Programmed release ambroxol—HCl dosage forms

Details Programmed release ambroxol—HCl dosage forms Programmed release ambroxol—HCl dosage forms

1995-01-30

2001-06-26

Harrison, Robert H. (Department: 1619)

Drug, bio-affecting and body treating compositions

Preparations characterized by special physical form

Capsules

C424S461000, C424S462000, C424S490000, C424S494000, C424S495000, C424S497000

Reexamination Certificate

active

06251429

ABSTRACT:

BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention relates to unique programmed-release pharmaceutical dosage forms comprising ambroxol hydrochloride.
2. Description of the Prior Art
Ambroxol, 4-[[(2-amino-3,5-dibromophenyl)methyl]amino]cyclohexanol or N-(trans-p-hydroxycylohexyl)-(2-amino-3,5-dibromobenzyl)amine, is a known compound (compare, for example, U.S. Pat. No. 3,536,713). Ambroxol hydrochloride too is known to this art, as is the pharmaceutical activity thereof. Ambroxol·HCl, for example, is a safe and effective expectorant. Nonetheless, it possesses a relatively short biological half-life and, therefore, it typically must be administered at least three times a day in order to elicit its full activity.
Thus, need continues to exist in this art for an improved dosage form of ambroxol·HCl that will permit a decrease in the number of administrations, to not only reduce the burden on the patient but also to increase his compliance, thus providing greater therapeutic benefits.
SUMMARY OF THE INVENTION
Accordingly, a major object of the present invention is the provision of improved programmed-release ambroxol·HCl dosage forms that slowly release its active ingredient, such that it will maintain therapeutically effective levels of the active drug in the bloodstream for a prolonged period of time.
Briefly, the present invention features a pharmaceutically acceptable dosage form of ambroxol hydrochloride that will slowly and programmedly release almost the totality of its content of active ambroxol·HCl over a time period of about 16 hours, in order to prolong the plasma levels thereof for almost 24 hours.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS OF THE INVENTION
More particularly according to the present invention, it will be appreciated that certain techniques have heretofore been proposed to this art for preparing slow-release pharmaceutical compositions containing ambroxol hydrochloride which are capable of retaining the concentrations of active ingredient in the blood for a somewhat prolonged period of time. Such dosage forms, however, suffer from the disadvantages that neither the minimum quantity of ambroxol hydrochloride is released therefrom “in vitro” after fixed intervals (programmed-release profile with indication of the minimum amount to be released at fixed intervals), nor are they immune to the influence and possible variations of the preparation during the aging or storage thereof (stability of the programmed-release rate of the preparation over time).
The unique dosage forms of this invention are conspicuously devoid of the above disadvantages and drawbacks and are produced via a seriatim procedure that first comprises the preparation of inert microgranules, preferably starch and sugar microgranules. Selection of the microgranules is next carried out by sieving them through a sieve opening ranging from 0.3 mm to 1.2 mm. The ambroxol hydrochloride, characteristically in admixture with talc or with other supports, for example aluminum or magnesium silicates or lactose, is then micronized until a mixture having particle sizes ranging from 1 to 150 microns is obtained. Application onto the inert microgranules of multiple, alternate microlayers of this powder mixture and of the delayed-release film-forming agent, which is advantageously a polyvinylpyrrolidone, polyvinylpyrrolidone/shellac mixture or shellac itself, is accomplished by spraying or atomizing, via a seriatim procedure, suitable aliquots of the suspensions or solutions thereof and then consolidating each microlayer to dryness, with air or without air.
The solvents for the film-formers are advantageously aqueous or mixtures of alcohol or of acetone.
The concentration of ambroxol hydrochloride in the microgranules according to the invention advantageously ranges from 100 to 500 mg per gram. The ambroxol hydrochloride is thus incorporated as microlayers on the granules, and same are coated with a delayed-release film-coating material, notably shellac, an acrylic resin (e.g., that marketed under the trademark Eudragit by Röhm Pharma, Germany) hydroxypropyl methylcellulose, ethylcellulose or derivatives thereof, or mixtures of the above materials dissolved in organic solvents, e.g., alcohol, acetone or others, or in aqueous mixtures with organic solvents;
talc is also added during this final operation.
Thus produced is a programmed-release ambroxol·HCl pharmaceutical dosage form, comprising a plurality of inert core microgranules of a variety of particle sizes ranging from 0.3 to 1.2 mm, such inert core microgranules being coated with alternating microlayers of (1) micronized ambroxol hydrochloride active agent and (2) delayed-release film material, such coated microgranules including an external microlayer of delayed-release film material, and such coated microgranules having particle sizes ranging from 0.6 to 1.5 mm.
The manufactured batches are subjected to a dissolution test to determine the release rate profile by means of the apparatus recommended by U.S.P. XXII, Model I at 100 revolutions per minute, using 900 ml of water as the immersion liquid. They are formulated to strictly satisfy the following release rate limits, also characterizing the present invention:
01st hour
20%-40%
08th hour
55%-75%
16th hour
>75%
The programmed-release microgranules of ambroxol hydrochloride may then be easily administered in the recommended doses, as they are more conveniently packaged in unitary daily dosage amounts in primary dosage forms composed of hard gelatin capsules.
In order to further illustrate the present invention and the advantages thereof, the following specific examples are given, it being understood that same are intended only as illustrative and in nowise limitative.
EXAMPLE 1
Inert microgranules of sugar and starch were prepared from 500 g of sugar and from 500 g of an aqueous solution of sugar and starch (1:1) and the film-coating thereof was demonstrated (two experiments).
400 g of an aqueous solution of sugar and starch were injected into a rotating pan containing 500 g of sugar and inert microgranules almost spherical in shape were produced. These inert microgranules were dried for 24 hours at 50° C. and sieved to a size of from 0.3 to 1.2 mm.
500 g of the neutral microgranules thus produced were added to 190 g of a micronized mixture of ambroxol hydrochloride and starch (98:2) having a particle size of about 10 microns, and incorporated into the mixture using a 20% solution of shellac (80%) and polyvinylpyrrolidone (20%) in isopropanol by means of an airless spraying (atomizing) system (about 100 g of solution).
During this step, the following parameters were maintained under constant control:
(a) The size of the particles at values ranging from 1 to 150 microns by conducing two tests therefor during the process;
(b) The amount of micronized ambroxol hydrochloride to be incorporated was controlled at from 100 to 500 mg/g of final product;
(c) The amounts and the proportions of the shellac and polyvinylpyrrolidone were varied, as required;
(d) For a better modulation of the programmed-release profile, another delayed-release film-forming agent could be added to the shellac, or substituted therefor.
EXAMPLE 2
Release Rates:
The products of the two experiments of Example 1 were tested according to the U.S.P. XXII system, Model I at 100 revolutions per minute, using 900 ml of water as the immersion liquid, and the following results reported in Table I were obtained:
TABLE I
Specifications
Release profile obtained
Product of Experiment 1
of Example 1
1st hour
20-40%
29%
8th hour
55-75%
72%
16th hour
>75%
89%
Product of Experiment 2
of Example 1
1st hour
20-40%
28%
8th hour
55-75%
72%
16th hour
>75%
91%
EXAMPLE 3
Stability tests were conducted to confirm the liberation or release profile and other basic parameters of the programmed-release microgranules of the two experiments of Example 1.
Five samples of 5 grams each of the two products from the experiments of Example 1 were sealed in amber glass bottles with plastic screw-caps and wer

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