Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Capsules
Reexamination Certificate
2000-10-10
2003-01-21
Page, Thurman K. (Department: 1615)
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
Capsules
C424S489000, C424S490000, C424S495000, C424S452000
Reexamination Certificate
active
06509034
ABSTRACT:
The present invention relates to wettable microcapsules having hydrophobic polymer coated cores and to processes for their preparation; in particular, to microcapsules with ethylcellulose coatings that are wettable so that they are suspendible in aqueous medium. The microcapsules produced by this invention are suitable to be manufactured into oral pharmaceutical dosage forms such as capsules, tablets, monodose sachets, syrups.
BACKGROUND OF THE INVENTION
Microencapsulation by phase separation is extensively used in the preparation of multiparticulate dosage forms. The process involves enveloping small particles of the material to be delivered (typically a drug), which may be a liquid or a solid, to produce minute discrete packages called microcapsules. They comprise cores coated with an external polymeric membrane. To the naked eye microcapsules appear as a fine powder. Their dimensions typically range between few microns and thousands of microns.
Phase separation processes exploit the physico-chemical properties of a polymeric coating material which allows separation of the polymeric material from solutions in a liquid state instead of precipitating the material as a solid. The material to be coated must be insoluble in the liquid vehicle used and be compatible with the coating polymer. The material to be coated, e.g. a drug, may already be coated with an insoluble coat before it is further coated by phase separation. The separation (or coacervation) phenomenon can be induced by a number of means such as by variation of temperature and/or pH, by adding a salt or non-solvent or incompatible polymers, or by polymer-polymer interaction. Microencapsulation systems are also described in U.S. Pat. No. 3,415,758 and U.S. Pat. No. 3,748,277.
The choice of both coating polymer and microencapsulation system depends on the physico-chemical characteristics of the material to be coated and the intended purpose (therapeutic use) of the microcapsules. Microcapsules having an outer coat of polymer with hydrophobic properties, such as for example, ethyl cellulose, are extensively used as, for example, sustained release or delayed release dosage forms or taste masked dosage forms etc. Such materials may also be used for the separation of incompatible drugs.
The hydrophobic nature of such coating materials gives rise to several drawbacks when the microcapsules are to be used in aqueous environment. For example, when the finished dosage form is placed into a glass of water the hydrophobic microcapsules tend to float and form aggregates (e.g. clumps or clusters) and some tend to attach to the glass wall. The floating effect also occurs for those microcapsules having a real density greater than the liquid medium. Accordingly, for dosage forms which are to be suspended there are problems of accuracy of dosing and problems of patient acceptability due to for example difficulty with swallowing.
Aggregation and water repellence also occur in physiological fluids following the intake of dosage form containing hydrophobic microcapsules. This aggregation of the microcapsules, not only decreases the dissolution profile of the active due to a lowering of the total surface area, but also can be responsible for local irritation occurring in the gastrointestinal mucosa. Such phenomena severely prejudice both patient acceptability and therapeutic efficiency of such micro-encapsulated drugs.
U.S. Pat. No. 4,259,315 attempted to solve the above-mentioned drawbacks by admixing surfactants with hydrophobic microcapsules obtained by phase-separation This system, requiring an additional mixing step is time consuming and has drawbacks with achieving uniformity of the mixture.
FR-A-2 641 188 discloses ethylcellulose microcapsules containing sodium docusate either in-bulk or deposited onto the microcapsule surface; the surface treatment, performed by mixing the microcapsules with a docusate solution, is reported to produce a lesser effect on dissolution times than the in-bulk treatment; the amount of docusate contained in the microcapsules is not specified.
There is a need therefore for microcapsules which are wettable and which preferably do not aggregate or suffer from any one or more of the drawbacks discussed above. There is also a need for microcapsules prepared using hydrophobic polymer which are readily dispersible in water.
The present invention provides wettable microcapsules comprising a drug encapsulated by ethylcellulose, and having deposited thereon one or more surfactants and optionally a binder, wherein:
(i) the quantity of dry surfactant expressed as % w/w over the hydrophobic cores ranges from 0.010% and 2.000%;
(ii) said surfactant and optional binder have been deposited by spray-coating the microcapsules, in a fluidized bed, with a solution having a concentration of surfactant+(optional) binder comprised between 0.01 and 10.0% by weight, in a solvent in which the said ethylcellulose forming the outer membrane of the microcapsule is insoluble, and drying,
(iii) said ethylcellulose being applied onto said drug by phase separation.
The present invention further provides a process to prepare said wettable microcapsules comprising spray-coating a drug particle encapsulated in ethylcellulose, with a solution having a concentration of surfactant+(optional) binder comprised between 0.1 and 10.0% by weight in a solvent in which the said ethylcellulose is insoluble, and drying to form an outer layer of surfactant.
The present invention further provides wettable microcapsules obtainable by any one of the processes described herein.
The wettability of the hydrophobic membrane of the microcapsules is achieved by coating the microcapsules (optionally) treated with surfactant during coacervation step and/or washing step as described below) with a surfactant layer, and optionally a binder. The surfactant layer is applied by spray coating the microcapsules in a fluidized bed with at least one surfactant dissolved in a suitable solvent in which the ethylcellulose forming the outer membrane of the microcapsule is insoluble, and drying.
The wetting solution composition comprises at least one surfactant and optionally a binder. The solvent may be aqueous or organic. The ethylcellulose membrane should be insoluble in the wetting solution solvent. A non limiting list of suitable binders includes gelatine, polyethyleneglycol, hydroxypropylmethylcellulose, methylcellulose, polyvinylpyrrolidones, pre-gelatinised starch, ethylcellulose, alginates, carboxymethylcellulose, arabic gum, tragacanth gum etc.
The wetting solution preferably comprises sodium docusate (DOSS) as surfactant and polyvinylpyrrolidine (PVP) as binder, both dissolved in purified water as solvent. Advantageously, the weight ratio of surfactant (eg DOSS) to binder (eg. PVP) is preferably in the range of 5:1 to 1:5, more preferably from 3:1 to 1:3. The wetting solution concentration (% w/w) of surfactant and binder (eg. DOSS+PVP) may vary from 0.1 to 10.0, advantageously from 2.0 to 6.0
To ensure the water wettability of the ethylcellulose microcapsules, the quantity of dry surfactant (eg DOSS), expressed as % w/w over the hydrophobic cores, ranges from 0.010 to 2.000, more preferably from 0.040 to 1.000.
The wettability of a solid is strictly related to its solid surface tension and that of the surrounding liquid. Solids will not be wetted if the critical surface tension is exceeded by the surface tension of the liquid. The wetting properties of a liquid medium are qualified through the determination of the contact angle (°) which is the angle between a liquid droplet and the surface over which it spreads and represents the grade of extension of a liquid on a solid surface.
The contact angle may vary from 0° signifying complete wetting, or may approach 180° at which wetting is insignificant. A primary function of the surfactants is to act as wetting agent because of their tendency to be adsorbed at the solid-liquid interfaces while reducing also the surface tension of the liquids. As a result the contact angle between the surface and the wettin
Bruschi Stefano De Luigi
Calanchi Massimo Maria
Gentilini Leonardo
Mapelli Luigi Giovanni
Bennett Rachel M.
Eurand International S.p.A.
Page Thurman K.
Thompson Hine LLP
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