US 3907983 A
Powders, the individual particles thereof coated with from about 0.5% to 10% by weight of a material which makes the powder nydrophilic, and which are free flowing as well as amenable to tabletting by direct compression are disclosed as well as a method for making such powders and tablets.
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Description (OCR text may contain errors)
United States Patent 5/1972 France Seth [451 Sept. 23, 1975 PHARMACEUTICAL PREPARATIONS OTHER PUBLICATIONS [751 Imam" Lalsflh, Arleshelm Davies et al., J. Pharm. Sci. 61(4): 618-622 April Swltzerland 1972, Batch Production of Pharmaceutical Granula-  Assignee: Hoffmann-La Roche Inc., Nutley, tions in a Fluidized Bed II. Effects of Various Binders NJ and their Concentrations on Granulations and Compressed Tablets.  Filed: Jan. 30, 1974  App]. No.: 438,135 Primary ExaminerShep K. Rose Attorney, Agent, or Firm-Samuel L. Welt; Jon S.
; 1d .R  Foreign Application Priority Data Saxe Gem S osen Feb. I6, Switzerland [52 US. Cl. 424/35 Powders the individual 1harticles theFeOf mated with 51 Int. A6lJ 3/02 fmm ahut 05% 10% by weight material which  Field of Search 424/35 makes the Powder hYdmPhihc, ahd which are free flowing as well as amenable to tabletting by direct  References Cited compression are disclosed as well as a method for making such powders and tablets.
10 Claims, No Drawings PHARMACEUTICAL PREPARATIONS BACKGROUND OF THE lNVENTlON Many pharmaceutically activesubstances, elg. medicines, vitamins, are administered in the form of tablets. These tablets are usually manufactured by firstforming granules from powders of the pharmaceutically active substance. The granules are prepared by either wet or dry granulation. After the addition of the usual carriers and/or excipients, the granules are pressed into tablets. Since it is desirable for the pharmaceutically active substances contained in the tablets to be rapidly absorbed by the body, it is desirable for the tablets to disintegrate in an aqueous medium into particles of the smallest possible size. In order to obtain greatest benefit from the active substance, the particles should either dissolve rapidly or be sufficiently wettable to be easily absorbed. In tablets which are manufactured by compression of granules, this does not generally occur since such tablets usually disintegrate initially into the granulate which then disintegrates, often very slowly, into the smaller particles. Since the individual particles of the pharmaceutically active substance are, in many cases poorly wcttable, the complete dissolution of the tablets or the pharmaceutically active substances is considerably delayed and in some cases never occurs.
DESCRIPTION OF THE INVENTION By means of the present invention the foregoing disadvantages inherent in tablets formed from conventionally produced granulations can be avoided by coating the surface of the individual particles of the pharmaceutically active substance with a film-of a hydrophilising material, i.e., a material which renders the particles water-wettable. In this manner a powder having advantageous properties is formed since such a powder is very rapidly water-wettable and in many cases is soluble because of the film of the hydrophilising material. 7
Such a powder is also advantageous because it is freeflowing and is directly compressible to tablets without prior granulation procedures. This is advantageous since, upon dissolution, such tablets disintegrate di rectly into the individual pharmaceatically active material particles and do not disintegrate in two steps as mentioned above i.e. into the granulate which, in turn, disintegrated into the individual particles. Because of their free-flowing properties the powders of this invention can also be readily incorporated into capsules.
Thus, the present invention in one aspect is concerned with powders of pharmaceutically active substances in which the surface of the individual particles of the active substance is coated with a film of a hydrophilising material, as well as with a process for their manufacture. The powders are water-wettable, free flowing and directly compressible into tablets.
The invention is also concerned with pharmaceutical preparations in a powdered form or in the form of tablets containing at least one pharmaceutically active substance in combination with conventional pharmaccutically acceptable tabletting adjuvants and/or excipients. The active substance or mixtures of active substances and, if necessary, the conventional carriers and/or excipients are present in the form of individual particles the surface of which is covered with a film of a hydrophilising material. Suitable pharmaceutically acceptable tabletting adjuvants and excipients are micro-crystalline cellulose. dextrose, lactose. sucrose.
mannitol, glucose, sorbitol; lubricants such as calcium stearate, stearic acid or magnesium stearate as well as mixtures thereof, Talc, cornstarch etc. can be mixed with the lubricants. Flavoring agents and coloring agents can also be used.
, The coating of the surface of the individual particles can be carried out by spraying the particles with a solution of a hydrophilising material and subsequently drying the product. This can also be accomplished by suspending the particles in a solution of a hydrophilising material and subsequently drying the product.
The amount of hydrophilising material which must be applied to the surface of the particles in order to produce the desired effect depends largely on the nature of the particles to be hydrophilised as well as on the hydrophilising material. Generally, a sufficient amount should be present to insure that the particles are made sufficiently waterwettable so tablets made therefrom disintegrate at the desired rate and in the desired manner. The amount required generally lies in the range of about 0.5 and 10% by weight based on the weight of the particles preferably between about 1 and 5% by weight and most preferred at about 2 to 3% by weight. The amount required to meet the criteria desired can be determined by means of the following wettability test. In this test, a known amount of dry hydrophilised powder is poured on to the surface of the water contained in a glass beaker and the time required by the powder layer to become wetted and sink into the water is observed. The wetting or sinking rate is classified into the following categories: (a) excellent, (b) good, (c) adequate. (d) poor, (e) inadequate. The amount of hydrophilising material required in each individual case can be readily determined according to the foregoing classification.
Examples of suitable hydrophilising materials which can be used in the present invention are, for example. the following: polyvinylpyrrolidone (m.w. 15000-35000), cold-swellable and water-soluble starches, certain mucins such as gum arabic and the like in combination with wetting agents as well as water-soluble, pharmaceutical grade and low viscosity grade (i.e. from about 2 to about 15 cps) cellulose derivatives, especially methylcellulose or hydroxyethylmethylcellulose, hydroxypropylmethylcellulose and the like. A preferred hydrophilising material is available under the trade name Pharmacoat 603" (Shinetzu Chemical Company, Tokyo). This cellulose derivative dissolves well in water and is also soluble in diverse organic solvents such as isopropanol, methylene chloride and the like. Furthermore, it has the ad vantage of an extremely low viscosity as a result of which relatively concentrated solutions possess good spraying characteristics.
Suitable solvents for the spraying of the hydrophilising material are especially those solvents in which the pharmaceutically active material to be hydrophilised is poorly soluble or insoluble. Since water fits these criteria it is the preferred solvent. The amount of hydrophilising material in the solution to be sprayed can vary but generally lies at between about 2-l57( (weightlvolume), preferably at between about 3-1071 (weight- /volumc) and most preferably at between about 5-l07r (weight/volume). Of the useful compositions the 5-l0% (weight/volume) aqueous solutions of Pharmacoat 603 are especially preferred.
a hydroxypropylmethylcellulose which is commercially The-procedure by which the hydrophilising material is applied to the surface of the individual particles must be carried out in a manner which insures that the particles do not become agglomerated. Except for this limitation any method which provides for the coating of one substance using a solution of another substance can be used.
"In accordance with the present invention it has been found that both the coating-drum method and the fluidized-bed method are especially suitable.
According to the coating-drum method, the particles to be hydrophilised are maintained in motion in a coating-drum by the rotation thereof. A solution of the hydrophilising material in a suitable solvent isthen slowly and continuously sprayed into the drum. During this procedure, care must be taken that the particles to be coated, do not become too damp since they would agglomerate and form a granulate. The coated particles can be subsequently dried in the drum or, in the case of large batches, transferred to a fluidized-bed drier and dried therein. 7
.According to the fluidized-bed method, the particles to be hydrophilised are placed in a fluidized-bed drier and maintained in motion by means of air, the input and output temperature of which is adjusted according to the solvent used. A solution of the hydrophilising material in a suitable solvent is continuously sprayed into the drier at a rate which ensures that the particles to be coated do not become too damp and conglomerate This avoids formation of a granulate. After completion of the spraying, the coated particles can be dried directly by a further input of suitably pro-warmed The individual particles coated with a hydrophilising material according to the previous methods form a powder which is free flowing and is directly compressib le tb tablets without prior granulation or other pre treatment. l
Individual particles of all poorly wettable or waterins oluble pharmaceutically active substances can be coated with a hydrophilising material in accordance with the present invention. This invention is particularly applicable to those pharmaceutically active substances which are administered in the form of tablets but is not limited thereto. Examples of such pharmaceutically active substances amenable to treatment accordingto this invention are sulfamethoxazole, trimethoprim, phenacetin, acetylsalicylic acid, benzodiazepinesand the like.
The powders of the present invention consist of individual particles each of which is individually coated with a film of a hydrophilising material. These powders can be directly compressed to tablets either as formed or after mixing with conventional pharmaceutically acceptable tabletting carriers and/or excipients. The powders can also be incorporated into capsules.
The following Examples illustrate the present invention:
EXAMPLE 1 10 g of Pharmacoat 603 dissolved in 90 g of water are continuously sprayed by means of a spray-gun for a period of minutes into a constant speed slowly rotating coating-drum of 400 mm diameter containing 500 g of sulfamethoxazole. The entire coating solution is sprayed into the drum which is left to rotate for 3 more hours by which time the contents are completely dry.
There is thus obtained a powder composed of individual particles of sulfamethoxazole which are freeflowing, directly compressible to tablets and coated with about 2% by weight of Pharmacoat 603.
In place of grams of water, there can be used with equivalent results 45 grams of water and 45 grams of ethanol or isopropanol.
EXAMPLE 2 300 g of Pharmacoat 603 dissolved in 2.7 liters of water are continuously sprayed by means of a spraygun for 20 minutes into a constant speed slowly rotating coating-drum of cm diameter containing 15 kg of sulfamethoxazole. The entire coating solution is sprayed into the drum which is left to rotate for 5 more minutes. Subsequently, the resulting slightly damp material is removed from the drum, sieved through a 0.5 mm sieve and dried for 0.5 hour in a fluidized-bed drier with an input temperature of 50C. There is thus ob tained a powder composed of individual particles of sulfamethoxazole which are free-flowing, directly compressible to tablets and coated with about 2% by weight of Pharmacoat 603.
In place of 2.7 liters of water there can be used with equivalent results an equal weight of a 1:1 (wt/wt) mixture of water and either ethanol or isopropanol.
EXAMPLE 3 15 kg of sulfamethoxazole are sieved through a 0.5 mm sieve and the powder obtained is added to a fluidized-bed drier having an input air temperature of 60C. The air is blown through the powder continuously until the temperature of the output air has reached 37C. A 7.5% (weight/volume) aqueous Solution of Pharmacoat 603 is then sprayed into the fluidized-bed drier at a rate such that a total amount of 4 kg of solution is sprayed during a period of 20 minutes. This causes the temperature of the output air to decrease to 26C. and then remain constant. After completion of the spraying, the material is dried for 15 minutes more in the apparatus, causing the temperature of the output air to rise to 30C. There is thus obtained a powder composed of individual particles of sulfamethoxazole which are free-flowing, directly compressible to tablets and which are coated with about 2% by weight of Pharmacoat 603.
EXAMPLE 4 In a manner analogous to that described in Example 1, Example 2 or Example 3, a powder composed of individual particles of trimethoprim which are freeflowing, directly compressible to tablets and coated with about 2% by weight of Pharmacoat 603.
EXAMPLE 5 7 EXAMPLE 6 g of finely powdered 5-(6-chlorophenyl)-l,3- dihydro-7-nitro-2H-l,4-ben2odiazepin-2-onc are suspended in a 5% aqueous solution of Pharmacoat 603 (prepared from g of Pharmacoat 603 and 380 ml of water). The aqueous suspension is then sprayed, by means of a spray-gun, onto 1 kg of lactose in a rotating coating-drum. The suspension is sprayed in such a manner that the lactose particles are uniformly coated and do not become too damp. The resulting product is dried at 40C. to give a free-flowing powder of a mixture of lactose particles and 5-(6-chlorophenyl)-l,3- dihydro-7-nitro-2H- 1 ,4-benzodiazepin-2-one particles each coated with about 2% by weight of Pharmacoat 603. The powder is water-wettable and can be compressed directly into tablets or incorporated into capsules.
In place of 380 ml of water there can be used with equivalent results 190 grams water and 190 grams ethanol or isopropanol.
1. A free-flowing water wettable powder which is directly compressible without prior granulation into rapidly absorbed tablets and which is composed of individ ual rapidly disintegrating particles of a pharmaceutically active substance spray-coated from aqueous solutions with from about 0.5% to about 10% by weight of a hydrophilising material selected from the group consisting of methyleellulose. hydroxyethylmethyleellulose and hydroxypropylmcthylcellulose.
2. The powder of claim 1 wherein the hydrophilising material is hydroxypropyl methyl cellulose.
3. The powder of claim 1 wherein the active substance is coated with about 1% to about 5% by weight of a hydrophilising material selected from the group consisting of methylcellulose, hydroxyethylmethylcellulose and hydroxypropylmethylcellulose.
4. The powder of claim 1 wherein the active substance is coated with about 2% to about 3% by weight of a hydrophilising material selected from the group consisting of methylcellulose, hydroxyethylmethylcellulose and hydroxypropylmethylcellulose.
5. The powder of claim 1 wherein the individual articles thereof are composed of a mixture of pharmaceutically active substances, each of which is coated with a hydrophilising material selected from the group consisting of methylcellulose, hydroxyethylmethylcellulose and hydroxypropylmethylcellulose.
6. The powder of claim 1 wherein the individual particles thereof are composed of a mixture of a pharmaceutically active substance and pharmaceutically acceptable tabletting adjuvants and excipients, each of which is coated with a hydrophilising material selected from the group consisting of methylcellulose, hydroxyethylmethylcellulose and hydroxypropylmethylcellulose.
7. The powder of claim 3 wherein the hydrophilising material is hydroxypropylmethyl-cellulose.
8. The powder of claim 1 wherein the active substance is sulfamethoxazole.
9. The powder of claim 1 wherein the active substance is a mixture of sulfamethoxazole and trimethoprim.
10. The powder of claim 6 composed of 5-(6- chlorophenyl )-l ,3-dihydro-7-nitro-2H-l ,4- benzodiazepin-2one and lactose.