.Contr.
See ol. Rel. Bioact. Mater 12 (1985).

An example of a cellulose ester latex suitable for producing the ultra-thin coatings of the present invention is cellulose acetate,
It is a latex made from cellulose acetate butyrate and cellulose acetate phthalate. Cellulose ester polymers are commercially available from numerous suppliers of industrial chemicals such as Eastman Kodak
Industrially manufactured and sold by Company, Kingsport, Tenn.

Examples of suitable plasticizers for cellulosic aqueous dispersions are:
Includes triacetin, diacetin and triethyl citrate.

As understood herein, the formulation can be, for example, granules, tablets, including tablets of pressure-coated granules of the drug, eg, asbilin (ASA), acetaminophen and ibuprofen.

The ultra-thin taste-masking film of the present invention is conveniently prepared by coating a solid drug base with an aqueous cellulose acetate dispersion in which the preferred plasticizer is triacetin. Triacetin is added to the dispersion and the mixture is mixed well. Generally, the amount of plasticizer is from about 50 to about 150 by weight of the solids content of the dispersion.
%, Preferably about 80-120%, optimally about 100%.
A cellulose acetate aqueous dispersion having a solids content of about 28-32% by weight is known as FMC Co in the name of CA398-10 latex dispersion.
Available from rporation.

The ultrathin taste-masking cellulose film of the present invention is
It is applied to solid formulations in a known manner and by standard pharmaceutical coating equipment. Coating is usually done by spraying into a pan or fluid bed.

The solids content of the aqueous cellulose ester coating formulation plus the plasticizer is about 10 to about 30% by weight, preferably 15-20% by weight. In the final dry coating, the amount of plasticizer present in the film coating is about
30 to about 60% by weight.

As already pointed out, effective taste-masking of standard pharmaceutical tablets such as aspirin can be achieved with the ultrathin cellulose ester film coating of the present invention at a coating level of about 0.4% by weight based on the weight of the total solid dosage form. Other types of solid dosage forms, such as granules, require somewhat higher coating levels. As far as has been determined so far, the overall coating level will range from about 0.3 to about 1.0% by weight for effective taste masking.

The amount of coating applied to the base can be controlled in a well known manner such as the solids content of the coating dispersion and the contact time.

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

Coating Conditions Constant Conditions: The following conditions were kept constant for both batches.

Coating equipment AccelaCota 24 inch (61cm) pan Batch size 10kg ASA core Inlet temperature setting 170-175 ° F (77-80 ° C) Pump type Peristaltic nozzle size 1.0mm Spraying speed 25psi (1.75kg / cm ² ) Batch 1 (Coating solution component 1 : ASA 325mg coated with CA latex) Actual inlet temperature (℃) 63-67 Discharge temperature (℃) 37-43 Bed temperature (℃) 35-42 Batch 2 (Coating solution component 2: Coated with CA latex having PVP) ASA 325 mg) Actual inlet temperature (° C) 62-66 Discharge temperature (° C) 38-41 Bed temperature (° C) 36-42 Uncoated aspirin (ASA) core and physical properties of coated ASA tablets The data are shown in Table I. After 5 minutes of coating, the ASA tablets coated with CA latex without PVP show a weight gain of 0.41% compared to a 0.38% weight gain for ASA tablets coated with CA latex with PVP. (This weight increase is Calculated from ) No detectable film could be measured for coated ASA tablets without PVP at 5 minutes, but 0.01 mm film (thickness) was measured for coated ASA tablets with PVP. When the coated tablets tasted after only 5 minutes of coating, the acid taste masking of aspirin was clearly better for ASA tablets without PVP in the film compared to ASA tablets with PVP in the film. Met.

Julian et al., In US Pat. No. 4,851,226, a water soluble polymer, PVP, is required to effect release of the drug acetaminophen from granules / tablets coated with cellulose acetate applied from a solvent system. It says that. Dissolution analysis was performed on the coated tablets of the invention to determine if PVP was required to help release aspirin from the tablets coated with cellulose acetate applied from an aqueous latex dispersion. It was Dissolution test, 500 ml 0.05M
Acetate buffer, pH 4.5 at 50 rpm at USP Appratus (Bas
ket). Sample Beckman DU-
Analyzed on a 7 UV / Vis spectrophotometer. The results of the dissolution analysis are
Shown in Table II and Figures 1 and 2.

For the figure, the dissolution profile of ASA tablets coated with ultra-thin CA latex is the control ASA.
The ASA release, which was essentially the same as the core, and as depicted in Figure 2, was faster than for the tablets coated with the CA latex / PVP blend of US Pat. No. 4,851,226 to Julian et al. Moreover, it was found that ASA tablets coated with CA latex without PVP showed superior taste masking compared to tablets coated with CA latex / PVP blend at about the same coating level.

Clearly there is no benefit to using PVP to provide water solubility, as described by Julian et al. It is for the following reasons.

1. More effective taste masking, using CA latex without PVP, compared to CA latex with PVP,
Achieved at low coating levels.

2. Dissolution analysis (ASA release) was faster for CA latex only coated aspirin tablets than with CA latex / PVP blends.

Claims (7)

(57) [Claims] 1. A taste-masked substance, wherein the taste-masking substance is a cellulose ester film wrapping the formulation in a thickness sufficient to act as a taste-masking barrier without interfering with the release of the active ingredient from the formulation. In the solid dosage form, the film is a dry residue of an aqueous plasticized cellulose ester and constitutes 0.3 to 1.0% by weight of the film-coated dosage form. 2. A formulation according to claim 1, wherein the plasticizer is present in the film in an amount of 33-60% by weight. 3. The preparation according to claim 1, wherein the plasticizer is triacetin. 4. A solid formulation with a taste-masked, unpleasant taste, encapsulated in a cellulose acetate film, which comprises a dry coating of an aqueous cellulose acetate dispersion, the film comprising 33-60% by weight of triacetin. The solid preparation according to claim 1, comprising a plasticizer. 5. The preparation according to claim 4, wherein the amount of the plasticizer is 50% by weight. 6. The preparation according to claim 4, wherein the drug having an unpleasant taste is selected from the group consisting of aspirin, acetaminophen and ibuprofen. 7. A formulation according to claim 6, which is in the form of granules, tablets or compression coated granules.