WO2005115346A2

WO2005115346A2 - Pharmaceutical composition containing risperidone

Info

Publication number: WO2005115346A2
Application number: PCT/IS2005/000014
Authority: WO
Inventors: Birkir Arnason
Original assignee: Actavis Group Hf.
Priority date: 2004-05-28
Filing date: 2005-05-30
Publication date: 2005-12-08
Also published as: IS7290A; WO2005115346A3; WO2005115346A9

Abstract

A formulation comprising risperidone as an active ingredient, used for generating a tablet by direct compression is provided and a method of manufacturing such formulations. The formulation is particularly suitable for the manufacture of low dose tablets, e.g. having a dose of risperidone in the range of 0.2-1 mg per tablet.

Description

Pharmaceutical composition containing risperidone

The present invention relates to a novel composition of a pharmaceutical dry blend mixture containing 3-[2-[4-(6-fluoro-l,2-benzisoxazol- 3-yl)-l-piperidinyl]ethyl]- 6,7,8,9-tetrahydro- 2-methyl-4H-pyrido[l ,2-α]pyrimidin- 4-one, herein after referred to as risperidone, which is subsequently used for generating tablets by direct compression and are suitable for containing the active component in low dose tablets.

Background of the Invention Risperidone is a well known antidepressant with the following chemical structure:

Risperidone has been described e.g. in EP0196132B1. The patent discloses series of compounds based on 1,2-benzisoxazol- 3-yl, useful as antipsychotic agents and the preparation of an oral solution, capsules, coated tablets prepared by wet granulation, an injectable solution and suppositories. Risperidone is practically insoluble in water, freely soluble in methylene chloride, and is sparingly soluble in alcohol. It also dissolves in dilute acid solutions.

Risperidone, which is used to treat antipsychotic conditions, is believed to gain its efficacy by antagonizing serotonin and dopamine in the brain. The drug is marketed in several countries, prepared as tablets, as freeze-dried rapid dissolving tablets or in a solution.

The wet granulation technique is not ideal for making tablets containing risperidone, due to the fact that risperidone is practically insoluble in water thus, requiring the use of an organic solvent, which necessitates the use of specially equipped facilities. Furthermore, compared to direct compression, wet granulation is a multi-step process, time consuming and generally more expensive.

Unfortunately, the development of a technique for direct compression is more challenging than for wet granulation. It is more difficult to achieve homogenous mixing of the dry blend composition than when using the wet granulation-technique, in particularly for the preparation of low dosage tablets. Furthermore, segregation or de-mixing and aggregation of components in the dry blend must be avoided to secure the homogeneity of the dry blend. Additionally, the formulation must have all the characteristics of a good free-flow mixture of the dry blend for direct compression, resulting in tablets with acceptable hardness, friability, which exit the dye intact after compression and to be economical in manufacturing. The composition must also be suitable for containing the active ingredient in a wide range of concentrations, importantly, in very low dosage forms. It can be a special challenge to formulate dry blend mixtures suitable for direct compression which provide acceptable content uniformity levels for very low concentrations,! i.e. low dose tablets

Consequently, relatively few compounds are known to possess the collective qualities needed for direct compression — characteristics that are hitherto unknown for risperidone. Therefore, a pharmaceutical composition containing risperidone, suitable for generating tablets using direct compression would be much appreciated.

WO 03/103629 discloses general formulation for orally disintegrating tablets, that is, tablets for peroral administration which disintegrate quickly in the cavity of the mouth. Said tablets contain at least 59,5% spray-dried mannitol and 10-18% microcrystalline cellulose. Exemplified formulations include 1 mg risperidone tablets.

However, for many patient groups and geographic markets, conventional tablets, i.e. not orally disintegrating, are preferred, both in cases of higher patient approval and due to practical advantages such as less need for taste-masking, many possibilities to coat tablets, generally more resistance to humidity and atmosphere, and the like. Object of the invention It has now surprisingly been found, that tablets containing risperidone can be generated with a formulation suitable for direct compression in accordance with the present invention. Risperidone tablets of the present invention fulfill product requirements of content uniformity and other quality criteria, e.g., with respect to hardness and friability and are economical in manufacturing. Advantageously, tablets with very low doses, e.g. in the range of 0,1-1 mg per tablet can be produced, which have excellent content uniformity. The formulations of the present invention are particularly suitable for conventional tablet forms, i.e. tablets intended for swallowing that do not dissolve rapidly in the oral cavity.

An objective of the invention is to develop a homogenous mixture of the dry blend, containing risperidone. Additionally, a further objective is to develop a dry blend mixture containing risperidone, with good free flow properties.

A further objective is to generate tablets by direct compression, from said dry blend mixture containing risperidone.

Importantly, an objective is to generate tablets by direct compression containing risperidone in very low concentration

Brief description of Figures Figure 1 shows drug release profiles (% dissolution as a function of time) of risperidone 4 mg tablets, generated by different crushing strength (see Example 6). Dissolution tested with standard basket test in 500 mL 0.01 HC1 at 50 rpm.

Summary of the Invention The present invention describes a dry blend formulation containing risperidone, which is subsequently used for direct compression tablets, in the range of about 0.2 to 10 mg risperidone per tablet. Surprisingly, the formulation is suitable for the provision of tablets containing the drug in very low concentration, such as in the range of about 0.2 to 2.5 mg risperidone per tablet, including the range of 0.2 to 1 mg per tablets, such as tablets containing 0.20 mg, 0.25 mg, 0.4 mg, 0.5 mg, 0.6 mg or 0.75 mg risperidone. The formulation in the current invention, provides a method for generating tablets wherein the content uniformity is low, preferably the relative standard deviation (RSD) of the content uniformity of the tablets is less than 20%, more preferably less than 10%, e.g. about 6% or less. More preferably the RSD of the content uniformity of the tablets is less than 5%, such as less than about 4% or less than about 3%.

As illustrated in the accompanying Examples, tablets with as little as 0.25 mg risperidone active ingredient have been formulated and manufactured by direct compression in accordance with the present invention. It has been found that one important premise of the invention is to provide risperidone with a suitable particle size. The risperidone material should have a particle size such that at least 90% of the particles have a particle size less than 150 μm_? preferably 90% of the particles are less than 110 μm, more preferably 90% of the particle are less than 100 μm, or 90% of the particle are less than 90 μm, even more preferably 90% of the particles are less than 75 μm, yet more preferably 90% of the particle are less than 60 μm, or 90% of the particle are less than 50 μm, or more preferably 90% of the particle are less than 40 μm.

The particle size distribution can be measured b,y any of the conventional means well known in the art.

In the following examples and claims that follow, references are made to several terms, which are defined to have the following meaning.

The term "risperidone" as used herein, includes all crystalline and amorphous forms, isomorphs, clathrates, salts, solvates and hydrates and non-hydrate forms of risperidone, unless specifically stated.

The term "dry blend" is used herein meaning a generally homogenous mixture of two or more particle materials in a dry powder form. The term "compression" means a method wherein the formulation can be compacted into a pharmaceutically acceptable tablet or core, wherein air is removed from the formulation. The term "free flowing" means the ability of the dry blend to flow without a mechanical agitation on standard tabletting equipment.

A selection of fillers can be employed in the preparation of the invention, to ensure that the tablet remains intact after compression. In a preferred embodiment the filler material comprises microcrystalline cellulose which has, besides its function as a filler, some lubricant and disintegrant properties which make it useful in tabletting. It furthermore, positively influences the resistance to crushing and friability of the tablets. A well known group of fillers are mineral salts, which may be used in the composition of the invention. These include, but are not limited to, e.g. calcium carbonates, magnesium carbonate, calcium sulfate dehydrate and calcium phosphates. Starches, including but not limited to pregelatinized starch, are also frequently used as i fillers in formulation of tablets. Pregelatinized starch is a preferred filler according to the present invention.

Sugars and polyols comprise the most diverse group of fillers, with lactose as one of the most widely used filler which is also known to be useful in immediate release tablets. The manufacturing of a tablet with dirpct compression usually requires the use of a direct compression grade of anhydrous lactose. Also belonging to this group are e.g. glucose, mannose, fructose and maltose. Dextrates are free flowing polysaccharides, which encompass, but are not limited to, e.g. dextrose, dextrin and maltodextrin. Also commonly used fillers include polyols such as, but not limited to, sorbitol, mannitol, xylitol and lactitol. Other well known fillers include, but are not limited to, e.g. gelatin, polyethylene glycol, waxes, natural and synthetic gums, polyvinylpyrrolidone, cellulosic polymers (e.g. hydroxypropyl cellulose (HPC) and hydroxypropyl methylcellulose (HPMC)). A combination of any of the above mentioned substances may as well be used as a filler in accordance with the present invention.

Disintegrants are used to facilitate disintegration of the medicament after administration. Disintegrants can also affect the bioavailability of the active compound. Suitable disintegrants include, bu^are not limited to, crosslinked 1 polyvinylpyrrolidone, sodium starch glycolate, calcium and sodium carboxymethylcellulose, pregelatinized starch and croscarmellulose sodium.

Lubricants are used to improve the flow properties of powders and prevent adhesion of the dry blend to the tooling equipment. Lubricants can be either water-soluble or insoluble. Depending on the concentration of the lubricant it may therefore have direct influence on the solubility of the active material and other excipients. Suitable lubricant include, but are not limited to, magnesium stearate, zinc stearate, sodium stearate, corn starch, talc, fatty acid esters, hydrogenated vegetable oil, sodium laurylsulfate, polyethylene glycols (PEG), sodium stearyl fumarate, sodium benzoate, leucine and glycine.

Suitable excipients for the formulation according to the present invention may be readily selected by the skilled person from any of the above mentioned fillers, disintegrants and lubricants. • '

It is beneficial for the invention that major excipients have a suitable particle size to ensure sufficient homogeneity and uniformity¹ of the dry blend. Preferably the major excipients, in particular substances used as filler and preferably also substances used as disintegants and/or other components have a particle size substantially within the range of about 25-250 μm, e.g. such that at least 90% of the particles of a substance have a particle size less than 200 μm, or more preferably that 90% of the particles of a substance are less than 150 μm. In useful embodiment, anhydrous lactose is used as filler, wherein at least 86% of the particles have a particle size less than 250 μm. When pre-gelatinised starch is used, the material has a particle size such as described above. In one embodiment, pre- gelatinised starch is used having a particle size such that at least 98% of the particles have a particle size of 100 mesh or less which is equivalent to 150 μm or less.

Surprisingly and very advantageously, it is found that the present invention provides very good content uniformity with respect to the active ingredient, even with very low dose tablets, including the above mentioned dosages. Preferably, the content uniformity is less then about 7,5%, more preferably less than about 5% and more preferably less than about 4% and yet more preferably less than about 3%, such as less than about 2%. Content uniformity in the case of low dose tablets is determined as the extent of drug (active principle) content uniformity. The USP test, as an example, can be suitably used to determine the homogeneity of a batch. Ten tablets are assayed individually, after which the arithmetic mean and relative standard deviation (RSD) are calculated. The USP criteria are met if the content uniformity lies within 85-115% of the label claim, and the RSD is not greater than 6%.

As illustrated in Example 7 herein, 0,25 mg tablets formulated in accordance with the present invention with a 10 min blending timejhad a content uniformity within 92,5% and 99,6% and the %RSD was 2,3% from the mean content. Even better uniformity is obtained with longer (12 or 14 min) blending times.

The tablets of the present invention preferably, have a %RSD deviation in the active principle content of less than 5%, more preferably less than 4%, yet more preferably less than 3% and more preferably less than 2% and even more preferably less than 1,5%, for tablet doses such as the above mentioned, or even smaller than 0,25 mg.

In useful embodiments of the invention, the tablets are coated, e.g. by sugar coating or more preferably by film coating. A number of substances may be used for film coating the tablets of the invention, including methyl cellulose, ethyl cellulose and hydroxymethyl cellulose based coatings as well as methyl hydroxyl ethyl cellulose, hydroxylpropyl cellulose and hydroxypropyl methyl cellulose (e.g. Methocel (Dow)) based coatings and coatings based on polymers of methacrylic acids and its esters (e.g. Eudragit systems (Pharm Rohma). Such coatings allow distinctive coloring and may enhance the stability of the tablets.

The present invention will be further illustrated by means of the following examples. It is however to be understood that the invention is not meant to be limited to the following examples.

Example 1. The particle size of risperidone powder used in subsequent tabletting was analyzed in a Malvern laser instrument. The following results were observed: of risperidone

The results show that the active ingredient has at least 90% of the particles smaller than 42 μm in size and 50% are under 16 μm in size.

Example 2.

The following example results in 300,000 compressed tablets containing 0.25 mg of risperidone, from a total of 27 kg of dry blend.' The active ingredient which is from the same production as the material measured in Example 1 has a specified particle size such that 90% of the particles are less than 50 μm in size.

Step 1:

Blend and then sieve through 0.5 mm sieve (to remove any coarse, coagulated starch): Risperidone 75 g Starch, pregelatinised 1500 g Step 2: Sieve through 0.5 mm sieve and blend with the powder mixture from step 1 : Cellulose, microcrystalline 2650 g

Step 3: Sieve through 0.8 mm sieve and blend with the powder mixture from step 2: Lactose, anhydrous 18580 g Starch, pregelatinised 4050 g

Step 4: Sieve through 0.8 mm sieve and blend with the powder mixture from step 3: Magnesium stearate 145 g

Step 5: Compress the mixture obtained from step 5 using a rotary tabletting machine and the following conditions: Description of punches : diameter of 6 mm, concave Tablet mass : 90 mg ± 5% Crashing strength target: 40 N Set the tablet weight at 90 mg and the machine at the rate specified in the manufacturing instructions. Dedust tablets after compression.

Table 2. Formulation of tablets containing 0.25 mg of risperidone

Example 3.

To test for the effect of disintegrant, in combination with other excipients, the following experiment was performed. Table 3. Formulation of tablets containing 4 mg of risperidone

Risperidone as in Example 1 was sieved through a 106 μm sieve in order to remove any coagulated particles and mixed with half of the lactose. Starch and cellulose was added and then sodium laurylsulfate and the rest of the lactose. Then, magnesium stearate was added and mixed. The flowability of the powder mixture was good. Quantity of magnesium stearate (0.56%) was suitable to overcome stress in dies. Tablets, 10 mm in diameter, were compressed with crushing strength of 75 N. The content uniformity of a mixed tablet sample, collected during the compression process, revealed relative standard deviations of ~5%. All other tablet characteristics were satisfactory.

Example 4.

To attempt to improve the content uniformity of the tablets, the following experiment was done.

Table 4. Formulation of tablets containing 4 mg of risperidone

Risperidone as in Example 1 was sieved through a 75 μm sieve and mixed with the starch, lactose and cellulose, microcrystalline. Then, magnesium stearate was added and mixed. The flowability of the powder mixture was good. The results of the content uniformity of a mixed tablet sample, was acceptable and all other tablet characteristics were satisfactory.

Example 5. To test if the formulation was suitable for generating tablets containing risperidone in higher concentration, the following composition was done. Risperidone was sieved through 75 μm sieve, and blending was done as in example 1. The flowability of the powder mixture was good. The results of the content uniformity of a mixed tablet sample, was acceptable and all other tablet characteristics were satisfactory.

of risperidone

Example 6.

To test for effect of different crashing strength on disintegration and dissolution of the tablets, similar in composition as in example 3, was tested.

Table 6. Composition of tablets to be tested for the effect of various crushing strength on disintegration and dissolution containing 4 mg of risperidone

Blending was done in same manner as in example 3, and 10 mm tablets were compressed with three different crashing strength targets. All crashing strength targets could easily be reached without any problems. As expected, disintegration time increased when crashing strength was increased, but all disintegrated within specified disintegration limit (<15 min.).

Table 7. Summary of crushing strength and disintegration

Effect on the dissolution profile of the tablets was subsequently investigated. The result from the dissolution study (Figure 1) showed that the dissolution profiles for all crushing strength targets tested are within the specified limits (>75% after 30 min.).

In conclusion, this shows that the direct compression of the formulation results in acceptable characteristics of both the disintegration and dissolution.

Example 7. Because of the low dosing of risperidone tablets an internal process specification was set for the content uniformity of the mixture. The mixture complies if each single result often samples is between 92.5% and 107.5% of the average content. It fails if outside of these limits or if one single result is, outside the limits of 85% to 115%. The samples were taken with a sample thief, from two independent preparations. Total of ten samples were taken from location points of a small radius, large radius and of the centre of the blender.

Claims

11. The tablet of claim 9 or 10 comprising in the range of about 0.25 to 8 mg risperidone.

12. The tablet of claim 11 comprising in the range of about 0.25 to 2.5 mg risperidone.

13. The tablet of claim 12 comprising in the range of about 0.25 to 1 mg risperidone 14. The tablet of any of claims 8-13 prepared with a crushing strength in the range of about 25-170 N.

15. The tablet of claim 14 prepared with a crushing strength in the range of about 30-140 N. > i 16. The tablet of any of claims 8 to 15 comprising anhydrous lactose as a filler, microcrystalline cellulose as filler, pre-gelatinized starch as disintegrant, and magnesium stearate as lubricant. ι i 17. The tablet of claim 16 comprising: a. in the range of 0,2-2 wt% risperidone i b. in the range of 40-80 wt% anhydrous lactose, c. in the range of 5-20 wt% micrqcrystalline cellulose, d. in the range of 10-30 wt% pregelatinized starch, and e. in the range of 0,2-2 wt% magnesium stearate.

18. The tablet of claim 17 comprising about 68 wt% anhydrous lactose, about 10 wt% microcrystalline cellulose, about 20 w% pregelatinized starch, and about 2 wt% magnesium stearate.

19. A method of making risperidone tablets comprising mixing a suitable amount of risperidone in dry powder form having a particle size less than 150μm with a filler substance, a disintegrant substance and a lubricant substance and optionally one or more further excipients, sieving the mixture one or more times, after addition of one or more of said excipients, compressing the dry mixture to tablets of a suitable size such that each tablet comprises a suitable dose of risperidone in the range of about 0,25-8 mg per tablet. 20. The method of claim 19, wherein the filler substance is selected from cellulose and anhydrous lactose or a combination tjhereof.

21. The method of claim 19 or 20 wherein tide disintegrant comprises pregelatinized starch.

22. The method of any of claims 19-21 wherjsin the lubricant comprises magnesium stearate.

23. The method of any of claims 19-22 whereiinn at least 90% of the risperidone particles have a particle size of less than 110 μm.

24. The method of claim 23 wherein at least 90% of the risperidone particles have a particle size of less than 60 μm.

25. The method of any of claims 19-24 wher reeiin: each tablet comprises a dose of risperidone in the range of 0.25-2.5 mg.

26. The method of claim 25 wherein each tablet comprises a dose of risperidone in the range of 0.25-1.0 mg.