MXPA98000809A

MXPA98000809A - Procedure to prepare forms of solid doses of very low dose of farm

Info

Publication number: MXPA98000809A
Application number: MXPA/A/1998/000809A
Authority: MX
Inventors: Sidney George Clark Michael; Albert Napper James; Mortimer Neil; Triona O Brien Karen; James Manek Sultan; Kumar Rajinder; Mary Loudon Julia
Original assignee: Smithkline Beecham Plc
Priority date: 1995-07-29
Filing date: 1998-01-28
Publication date: 1998-04-01

Abstract

A method of formulation comprising mixing vehicle particles with a drug solution in water in an amount of 1-3% by weight of solution to total mixture and a method of treatment and / or prophylaxis of dementia, which method comprises administering to the [R- (Z)] - alpha- (methoxyimino) -alpha- (1-azabicyclo [2.2.2] oct-3-yl) acetonitrile monohydrochloride patient at a daily dose lower than 0.01 mg / kg and pharmaceutical compositions used in the present

Description

PROCEDURE FOR PREPARING FORMS OF SOLID DOSES OF VERY LOW DOSES OF THE DRUG DESCRIPTIVE MEMORY This invention relates to a method for formulating solid dose forms of drugs and solid dosage forms produced thereby, in particular solid dose forms containing low dose of drug. The invention also relates to a method for the treatment and / or prophylaxis of dementia and unit dosage forms useful herein. The common challenge in the manufacture of solid dose forms of drugs of very low dose, for example, with active doses of about 5-125 micrograms (μg) (eg, 0.004-0.1% by weight of drug to total solid) , is to ensure homogeneity. The technical problem is how to distribute the substance of the drug evenly among the large amount of excipient particles. The simplest way to make tablets is to simply mix all the ingredients like dry powders and make them tablet ("direct compression"). This is rarely successful for low-dose drugs; A common problem is the segregation of the powder mixture during tablet formation. A variation of this method that has been successful for low dose drugs is known as "titration," and is sometimes referred to as "orderly mixing" or "interactive mixing." First, very fine particles of the drug are mixed with a small portion of excipient; then the product is mixed with a slightly larger portion of excipient and so on until the desired mixture is obtained. This method depends on the fine particles of the drug that adhere electrostatically to large particles of the excipient, thus preventing segregation. The method works with some drugs, but success depends on the surface properties of both the drug and the excipient, and the method is very laborious. EP0503521 describes the application of this method to steroid drugs with high binding affinity and low non-mixing potential for certain excipients. A preferred alternative method for formulating low dose drugs is known as "wet granulation". The drug is dissolved in water or another solvent, and mixed with excipients including a binder, for example, povidone, to form a moist mass containing 5-20% by weight of solution to total weight of granulation mixture, which is dry later in a separate step. The binder causes the particles of the excipient to kneade together, and as the dry mass these lumps ("granules"), contain or coat with the drug. This is effective but difficult to handle, since the drying step requires special equipment, and usually involves high temperatures that can degrade labile drugs. Also, the use of the binder requires the additional inclusion of a disintegrant such as sodium starch glycolate or starch to help the tablet, which is cohesive, to disperse in the mouth. Fluid-bed granulation has been used to achieve uniformity of the low-dose tablet content (lμg-lOmg) (Thiel et al, J. Pharm Pharmacol 1986, 335-343). In this process, the micronized drug is mixed as a powder with other excipients, then loaded into a fluid bed granulator, and the powders are agglomerated by spraying in a solution of a binder; drying occurs concomitantly. The process does not require a separate drying step, but requires the use of micronized drug, and also incorporates a separate mixing step prior to granulation. It also requires specialized equipment and precise optimization of the parameters of the procedure. Another method for formulating low dose drugs is known as vehicle granulation (Michoel et al., Pharmaceutical Technology, June 1988, 66-84). This works by spraying a binder solution such as povidone in water into relatively large excipient particles such as hydrated lactose and then by spraying small particles of dry drug substance., thus coating the excipient with drug particles sticking thereto by the binder. The amount of solution used was 3.3-3.5% by weight of solution to the total granulation mixture. The method was applied to a formulation containing 4-5% drug by weight. This method also requires drying, the particle size of the drug needs to be very small, which often requires an additional grinding step and the very fine powder of the drug may not flow very well; and the formula still requires a disintegrant. Dahl et al., Drug Development and Industrial Pharmacy 1990, 16 (12), 1881-1891, describes the preparation of solid capsule formulations using a liquid drug sprayer vehicle. The model drug is dissolved in a non-volatile solvent, propylene carbonate, and sprayed in a compressible sugar at a loading of about 0.01% by weight of drug to total solid, to give a final unit dose of 35μg. The solvent, being non-volatile, remains in the mixture. About 5% by weight of the total formulation is added; lower solvent to solid ratios resulted in reduced ability to disintegrate and dissolve. The resulting dust, somehow sticky, showed some difficulties in automatic encapsulation machines, and would probably give significant problems for tablet formation. Yal Owski (US 4,489,026) describes a process involving very slow spraying of a dilute solution of drug in a volatile inert solvent, preferably an organic solvent having a boiling point lower than 80 ° C, in the excipient powder in an open liner tray; a continuous flow of dry air the product during the sprinkling process. This procedure was applied to drugs with a unit dose of 10 μg or less. The spray speed is limited to l-10ml / min, making the procedure suitable only for very small load sizes (the aforementioned example prepared 1000 tablets). The weight ratio of solution to vehicle used was 15%; Also, the use of volatile organic liquids is now considered a significant hazard, requiring solvent recovery procedures and explosion-proof equipment. Katdare (US 4,989,736) describes a simplified version of this procedure, suitable for unit doses of 50-1000μg; the drug, dissolved in an easily evaporated solvent such as ethanol, methanol, acetone or rahydrofuran tet, is simply mixed with excipients in a ratio of 2.26% or 6.75% and then dried, followed by lubrication and tablet formation. This procedure is suitable in principle for commercial scale manufacturing, but still does not have the problems associated with the use of volatile organic solvents. In accordance with the present invention, there is provided a method of drug formulation comprising mixing vehicle particles with a drug solution in water in an amount of 1-3% by weight of solution to total mixture. The resulting mixture can be formulated into a suitable unit dose presentation, for example, by the tablet formation and optionally film coating of the tablets or by encapsulation. It may be convenient to do the initial mixture of drug / vehicle with a higher drug concentration, and then in a separate step mix this with additional vehicle, and this may be particularly useful where a tablet resistance scale is required. The separate mixing step aids drying by the dilution effect, ie the waste water is distributed through a larger amount of vehicle powder, and by the longer mixing time. Dilution is conveniently on the scale of 4/1 to 40/1 vehicle / concentrate by weight, depending on the processing characteristics of the vehicle. A convenient dilution ratio for lactose monohydrate is 10/1. Where the dilution step is not employed, the weight ratio of solution / mixture is more preferably up to 2% by weight. The optimum amount of solution will depend on the absorbing qualities of the vehicle particles, the solubility of the drug and the characteristics of the mixing device, the amount of solution chosen to allow even distribution of drug at the same time avoiding the need for a Hot drying step. The mixing step is preferably carried out in a high shear mixer. The vehicle can be any pharmaceutically acceptable excipientdirectly compressible, soluble, suitable such as anhydrous lactose, lactose monohydrate, mannitol, or a pharmaceutically acceptable, directly compressible, insoluble excipient such as microcrystalline cellulose or dicalcium phosphate, preferably a soluble excipient. Any drug having a sufficient degree of water solubility can be formulated by the process of the invention. The concentration of drug in the solution depends on the unit dose of drug required, the upper limit being dependent on the solubility of the drug. During mixing, the carrier particles are coated evenly with a very thin film of drug solution. Some of the water dries naturally during mixing, since there is usually a small air flow through the mixer; the remaining amount is so low that drying is not specifically required. If the tablets are coated with film, an additional degree of drying can be obtained during the coating process. The process of the invention has a number of advantages: it does not require grinding of the drug substance - a drying step is not needed. This simplifies processing and reduces production costs; Heat-labile drugs do not suffer at the temperature required for drying; for drugs that are highly potent, the omission of the drying step makes it easier to contain dust, improving safety for the factory worker - the use of volatile organic solvents is avoided - no need to add a binder - no need to add a disintegrant when the excipient is a highly soluble one. Optional additives in the final mixture include a disintegrant; a variety of acidic or alkaline excipients to improve the chemical stability of the drug in the formulation such as sodium dihydrogen citrate, preferably included in the initial mixture; a lubricant such as magnesium stearate; and a slip agent such as colloid silica. The present invention further provides a pharmaceutical composition comprising a drug formulated in accordance with the method of the invention and the use of said composition as an active therapeutic substance. The invention further provides a pharmaceutical composition comprising a drug, which can be obtained by the process of the invention and the use of said composition as an active therapeutic substance. The process of the invention is particularly useful for formulating [- (Z)] - a- (methoxyimino) -a- (l-azabicyclo [2.2.2] oct-3-yl) acetonitrile monohydrochloride (compound X) with active doses of about 5-125 micrograms (μg). Compound X and methods for its preparation are described in EP-A-0392803, W095 / 31456 and W093 / 17018. The compound improves the function of acetylcholine by means of an action on muscarinic receptors within the central nervous system, and therefore is of potential use in the treatment and / or prophylaxis of dementia in mammals. In particular, the invention provides a pharmaceutical composition comprising a pharmaceutically acceptable carrier and compound X at a level of up to 0.1% by weight of drug to vehicle, 0% of volatile organic solvent and 0% of binder. EP-A-0392803 suggests the appropriate daily dose for compound X and other compounds described therein as 0.01-5mg / kg. Surprisingly, it has been discovered through administration to human patients that efficacy as a cognition enhancer can be obtained at lower daily doses of O.Olmg / kg, more in particular 0.003mg / kg and less, for example, 0.0001- 0.003mg / kg, such as 0.00035-0.003mg / kg, 0.0007-0.003mg / kg, 0.0001-0.0007mg / kg or 0.00035-0.002mg / kg. Accordingly, the present invention provides a method of treatment and / or prophylaxis of dementia, and more particularly a method of improving cognition in a patient, which method comprises administering compound X to the patient at a lower daily dose of O. Olmg / kg, more preferable 0.003mg / kg or less. The invention also relates to the use of compound X in the manufacture of a medicament for the treatment and / or prophylaxis of dementia at a lower daily dose of O.Olmg / kg, more preferably of 0.003mg / kg or less. The invention further relates to a pharmaceutical composition for the treatment and / or prophylaxis of dementia which comprises compound X at a unit dose suitable for administration at a lower daily dose of O.Olmg / kg, more preferably 0.003mg / kg or less, and a pharmaceutically acceptable vehicle. The appropriate unit doses to achieve these daily doses are 5, 12.5, 25, 50 or 75μg, administered twice a day and, in the case of 50μg, once a day. The invention extends to the method, use or composition defined above wherein compound X is provided in said unit doses. The invention further provides a pharmaceutical composition comprising the compound X of the invention and / or formulated in accordance with the process of the invention, in the form of a unit dose selected from the scale of 5-125μg per unit dose, such as 5, 12.5, 25, 50 or 75μg per unit dose and the use of said composition as an active therapeutic substance, in particular in the treatment and / or prophylaxis of dementia.

EXAMPLE FORMULATION OF COMPOUND X To make lOOg of mixture for tablet formation or encapsulation, at lOOug of drug per 150mg of excipient: - dissolve 67g of drug in 1 liter of water (i.e., 1% water (1067% solution) on a weight) - slowly add this to 100kg of a "direct compression" grade of lactose monohydrate in a high shear mixer-granulator - mix with 0.25kg of lubricant (Magnesium Stearate) and 0.15kg of Sliding Agent (Colloidal Silica) - tablet - film coating (optional) To make 100kg of mixture for the tablet formation or encapsulation, to lOOug of drug per 150mg of excipient, by means of a concentrate: - dissolve 67g of drug in 0.1 liter of water - add slowly this to 9.8kg of a grade of "Direct compression" of lactose monohydrate and 0.2kg of acidifying agent (Sodium Dihydrogen Citrate) in a high-shear ezclador-granulator, followed by another 0.1 liter of water to rinse the used containers, at the same time mixing vigorously with a crumbling speed of about 1500 rpm and then raising the speed to about 3000 rpm, during 10-20 minutes of total mixing time (i.e., a total of 2% water (2.67% solution) is added over a base in weight with respect to the amount of concentrate) - sift the resulting concentrate in a drum mixer - mix with 88kg of additional lactose and 1.8kg of Sodium Dihydrogen Citrate, then mix in 0.15kg of Sliding Agent (Colloidal Silica ) and 0.25kg of lubricant (Magnesium Stearate) - tablet - film coating (optional) To make unit doses of 75, 50, 25, 12.5 and 5μg in 150mg of excipient, the amount of rmaco used in the above methods is 50, 33.6, 16.8, 8.4 and 3.3g respectively.

Claims

NOVELTY OF THE INVENTION CLAIMS

1. - A process for preparing a drug formulation comprising mixing vehicle particles with a drug solution in water in an amount of 1-3% solution to total mixture.

2. A method according to claim 1, further characterized in that the vehicle is a pharmaceutically acceptable excipient, directly compressible, soluble or an insoluble.

3. A method according to claim 2, further characterized in that the vehicle is a soluble excipient selected from anhydrous lactose, lactose monohydrate and mannitol.

4. A process according to claim 3, further characterized in that the mixture comprises an acid or alkaline excipient to improve the chemical stability of the drug in the formulation.

5. A method according to any preceding claim, further characterized in that it comprises mixing the mixture with additional vehicle and / or one or more additives selected from a disintegrant; an acid or alkaline excipient to improve the chemical stability of the drug in the formulation, a lubricant and a slip agent.

6. - A method according to claim 5, further characterized in that the mixture is mixed with additional vehicle in a weight ratio of 1/4 to 1/40.

7. A method according to any preceding claim, further characterized in that the mixture is formulated in a unit dose presentation.

8. A method according to any preceding claim, further characterized in that the drug is [R- (Z)] -oc- (methoxyimino) -a- (l-azabicicio [2.2.2] oct-3-yl monohydrochloride. Acetonitrile.

9. A pharmaceutical composition comprising a drug, which can be obtained by the method according to any preceding claim.

10. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and [R- (Z)] - a- (methoxyimino) -a- (l-azabicyclo [2.2.2] oct-3-yl) acetonitrile monohydrochloride at a up to 0.1% by weight of drug to vehicle, 0% of volatile organic solvent and 0% of binder.

11. A composition according to claim 10, further characterized in that the vehicle is a pharmaceutically acceptable excipient, directly compressible, soluble or insoluble.

12. A composition according to claim 11, further characterized in that the vehicle is a soluble excipient selected from anhydrous lactose, lactose monohydrate and mannitol.

13. A composition according to any of claims 10 to 12, further characterized in that it also comprises one or more additives selected from a disintegrant; an acidic excipient to improve the chemical stability of the drug in the formulation, a lubricant and a slip agent.

14. A composition according to claim 13, further characterized in that it comprises lactose monohydrate, sodium dihydrogen citrate, colloid silica and magnesium stearate.

15. A composition according to any of claims 10 to 14, further characterized in that it is formulated in a unit dose presentation.

16. The use of [R- (Z)] - a- (methoxyimino) - - (l-azabicyclo [2.2.2] oct-3-yl) acetonitrile monohydrochloride in the manufacture of a medicament for the treatment and / or dementia prophylaxis, by administering the medicament to provide a lower daily dose of O.Olmg / kg.

17. A pharmaceutical composition for the treatment and / or prophylaxis of dementia comprising monohydrochloride of [R- (Z)] - a- (methoxy i) -oc- (l-azabicyclo [2.2.2] oct-3-) il) acetonitrile at a suitable unit dose for administration at a lower daily dose of O.Olmg / kg, and a pharmaceutically acceptable carrier.

18. A method, use or composition according to claim 16 or 17, further characterized in that the daily dose is 0.003mg / kg or less.

19. A method, use or composition according to claim 18, further characterized in that the daily dose is 0.0001-0.003mg / kg.

20. A method, use or composition according to claim 19, further characterized in that the daily dose is 0.00035-0.003mg / kg.

21. A method, use or composition according to claim 19, further characterized in that the daily dose is 0.0007-0.003mg / kg.

22. A method, use or composition according to claim 19, further characterized in that the daily dose is 0.0001-0.0007mg / kg.

23. A method, use or composition according to claim 19, further characterized in that the daily dose is 0.00035-0.002mg / kg.

24. A method, use or composition according to claim 16 or 17, further characterized in that the compound is presented in a unit dose of 5, 12.5, 25, 50 or 75μg, administered twice a day, or in the case of 50μg, once a day.

25. A pharmaceutical composition according to claim 9 dependent on claim 8 or according to any of claims 10 to 15, further characterized in that it is in the unit dose form selected from the scale of 5-125μg per dose unitary

26. A pharmaceutical composition according to claim 25, further characterized in that it comprises 5, 12.5, 25, 50 or 75 μg per unit dose.

27. The use of a pharmaceutical composition according to claim 9, according to any of claims 10 to 15 or according to claim 25 or 26, further characterized as an active therapeutic substance in the preparation of a drug for the treatment and / or prophylaxis of dementia.

28. The use of a pharmaceutical composition according to claim 9 dependent on claim 8, further characterized in the preparation of a medicament for use in the treatment and / or prophylaxis of dementia.

29. Use of a pharmaceutical composition according to claim 28, further characterized in the manufacture of a medicament for the treatment and / or prophylaxis of dementia.