Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Particulate form
Reexamination Certificate
1999-09-21
2001-07-17
Page, Thurman K. (Department: 1615)
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
Particulate form
C424S490000, C424S493000, C424S496000, C424S497000, C424S456000, C424S464000
Reexamination Certificate
active
06261602
ABSTRACT:
The present invention relates to a process for the preparation of a pharmaceutical formulation suitable for the administration of drugs and in particular of microcapsules of drugs in a monodose sachet form, the contents of which form a rapid suspension in water or an aqueous medium, for instance, saliva in the mouth.
In the description and the claims which follow we will use mostly the terms microcapsules or microcapsulated drugs, but the present invention can also be applied to solid drugs particles (powders, crystals, granules) which are insoluble or slightly soluble in water or drinkable aqueous liquids (milk, fruit juices, etc.) and of which one desires to obtain an extemporary and homogeneous suspension.
In the following description and claims the term:
“microcapsule” is used to indicate drug particles, powders, crystals, granules, pellets and also liquid drops, coated in a polymeric membrane.
“microencapsulation” is generically the process used for the application of a membrane.
“pack or monodose sachet” is a container which contains a single dose of drug plus the excipients of the formulation.
“thickening or suspending substances” are substances which dissolve in water and which increase in density and viscosity allowing solid particles to be suspended.
Microencapsulation is a process known from some time and consists of coating substances with a continuous film based on natural or synthetic polymers.
The processes of microencapsulation are numerous. Many of these and the relative patents are cited and described in the volumes “Microcapsules and microencapsulation Techniques”(published in 1976) and “Microcapsules and other Capsules. Advance since
1975
”(published in 1979) both by M. H. Guttcho. Among the preferred processes are those described in the U.S. Pat. Nos. 3,196,827 and 3,253,944 by D. E. Wurster which described methods of mechanical coating consisting of spraying a membrane around particles using suitable apparatus, and those cited in U.S. Pat. Nos. 3,415,758, 3,155,590 and 3,341,416 which described methods of chemicophysical coating based on the coacervation or separation of phases, in which polymer making up the membrane is dissolved in a suitable solvent or vehicle of microencapsulation and the substance to be dissolved is suspended in this solution and kept in agitation.
The coacervation of the polymer around the substance to be coated is obtained in various manners, such as for example temperature variation, addition of another more soluble polymer in the vehicle, addition of a non solvent of the polymer constituting the membrane, etc. The membrane can be hardened and so the microcapsules are separated from the vehicle for example by filtration or centrifuging and finally drying.
In the pharmaceutical field, microencapsulation is used to mask unpleasant tastes, for slowing down the release of the drug, for preventing irritation arising from contact of the drugs with the gastrointestinal mucosa, for protecting drugs from degradation, for separating drugs which react with each other, for transforming the drug into a more easily used form, such as for example, converting it from a liquid state into a powder composed of microcapsules.
A common form of dosage for the oral administration of drugs, and especially of microencapsulation drugs, is that of monodose sachets. This moreover is the most convenient solution, if not the only one, if one must administer high doses of drugs. Monodose sachets containing microcapsules have been prepared in the past, sometimes also on an industrial scale, as cited in the volume “Microencapsulation” by J. R. Nixon, Chapter 7, page 93.
However, they often present various disadvantages due especially to the hydrorepulsion of polymers making up the microcapsule membrane (for example polymers with a base of cellulose or waxy substances) and to the specific weight of the microencapsulated substances and therefore of the said microcapsules.
In fact when the contents of the sachets were poured out, as usual, in a glass of water or in fruit juice or in milk, the microcapsules formed a sediment on the bottom of the glass or floated on the surface, adhering partly to the walls of the said glass. This brought a notable inaccuracy to the quantity of the drug taken as well as poor acceptance by the patient who saw the particles floating or felt unpleasant scraping sensation in the mouth or throat when swallowing the contents at the bottom of the glass where the mass of sedimented particles was found.
The addition of thickening substances would delay and maybe also eliminate the separation of the nicrocapsules, but in practice has given negative results because these substances tend to form lumps on contact with water which dissolve slowly and only by resorting to vigorous mechanical agitation. It was attempted to disperse these thickening substances together with other components of the formula by mixing them in the usual powder mixers. Also with this method the formation of lumps could not be avoided, but was only partly reduced.
The above mentioned difficulties were mainly solved by the invention described in Italian patent no. 1183574 which refers to a formulation, and a method for obtaining it, characterised in that:
1) a thickening agent is micronized;
2) the thickening agent is suspended in an organic solution also containing a binding agent;
3) this suspension is applied by spraying it on to the surface of a substance which is easily soluble in water (sugar, sorbitol); and
4) the product obtaining is dried and once mixed with the microcapsules and the flavouring is used for filling the monodose sachets.
When the contents of the sachets are poured in water and agitated, as described in the examples of the patents cited, in about 1 minute a homogeneous microcapsule suspension is obtained.
In practice however it is seen that the patients, after having poured the sachet contents into water, do not stir with a spoon for at least 60 seconds, but stop after 20-30 seconds at the most. After this time the thickener is still not sufficiently dissolved and so a homogeneous suspension is not obtained and the previously cited difficulties are only partially eliminated.
WO 92/00731 discloses a system which reduces the mixing times. It was found that if an acid and a base substance are added, the thickening of the liquid and the homogeneous suspension of the microcapules is generally obtained by mixing for only 15-20 seconds. The solid pharmaceutical composition for addition to water to produce a suspension of a drug comprises:
a) a drug which is substantially water-insoluble or microencapsuled;
b) a thickening or suspending agent;
c) a pharmaceutically acceptable acid;
d) a pharmaceutically acceptable carbonate or bicarbonate. The weight ratio of c+d:b is from 1:1.5 to 1:15 and the amount of c+d is sufficient to obtain rapid hydration of the thickening or suspending agent b) when the composition is mixed with water such that a homogeneous suspension of the drug is obtained with 30 seconds. WO 92/00731 states that it is necessary that the acid and base substances, are very thoroughly mixed with the thickening substance and therefore they must be soluble, or suspended in the form of micronized powder, in the organic solvent used for applying of the suspension containing the thickener.
The process disclosed in WO 92/00731 has the disadvantage of using an organic solvent which may cause a problem as a result of flammability or pollution. The process also has the disadvantage of being an manufacturing method with the disadvantage of a low concentration of thickening agent. In consequence, in order to reach a viscosity suitable for maintaining the microcapsules in a homogeneous suspension, monodose sachets had to be filled with a large amount of ingredients which also caused high costs.
The present invention provides a novel pharmaceutically useful carrier for a water-insoluble or microencapsulated drug. The pharmaceutical compositions containing the carrier and the drug are capable of being dispersed rapidly when added to water or an aqueou
Calanchi Massimo Maria
Mapelli Luigi Giovanni
Marconi Marco Giuseppe Raffaele
Eurand International S.p.A.
Page Thurman K.
Thompson Hine LLP
Tran S.
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