MXPA99001493A - Granulates comprising a water soluble compound and cellulose - Google Patents

Abstract

A granulate consisting of a water soluble active ingredient, up to and including 100 wt.%of a cellulose product, such as microcrystalline cellulose and up to and including 0.5 wt.%of a wet granulation binding agent is provided. The granulate is prepared by a wet granulation technique. Compositions based upon the said granulate are disclosed.

Description

GRANULATES THAT COMPRISE A SOLUBLE COMPOUND IN WATER AND CELLULOSE The present invention relates to a granulate containing a water soluble compound, a process for the preparation thereof and compositions based on said granulate. BACKGROUND OF THE INVENTION Generally, if a rapid onset of a drug is intended from a solid dosage form, such as a tablet, the composition and method of making such a tablet will be carefully selected in order to allow a rapid disintegration of the tablet and a dissolution of the drug, when placed in an aqueous environment. EP-B-0330284 discloses a process for the preparation of a pharmaceutical granulate by granulating a drug, having a solubility in water of less than 10% by weight, and 20-100% by weight of microcrystalline cellulose with water without using a substantial amount of a wet granulation binder. The amount of water to be used varies between about 60% by weight and 135% by weight, the percentages based on the weight of the active ingredient. From a granulate, obtained in this way, fast-disintegrating tablets can be prepared. However, the incorporation of active ingredients having a solubility in water of more than 10% by weight in the tablet compositions may present problems as to the disintegration thereof and consequently the dissolution of the active ingredient. Z.T. Chowhan and cois. (1982) in Drug Developm. of Industr. Pharm. 8. (2), p. 145-168, mentions that tablets containing a high percentage (66% by weight) of a water-soluble and hygroscopic drug (naproxen sodium) did not disintegrate when a dissolution test was run. The drug was mainly dissolved in the area of the effective surface of the tablet, which was exposed to the dissolution medium. Consequently, great variability from tablet to tablet of such tablets was observed in the dissolution test. The addition of disintegration agents (sodium starch glycolate and sodium carboxymethyl cellulose in addition to 10% starch) did not improve the dissolution variability or increase the dissolution rate of the drug. The results further suggested that the formulation in which a larger portion of the excipients were not wet granulated together with the drug, resulted in a higher dissolution variability from tablet to tablet. In view of these results it seems to be difficult to develop a tablet formulation containing a water soluble active ingredient, which will give reproducible and reliable effects when administered to humans or animals. A well-known dosage form for water-soluble compounds is an effervescent tablet. By placing such a tablet in the water it disintegrates easily and the solution must be achieved in a few minutes. However, it is not convenient to administer these tablets without first dissolving the tablets in water, due to the simultaneous release of carbon dioxide. Another disadvantage of an effervescent tablet and an important reason for its use in some limited way, refers to the difficulty of producing a chemically stable product, due to the moisture sensitivity of the effervescent element. Since many active compounds, such as drugs, are soluble in water, the problem to be solved by the present invention was to provide a method of preparation or formulation, which generally could be applied to all classes of water-soluble active ingredients, for compositions of rapid dissolution and rapid disintegration. SUMMARY OF THE INVENTION A granulate is provided consisting of, a water-soluble active ingredient, 0-100% by weight of a cellulose product, such as microcrystalline cellulose and 0-0.5% by weight of a wet granulation binder , all percentages based on the weight of the active ingredient. A process for the preparation of said granulate includes wetting the component (s) to be granulated with an essentially aqueous liquid without using a substantial amount of a wet granulation binder and consecutively spraying the wet mass, dry the granules and screen these. The granulate can be used as such or can be incorporated into compositions together with excipients, such as microcrystalline cellulose and a disintegrant. DETAILED DESCRIPTION OF THE INVENTION A water soluble active ingredient according to the present invention is a substance that is soluble in water at room temperature in a ratio of 1: <; 10. There are numerous examples of such compounds, which can be found among all classes of physiologically and cosmetically active substances. The most important active substances are vitamins, nutritional agents and drugs. The vitamins include, for example, ascorbic acid, pyridoxine hydrochloride and thiamine hydrochloride. The nutritive agents are several amino acids. Water-soluble drugs can be found in many different classes of therapeutic compounds: mucolytics such as, N-acetyl-cysteine and S-carboxymethyl-cysteine; antimicrobial agents such as, neomycin sulfate and the water soluble salts of beta-lactam antibiotics; iron salts such as, ferrous gluconate and ferric ammonium citrate; tuberculostatic and tuberculocidal such as, ethambutol hydrochloride and isoniazid; beta-adrenoceptor blocking agents such as, metoprolol tartrate and sotalol hydrochloride; certain bisphosphonic acids and the salts thereof; antimalarials such as various quinine salts, etc. Preferred water-soluble compounds are the potassium salts of feneticilin of β-lactam antibiotics, the sodium and potassium salt of phenoxymethylpenicillin and the sodium salt of flucoxacillin. The granulate according to the invention may consist essentially of the active ingredient soluble in water or may contain the same ingredient in admixture with commonly used excipients, which are cellulose products such as microcrystalline cellulose, microfine cellulose or a mixture thereof, in a concentration of up to 100% by weight inclusive, the percentage based on the weight of the active ingredient. Advantageously, the granulate contains at least 50% by weight of the water-soluble compound. In particular, when high doses of such a compound have to be incorporated in a digestible oral dosage form, the use of large quantities of excipients should be avoided as much as possible. Preferred concentrations of the water-soluble active ingredient in the granulate are at least 75% by weight but more preferably at least 85% by weight. The granulate is prepared at room temperature by a wet granulation technique, using an essentially aqueous liquid as the granulation liquid, however without using the substantial amounts of wet granulation binder. The granulation liquid may contain up to 10% by weight of ethanol. In said aqueous liquid can be dissolved up to 0.5% by weight inclusive, preferably 0-0.1% by weight of a wet granulation binder, the percentages based on the weight of the active ingredient. Suitable wet granulation binders include water-soluble celluloses such as hydroxypropyl celluloses and sodium carboxymethyl cellulose, starches (soluble, pregelatinized), polyvinylpyrrolidone, although naturally occurring binders such as gum arabic may also be used. wheat starch, sugars and polyhydroxy compounds such as mannitol. The amount of granulation liquid to be used depends on the active ingredient, the ratio between the active ingredient and the cellulose product and the composition of the granulation liquid and the percentages can vary based on the weight of the active ingredient from 1 to 40% by weight and preferably from 2.5 to 20% by weight. The granulate can be prepared by gradually adding the essentially aqueous solution, optionally containing up to 0.5% by weight inclusive, of the wet granulation binder, to the component (s) to be granulated and mixing the dough for 15 to 20 minutes, preferably 20 minutes, and subsequently screening the wet mass thus obtained through at least one 2.0 mm screen. Alternatively, most of the water-soluble compound, optionally mixed with the cellulose product, can be granulated with an aqueous solution, which contains the remaining part of the same compound. After drying the granules in a fluidized bed dehydrator at an aspirated air temperature of between 30 and 60 ° C, preferably 45 ° C, these are screened again, but now through a screen having pores of at least 0.71 mm, but preferably between 1.00 and 1.50 mm. Alternatively, the wet mass can be pulverized, for example, in a mill. The particle size distribution of the granulate should meet special requirements if the granulate is intended to be used for rapidly dispersible or rapidly disintegrating compositions. A suitable distribution is, for example: >; -1.400 mm 0.3% 1.000-1.400 mm 28.2% 0.710-1.000 mm 23.8% 0.500-0.710 mm 20.2% 0.355-0.500 mm 12.7% 0.250-0.355 mm 7.6% 0.180-0.250 mm 3.6% 0.125-0.180 mm 2.3% 0.090-0.125 mm 0.8% Apparatus suitable for the production of the granulate include a planetary mixer, but also a fluid bed granulator, a high shear mixer or a high speed mixer. It has been observed that the optimum mixing time depends on the apparatus used, the mixing speed and the particle size of the powders to be granulated. In case a high speed mixer is used, a considerable reduction of the mixing time can be achieved. The granules obtained according to the present invention show satisfactory properties such as a good flow and a Hausner ratio. Dissolution studies revealed a rapid dissolution of the active ingredient. Another advantage is that an organic solvent, with all environmental and safety risks, can be avoided as a granulation liquid. Furthermore, it has been observed that the flavor of the active ingredient, if considered necessary, can be relatively easily improved by means of the addition to the flavor granules and sweetening agents according to the present invention. Organoleptic tests performed on volunteers have shown that the taste masking of a water-soluble ß-lactam antibiotic such as a potassium of phenoxymethylpenicillin in granular form is no more than a problem of taste masking of the granules containing a slightly soluble form of the same antibiotic (phenoxymethylpenicillin). It is advantageous that a granulate, which contains a water-soluble drug for the most part, can be obtained by a wet granulation technique using an essentially aqueous liquid as the granulation liquid in a special way since normally a liquid in which the powders to be granulated are only slightly soluble, they would be selected as the granulation liquid. Despite the fact that the solubility of a compound in the granulation liquid is high and the powder which is in contact with the granulation liquid will dissolve therein, it has also been possible to distribute the liquid throughout the powder. Excess moisture of the powders to be granulated would be avoided, as well as the formation of granules in the form of very hard fiber after drying and wet screening, whose granules are not suitable for tablet compression without further processing. Furthermore, it is an advantage that the wet screening process proceed very smoothly because the pores of the screen will not gradually azolvate. To obtain rapidly dispersible dosage forms that can be administered orally, the water-soluble active ingredient in a granular form is mixed with a cellulose product, which is microcrystalline cellulose, microfine cellulose or a mixture thereof, one or more disintegrants, and optionally sweeteners, flavorings and flavors, lubricants, anti-adhesives, flow promoters, etc. The total percentage of active ingredient and cellulose product can vary from about 80 to about 85% by weight, the percentage based on the final dosage form. The ratio of active ingredient and cellulose product can vary from 1: 0.5 to 1: 1, with the preferred ratio being 1: 0.9 (total of intra or extragranular amounts). The cellulose product may have an average particle size ranging from 50 to 250 μm, but preferably a product having an average particle size of 100 μm, such as Avisel® PH 102 microcrystalline cellulose, is used. a reduction in the size of the compressed dosage form, the cellulose product can be partially replaced by a calcium phosphate, which is commercially available under the trade name Emcompress®. However, an increase in the disintegration time of such compressed dose forms has been observed. The disintegration time of the solid oral dosage forms according to the invention, such as capsules and tablets, is determined by means of a disintegration time apparatus, operated without using disks, for example, according to the European Pharmacopoeia or British (ERWEKA), however with an additional modification of the movement (22 mm instead of 55 mm) simulating a user situation. The maximum disintegration time of the dosage forms according to the invention is 2 minutes, but preferably less than one minute. It is also possible to determine a dispersion time, especially of sachet formulations, in a beaker. In addition, dispersible tablets must also meet the requirements of the European or British Pharmacopoeia for such tablets. Useful disintegrants appear to be among other super disintegrants and include modified starches such as sodium starch glycolate, cross carmellose, sodium carboxymethyl cellulose, degraded polyvinylpyrrolidone, polacrilin potassium (Amberlite® IRP 88) and substituted hydroxypropyl cellulose. Such disintegrants, alone or in combination, can be advantageously used in dosage forms in order to allow them to disperse rapidly when placed in an aqueous environment. The disintegrant or disintegrant mixture is generally used in a concentration of between 6 and 15% by weight of the percentage, based on the dosage form. However, 7-11% by weight and more preferably 8.5-9.5% by weight is preferably used. The granular form of the water soluble active ingredient to be used in the compositions can be obtained according to the process, as described above. However, in case of very unpleasant compounds it may be useful to add a coating film to the granules, which contain the active ingredient soluble in water. This can be done after preparing the granulate as described above, but it is also possible during the granulation process. The polymers that form the film are, for example, cellulose derivatives and polymer based on acrylic acid. Due to the solubility characteristics of the agents forming the commercially available film just mentioned, usually no aqueous liquid can be used as the solvent. Advantageous results have been obtained with granulates prepared by the wet granulation technique, using an alcoholic solution of polyacrylates forming the film such as Eudragit® E100. By applying an aqueous dispersion of the film-forming polyacrylates such as Eudragit® E30D and RL30D, the film coating and granulation processes can be combined. The concentration of the agent forming the film in the dosage form can be up to 5% by weight. The granulates can be prepared with aqueous solutions containing up to 5% by weight but preferably up to 0.5% by weight, the percentage based on the dosage form, of the cellulose derivatives forming the film such as, hydroxyethyl cellulose, cellulose hydroxypropyl, hydroxypropylmethyl cellulose and sodium carboxymethyl cellulose. The active ingredient in granular form, obtained according to any of the methods described above, should have the same characteristics with respect to particle size and flow properties, as the granulates prepared by the process, using an aqueous solution that does not contain substantial amounts of the wet granulation binder. The dosage forms according to the present invention are very versatile since they can be used for the preparation of capsules, tablets, sachet presentations, etc. of disintegration and / or rapidly dispersible. The bioavailability of the active ingredient from the dosage form when dispersed in water before administering or digesting it as such, is similar. As already mentioned, the taste of the active ingredients can be masked relatively easily by means of a careful selection of flavors and sweetening agents. The polyhydroxy compounds or sugars are no longer required. Although the above invention has been described in some detail by way of illustration and example for the purposes of clarity and understanding, it will be readily apparent to those of ordinary skill in the art in light of the teachings of this invention, that certain changes and modifications may be made thereto without departing from the spirit and scope of the appended claims. The following examples further illustrate the invention. EXAMPLES Examples 1-7 The amount of 400-800 g of the water-soluble compound, as mentioned in Table 1, was granulated at room temperature with water, as specified in Table 1, for 20 minutes in a planetary mixer ( HOBART). Then, the wet mass was screened through at least one screen 2.0 mm (2.0-4.0 mm). Subsequently, the granulate is dried in a fluid bed dehydrator (RETSCH) for 30-45 minutes at a suction air temperature of 45 ° C. Then, the dried product was sieved in an oscillating granulator (FREWITT or ERWEKA), equipped with a 1.0 or 1.25 mm screen. Examples 8-10 The amount of 800 g of the water-soluble compound, as mentioned in Table 2, was granulated at room temperature with an aqueous granulation liquid containing 10% ethanol, as specified in the table. 2, according to the method described in examples 1-7. Examples 11-13 The amount of 800 g of a water-soluble compound, as mentioned in table 3, and 133.3 g of microcrystalline cellulose was granulated with water, as specified in table 3, during the period, shown in same table, in a planetary mixer (HOBART). After spraying the wet mass, the granulate is subsequently dried in a fluid bed dehydrator (RETSCH) for 30 minutes at a suction air temperature of 45 ° C. Finally, the dry product was sieved in an oscillating granulator (FREWITT or ERWEKA), equipped with a 1.25 mm screen. Examples 14-19 Phenoxymethylpenicillin potassium optionally mixed with microcrystalline cellulose (see table 4) was granulated with water (see table 4) at room temperature for 20 minutes in a planetary mixer (HOBART). Then, the wet mass was screened through a 2.0 mm screen. Subsequently, the granulate was dried in a fluid bed dehydrator (RETSCH) for 35 minutes at a suction air temperature of 45 ° C. Then, the dried product was screened in an oscillating granulator (FRE ITT), equipped with a 1.25 mm screen. Examples 20-25 800 g of ferrous gluconate, thiamine hydrochloride or ascorbic acid, mixed with an amount of microcrystalline cellulose, as shown in tables 5, 6 and 7, respectively, were granulated with an amount of water, as specified in the same tables, according to the method described in examples 11-13. EXAMPLE 26 The granules obtained according to examples 1-25 were mixed with the excipients according to the formula below in a mixer (TURBULA), and compressed into tablets using a round 14 mm flat bevel tool. The tablets had an average weight of about 900 mg and had the properties, which are shown in Tables 1-7: water-soluble compound 400 mg microcrystalline cellulose 365 mg (total intragranular and extragranular amount) polyvinylpyrrolidone degraded 73 mg silicon dioxide 1 mg magnesium stearate 5 mg flavoring qs Table 1 * based on the weight of the active ingredient Table 2 * based on the weight of the active ingredient Table 3 Table 4 Table 5 Example Amount of Quantity Hardness Time Friability water cellulose disintegration of the tablet microcrystalline tablet tablet (%) (% by weight) * (% by weight) * (sec.) (KP) 20 33.3 26.6 43 8.5 0.10 21 100.0 40.0 53 7.7 0.17 * based on the weight of the active ingredient Table 6 Table 7 Example 27 A granulate, containing ascorbic acid as the active ingredient, was prepared according to the method described in Examples 1-7. From this granulate, tablets having the composition were made, as shown in example 26, except that the microcrystalline cellulose was replaced by microfine cellulose (Elcema G250®). The tablets obtained in this way disintegrated in water in 31 seconds, having a hardness of 6.3 kP and friability of 0.80%. Examples 28-32 A granulate, containing ascorbic acid as the active ingredient, was prepared according to the method described in Examples 1-7. From this granulate, tablets containing the composition were made, as shown in Example 26, except that the degraded polyvinylpyrrolidone was replaced by another disintegrant at various concentrations. The total amount of microcrystalline cellulose and the disintegrant together was the same as in Example 26. The properties of the tablets obtained in this way are shown in the table.

Table 8 * based on the weight of the dosage form. Example 33 200 g of potassium of phenoxymethylpenicillin were granulated with 30 ml of a solution containing 5% soluble starch (Paselli® SA-2) in a planetary mixer for 20 minutes. After screening the wet mass through a 2.0 mm screen and drying the product obtained in this way for 35 minutes in a fluidized bed dehydrator at a suction temperature of 45 ° C, the granulation process was repeated. After drying the product obtained in the second granulation process, the granulate was screened in an oscillation granulator equipped with a 1.0 mm screen. Example 34 4000 g of potassium of phenoxymethylpenicillin were granulated with 550 ml of water in a high speed mixer operated at 200 rpm for periods between 55 and 120 seconds. Then, the wet mass was screened through a 2.0 mm screen. The granulate is dried in a fluidized bed dehydrator at a suction temperature of 45 ° C for 35 minutes. The dried product was screened through a 1.0 mm screen.

Claims (4)

1. NOVELTY OF THE INVENTION Having described the present invention, it is considered as a novelty and therefore the property described in the following claims is claimed as property. 1. A granulate consisting of an active ingredient soluble in water up to 100% by weight inclusive of a cellulose product, such as microcrystalline cellulose and up to 0.5% by weight inclusive of a wet granulation binder, all percentages based on to the weight of the active ingredient. 2. A process for the preparation of the granulate according to claim 1, characterized in that it comprises the steps of: a. moistening the component (s) by making the granulate with an aqueous solution optionally containing the wet granulation binder; b. spray the wet mass through at least a 2 mm screen; c. drying the granulate obtained in step b; d. Screen the dried granulate through at least one 0.71 mm screen. 3. A process according to claim 2, characterized in that 1-40% by weight, preferably
2. 2.5-20% by weight of the aqueous solution is used, the percentage based on the weight of the active ingredient. A composition containing the granulate according to claim 1 or the granulate prepared according to claim 2 or 3, a cellulose product, such as microcrystalline cellulose, a disintegrant and optionally other excipients.