Synthetic resins or natural rubbers -- part of the class 520 ser – Synthetic resins – Mixing of two or more solid polymers; mixing of solid...
Reexamination Certificate
2001-03-23
2003-06-17
Seidleck, James J. (Department: 1711)
Synthetic resins or natural rubbers -- part of the class 520 ser
Synthetic resins
Mixing of two or more solid polymers; mixing of solid...
C525S071000, C525S531000, C525S438000, C525S496000, C525S407000, C525S408000, C525S409000, C525S418000
Reexamination Certificate
active
06579953
ABSTRACT:
The invention relates to the use of water-soluble or water-dispersible polyether-containing polymers as coating agent, binder and/or film-forming excipient in pharmaceutical presentations.
Solid pharmaceutical presentations such as tablets, capsules, pellets, granules, crystals etc. are provided with a film coating for a wide variety of reasons. It is possible in this way, for example, to mask an unpleasant odor or taste, and improve the swallowability. The stability of the active ingredient can be increased by the coating, since less water vapor and oxygen reaches the interior of the tablets. The presentations have a better appearance and can be distinguished better by incorporating dyes. In addition, in particular the rate of release of the active ingredient can be adjusted by the film coating.
A distinction is made in general between instant release forms and slow release forms.
In the case of instant release forms, the disintegration of the tablet and the release of the active ingredient from the presentation should, where possible, be unaffected by the coating, for which reason the film coating must dissolve rapidly in gastric fluid. In addition, it must have good film properties. The tensile strength and the ultimate elongation should be high so that the film coating withstands mechanical effects like those occurring during pharmaceutical processing—especially packaging—and during transport and storage.
A product which is frequently employed for coating instant release tablets is hydroxypropylmethylcellulose (HPMC). Hydroxypropylmethylcellulose shows a steep rise in viscosity with increasing concentration in aqueous solution. Hydroxypropylcellulose (HPC) also shows a similar behavior.
Since the film former solution must be finely atomized for coating tablets, and the drops which are formed must thoroughly wet the surface of the tablets, and moreover spread well, the viscosity must not exceed a certain limit (between 150 and 250 mPas) which depends on the type of spray nozzle and the equipment. It is therefore possible in the case of HPMC to employ only relatively low film former concentrations.
The recommendation given in the literature for the concentration of Pharmacoat® 606 (from Shin-etsu) is 5 to 7% by weight (Pharmaceutical Coating Technology, edited by Graham Cole, Taylor and Francis Ltd. 1995 and manufacturers' technical data sheet). These low spray concentrations result in relatively long processing times and thus high costs.
In addition, hydroxypropylmethylcellulose has other disadvantages, inter alia in the wetting characteristics, in the adhesiveness on the tablet surface, in the pigment binding capacity, in the mechanical properties of the films, in the hygroscopicity and in the permeability for water vapor and oxygen, in the rate of dissolution and in the difference in disintegration time between film-coated tablets and core.
The low elasticity of hydroxypropylmethylcellulose films frequently leads to the film-coated tablets splitting open on storage in moist conditions, as a consequence of the swelling of the core. Even the use of plasticizers results in negligible improvements in this problem. On the contrary, it might lead to tacky films and, through migration, to changes in the tablet properties.
Oral drug forms which release the medicinal substance over a lengthy period with the aim of prolonging the effect of the active component (generally slow release drug forms) are becoming increasingly important. They are associated with the advantages of improved patient compliance through a reduced frequency of intake, a reduction in side effects through avoidance of plasma peaks, more uniform blood levels of the medicinal substance, and the avoidance of local irritation. Besides the formulation of medicinal substance-containing cores which are coated with a film which is insoluble in water but is semipermeable or contains pores through which the medicinal substance diffuses, release can be controlled and prolonged by embedding the medicinal substance in matrices. It is possible in addition to use ion exchange resins and therapeutic systems (e.g. OROS).
Embedding of the medicinal substance in hydrocolloid matrices in particular provides the advantages of simple and low-cost manufacture and a high degree of drug safety because no dose dumping effects can occur. The excipients normally employed for this purpose such as hydroxypropylmethylcellulose (HPMC), hydroxypropylcellulose, alginic acid or alginates, and xanthan have disadvantages on use. Those which may be mentioned are: deficient flow properties which makes direct tableting difficult, a dependence of the release of medicinal substance on the osmolarity (salt content) and on the pH of the release medium. This applies equally to HPMC and to hydroxypropylcellulose, xanthan and alginates. The use of xanthan moreover results in tablets whose hardness is low, and the direct tableting of alginates results in compacts with only slight release-slowing properties (max. 8 h). The natural swelling substances (e.g. alginates) show overall a wide variability between batches.
It has been found, surprisingly, that the polymers described hereinafter do not have these disadvantages and are advantageous for use as matrix for release of the active ingredient in oral pharmaceutical preparations.
Binders are employed in pharmaceutical presentations in order to increase the processability and the mechanical strength. They are normally employed in tablets, granules and pellets and result in improved flowability, greater hardness and less friability.
The binders used at present such as maltodextrin or polyvinylpyrrolidones frequently do not result in satisfactory hardnesses and friabilities. Other binders such as starch paste and hydroxypropylmethylcellulose (HPMC) can be employed only in low concentrations because of their high viscosity.
In addition, film-forming excipients are employed in solutions and sprays which are applied to the skin or mucous membrane or else introduced systemically into the body. Examples thereof are preparations for wound treatment and spray-on dressings, but also preparations for application to intact skin or mucous membrane. In this case, the skin is protected by a film, and the active ingredients can penetrate into or through the skin.
Great flexibility is necessary for transdermal therapeutic systems and for wound plasters, just as for the abovementioned presentations, but the products available at present do not have this. The use of possible plasticizers to achieve the necessary flexibility is undesirable for toxicological and pharmacological reasons.
It is an object of the present invention to provide water-soluble or water-dispersible polymers as coating agents, binders and/or film-forming excipients in pharmaceutical presentations which do not have the abovementioned disadvantages.
We have found that this object is achieved by the use of polymers, in particular polymers which are soluble or dispersible in water and are obtainable by polymerization of
a) at least one vinyl ester of aliphatic C
1
-C
24
-carboxylic acids, in the presence of
b) polyethers of the general formula I,
in which the variables have, independently of one another, the following meanings:
R
1
hydrogen, C
1
-C
24
-alkyl, R
9
—C(═O)—, R
9
—NH—C(═O)—, polyalcohol residue;
R
8
hydrogen, C
1
-C
24
-alkyl, R
9
—C(═O)—, R
9
—NH—C(═O)—;
R
2
to R
7
—(CH
2
)
2
—, —(CH
2
)
3
—, —(CH
2
)
4
—, —CH
2
—CH(CH
3
)—, —CH
2
—CH(CH
2
—CH
3
)—, —CH
2
—CHOR
10
—CH
2
—;
R
9
C
1
-C
24
-alkyl;
R
10
hydrogen, C
1
-C
24
-alkyl, R
9
—C(═O)—;
A —C(═O)—O—, —C(═O)—B—C(═O)—O—, —C(═O)—NH—B—NH—C(═O)—O—;
B —(CH
2
)
t
—, arylene, optionally substituted;
n 1 to 8;
s 0 to 500;
t 1 to 12;
u 1 to 5000;
v 0 to 5000;
w 0 to 5000;
x 1 to 5000;
y 0 to 5000;
z 0 to 5000
as coating agent, binder and/or film-forming excipient in pharmaceutical presentations.
Graft polymers containing polyalkylene oxides have already been disclosed inter alia as ancillary substances in pharmaceutical preparations.
Thus,
Angel Maximilian
Gotsche Michael
Kolter Karl
Leinenbach Alfred
Sanner Axel
Asinovsky Olga
BASF - Aktiengesellschaft
Keil & Weinkauf
Seidleck James J.
LandOfFree
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