KR19990035972A - Process for the preparation of solid dosage forms of trace amounts of drug - Google Patents

Abstract

Drug formulation method and [R- (Z)]-α- (methoxyimino) -α comprising mixing the carrier particles with the drug solution in water in an amount of 1 to 3% by weight relative to the total mixture Treating and / or treating dementia comprising administering (1-azabicyclo [2,2,2] oct-3-yl) acetonitrile monohydrochloride to a patient at a daily dosage of less than 0.01 mg / kg. Preventive methods and pharmaceutical compositions used herein.

Description

Process for the preparation of solid dosage forms of trace amounts of drug

The present invention relates to a method of formulating a solid dosage form of a drug and to a solid dosage form prepared thereby, and more particularly to a solid dosage form containing a low dosage drug. The invention also relates to methods of treating and / or preventing dementia and unit dosage forms used therein.

A generally difficult challenge in preparing solid dosage forms with an active dosage of very low dose drugs, for example about 5 to 125 μg (eg 0.004 to 0.1 wt% of the total solids), ensures homogeneity. It is. A technical problem is how to distribute this drug evenly among a large amount of excipient particles.

The simplest way to make tablets is to simply mix all the ingredients as dry powder and tablet them (direct compression). This method is rarely successful with low dose drugs; A common problem is the separation of the powder mixture during tableting. A variation of this method that has been successful for low dose drugs is known as "trituration" and is sometimes called "sequential mixing" or "interactive mixing". Very fine particles of the drug are first mixed with a very small amount of excipient; The product is then continuously mixed with a slightly larger amount of excipient until the desired mixture is obtained. This method relies on the mechanism by which fine drug particles electrostatically attach to larger excipient particles to prevent separation. This method works well for some drugs, but success depends on the surface properties of both the drug and the excipient, which is very difficult. EP0503521 describes the application of this method to steroidal drugs with high binding affinity and low separability for certain excipients.

Another preferred method of formulating low dose drugs is known as "wet granulation." The drug is dissolved in water or another solvent and mixed with an excipient comprising a binder such as povidone, for example, to form a wet mass containing a 5-20% by weight solution relative to the total weight of the granule mixture. This is completely dried in a separate process. The binder causes the excipient particles to aggregate together, and when the mass is dried, these aggregates (“granules”) contain the drug or are coated with the drug. This method is effective but detrimental because the drying step requires special equipment and generally involves high temperatures that can break down unstable drugs. In addition, the use of a binder necessitates the further inclusion of a disintegrant such as sodium starch glycolate or starch in order to help the coherent tablets spread in the stomach.

Fluid bed granulation methods have been used to achieve content uniformity of low dose (1 μg to 10 mg) tablets (Thiel et al., J. Pharm. Pharmacol. 1986, 38, 335-343). In this method, the finely divided drug is mixed with other excipients as a powder, then placed in a fluidized bed granulator, and the powder is continuously sprayed with a binder solution to agglomerate and simultaneously dried. This process does not require a separate drying step, but requires the use of a milled drug and also includes a separate mixing step prior to granulation. This process also requires precise control of special equipment and process parameters.

Another method of formulating low dose drugs is known as carrier granulation (Michael et al., Pharmaceutical Technology June 1988, 66-84). This works by spraying a binder solution such as povidone in water onto relatively large excipient particles such as hydrous lactose and subsequently spraying small, dried drug particles thereon, coating the excipient with drug particles attached by the binder. . The amount of solution used was 3.3 to 3.5% by weight relative to the total granule mixture. This method was applied to formulations containing 4-5% by weight of drug. In addition, this method requires drying; Since drug particles must be very small in size, this often requires a separate milling step and very fine drug powders may not flow well; The formulation still requires a disintegrant.

Dahl et al. Describe the preparation of solid capsule formulations using nebulized liquid drug carriers in Drug Development and Industrial Pharmacy 1990, 16 (12), 1881-1891. The model drug is dissolved in propylene carbonate, a non-volatile solvent, and sprayed onto the compressible sugar at a ratio of about 0.01% by weight of the drug relative to the total solids to bring the final unit dose to 35 μg. This nonvolatile solvent remains in the mixture. It is added at about 5% by weight of the total formulation; Lower solvent to solid ratios reduced the ability to degrade and dissolve. The resulting tacky powder to some extent presents some difficulties in automated encapsulation devices and may present significant problems in tableting.

Yalkowski describes a method comprising spraying a dilute solution of a drug in a volatile inert solvent, preferably an organic solvent having a boiling point below 80 ° C., very slowly onto the excipient powder inside an open coating pan. Patent number 4,489,026; A continuous stream of air dries the product during the spraying process. This method was applied to drugs with unit doses of 10 μg or less. The spray rate was limited to 1-10 ml / min to make this method only suitable for very small batch-sizes (1000 tablets in the example cited). Used solution: carrier weight ratio was 15%; In addition, the use of volatile organic liquids is now considered seriously dangerous, requiring solvent-recovery processes and explosion-safe equipment.

Katdare describes a simplified variant of this method suitable for unit doses of 50 to 1000 μg in US Pat. No. 4,898,736; Drugs dissolved in easily evaporating solvents such as ethanol, methanol, acetone or tetrahydrofuran are simply mixed with excipients at a rate of 2.26% or 6.75%, dried, lubricated and tableted. This method is generally suitable for commercial scale production, but still involves problems associated with the use of volatile organic solvents.

According to the present invention there is provided a drug formulation method comprising mixing the carrier particles with a drug solution in water in an amount such that the solution is 1 to 3% by weight relative to the total mixture.

The resulting mixture may be formulated in a suitable unit dosage form, for example by tableting and optionally film coating the tablet, or encapsulating.

It may be convenient to prepare the original drug / carrier mixture as a more concentrated drug and subsequently to mix it with additional carriers in a separate step, which may be particularly useful in applications where a range of tablet strengths are required. . A separate mixing step promotes drying by the dilution effect, ie by distributing the remaining water through a larger amount of carrier powder, and by further lengthening the mixing time. Dilution is preferably in the range of 4/1 to 40/1 weight carrier / concentrate, depending on the processing properties of the carrier. The preferred dilution ratio for lactose monohydrate is 10/1.

If no dilution step is involved, the solution / mixture weight ratio is more preferably 2% by weight or less.

The optimal amount of solution will depend on the absorption properties of the carrier particles, the solubility of the drug and the nature of the mixing device, and the amount of solution is chosen to evenly distribute the drug without requiring a heat drying step.

Preferably the mixing step is carried out in a high shear mixer.

The carrier may be any of soluble directly compressible and pharmaceutically acceptable excipients such as anhydrous lactose, lactose monohydrate, mannitol, or directly compressible and pharmaceutically acceptable excipients such as amorphous cellulose or dicalcium phosphate, Soluble excipients are preferred.

Any drug with a sufficiently high solubility in water may be formulated by the method of the present invention. The concentration of drug in solution depends on the unit dose of drug required and the upper limit depends on the solubility of the drug.

During mixing the carrier particles are uniformly coated with a very thin film of drug solution. Some of the water is naturally dried during mixing because there is usually a small airflow through the mixer; The amount of residue is so small that no drying is required. If tablets are film-coated, they may be somewhat more dry during the coating process.

The method of the present invention has a number of advantages:

Does not require grinding of the drug.

No drying step is required. This simplifies the process and reduces production costs; Heat labile drugs are not compromised at the temperatures required for drying; For highly potent drugs, the omission of the drying step makes it easier to contain dust, thus improving safety for factory workers.

Do not use volatile organic solvents.

No need to add a binder.

When the excipient is very soluble it is not necessary to add a disintegrant.

Any additives in the final mixture may be disintegrants; In the formulation, such as sodium dihydrogen citrate, a range of acidic or alkaline excipients, preferably for increasing the chemical stability of the drug contained in the initial mixture; Lubricants such as magnesium stearate; And a lubricant such as colloidal silica.

The present invention also provides pharmaceutical compositions comprising the drugs formulated according to the methods of the invention and the use of such compositions as active therapeutic substances.

In addition, the present invention provides pharmaceutical compositions comprising the drugs obtained by the methods of the invention and the use of such compositions as active therapeutic substances.

The method of the present invention provides a [R- (Z)]-α- (methoxyimino) -α- (1-azabicyclo [2,2,2] oct-3- having an active dosage of about 5 to 125 μg. I) particularly useful for formulating acetonitrile monohydrochloride (Compound X). Compound X and methods for its preparation are disclosed in EP-A-0392803, WO 95/31456 and WO 93/17018. This compound promotes acetylcholine function by action on muscarinic receptors in the central nervous system, and thus can be used for the treatment and / or prevention of dementia in mammals.

In particular, the present invention provides a pharmaceutical composition comprising up to 0.1% by weight of Compound X, 0% volatile organic solvent and 0% binder, relative to a pharmaceutically acceptable carrier.

EP-A-0392803 proposes a suitable daily dosage of 0.01 to 5 mg / kg for Compound X and the other compounds disclosed herein. Efficacy as a recognition enhancer is less than 0.01 mg / kg, more preferably 0.003 mg / kg and less, for example 0.00035 to 0.003 mg / kg, 0.0007 to 0.003 mg / kg, 0.0001 to 0.0007 mg / kg or 0.00035 to 0.002 It has been surprisingly found by administering to a patient that it can be achieved at a daily dosage of 0.0001 to 0.003 mg / kg, such as mg / kg.

Accordingly, the present invention provides a method of treating and / or preventing dementia, and more particularly, a method for enhancing the cognition of a patient, which method comprises Compound X 0.01 mg / kg, more preferably 0.003 mg / kg. Administration to a patient at the following daily dosages. The present invention further relates to the use of compound X in the daily dosage of 0.01 mg / kg, more preferably 0.003 mg / kg or less, in the manufacture of a medicament for the treatment and / or prophylaxis of dementia. The invention also provides for the treatment and / or prophylaxis of dementia comprising a unit dose of Compound X suitable for administration at a daily dosage of 0.01 mg / kg or less, more preferably 0.003 mg / kg or less. Pharmaceutical compositions and pharmaceutically acceptable carriers.

Suitable unit dosages for achieving such unit dosages are 5, 12.5, 50 or 75 μg when administered twice daily and 50 μg once daily. These unit doses are calculated based on the individual 50-70 kg. The present invention extends to the aforementioned methods, uses or compositions wherein Compound X is provided in such unit dosages.

In addition, the invention provides formulations in accordance with the method of the invention and / or in accordance with the method of the invention and / or in the unit dosage form selected from the range of 5 to 125 μg per unit dose, such as 5, 12.5, 25, 50 or 75 μg per unit dose formulation. As pharmaceutical compositions comprising the compounded Compound X and active therapeutic substances, in particular the use of such compositions in the treatment and / or prevention of dementia is provided.

Formulation of Compound X

To make 100 kg of the mixture for tableting or encapsulating with 100 μg of drug per 150 mg of excipient:

Dissolve 67 g of the drug in 1 liter of water (i.e., 1% water (1.067% solution) by weight).

-Slowly add to 100 kg of "direct compression" lactose monohydrate in the high-shear mixer-granulator.

Mix with 0.25 kg of lubricant (magnesium stearate) and 0.15 kg of lubricant (colloidal silica).

Tableting.

-Film coating. (Arbitrary process)

To make 100 kg of the mixture for tableting or encapsulating with 100 μg of drug per 150 mg of excipient:

Dissolve 67 g of the drug in 0.1 liter of water.

9.8 kg of "direct compression" grade lactose monohydrate and 0.2 kg of oxidant (sodium dihydrogen citrate) are slowly added in a high-shear mixer-granulator and chopper at about 1500 rpm for a total mixing time of 10-20 minutes. vigorously mix at the chopper rate and then increase the speed to about 3000 rpm while adding additional 0.1 liters of water (ie 2% total water (2.67% solution) by weight in proportion to the amount of concentrate) ) Clean the used containers.

The resulting concentrate is sieved into a rotary dry-mixer.

Mix with an additional 88 kg of lactose and 1.8 kg of sodium dihydrogen citrate, then mix in 0.15 kg of the suspending agent (colloidal silica) and 0.25 kg of the lubricant (magnesium stearate).

Tableting.

-Film coating. (Arbitrary process)

In order to make 75, 50, 25, 12.5 and 5 μg unit dosage forms in 150 mg of excipients, the amounts of drug used in the above described methods were 50, 33.6, 16.8, 8.4 and 3.3 g, respectively.

Claims (31)

A method of formulating a drug comprising mixing the carrier particles with a drug solution in water in an amount such that the solution is 1 to 3% by weight relative to the total mixture. The method of claim 1, wherein the carrier is a soluble or insoluble, directly compressible pharmaceutically acceptable excipient. The method of claim 2, wherein the carrier is a soluble excipient selected from anhydrous lactose, lactose monohydrate and mannitol. The method of claim 3, wherein the mixture further comprises an acidic or alkaline excipient to increase the chemical stability of the drug in the formulation. The mixture according to any one of claims 1 to 4, wherein the mixture is selected from additional carriers and / or disintegrants, acidic or alkaline excipients to increase the chemical stability of the drug in the formulation, lubricants and lubricants. Further comprising mixing with the above additives. The method of claim 5, wherein the mixture is mixed with the additional carrier in a weight ratio of 1/4 to 1/40. The method of any one of claims 1 to 6, wherein the mixture is formulated in unit dosage form. The compound according to any one of claims 1 to 7, wherein [R- (Z)]-α- (methoxyimino) -α- (1-azabicyclo [2,2,2] oct-3-yl) A method for formulating acetonitrile monohydrochloride. A pharmaceutical composition comprising a drug, obtained by the method of any one of claims 1 to 8. 0.1 weight of [R- (Z)]-α- (methoxyimino) -α- (1-azabicyclo [2,2,2] oct-3-yl) acetonitrile monohydrochloride relative to pharmaceutically acceptable carrier A pharmaceutical composition comprising less than%, 0% volatile organic solvent and 0% binder. The composition of claim 10, wherein the carrier is a soluble or insoluble, directly compressible pharmaceutically acceptable excipient. The composition of claim 11 wherein the carrier is a soluble excipient selected from anhydrous lactose, lactose monohydrate and mannitol. 13. The composition of any one of claims 10-12, further comprising at least one additive selected from disintegrants, acidic excipients, lubricants and lubricants to increase the chemical stability of the drug in the formulation. The composition of claim 13 comprising lactose monohydrate, sodium dihydrogen citrate, colloidal silica and magnesium stearate. 15. The composition of any one of claims 10-14, which is formulated in unit dosage form. [R- (Z)]-α- (methoxyimino) -α- (1-azabicyclo [2,2,2] oct-3-yl) acetonitrile monohydrochloride less than 0.01 mg / kg per day A method of treating and / or preventing dementia comprising administering to a patient at a dosage. [R- (Z)]-α- (methoxyimino) -α- (1-azabicyclo [in the manufacture of a medicament for treating and / or preventing dementia at a daily dosage of less than 0.01 mg / kg. 2,2,2] oct-3-yl) acetonitrile monohydrochloride. [R- (Z)]-α- (methoxyimino) -α- (1-azabicyclo [2,2,2] oct- in unit dosages suitable for administration at a daily dose of less than 0.01 mg / kg. A pharmaceutical composition for the treatment and / or prevention of dementia comprising 3-yl) acetonitrile monohydrochloride and a pharmaceutically acceptable carrier. 19. The method, use or composition according to claim 16, 17 or 18, wherein the daily dose is 0.003 mg / kg or less. The method, use or composition according to claim 19, wherein the daily dose is 0.0001 to 0.003 mg / kg. The method, use or composition according to claim 20, wherein the daily dose is 0.00035 to 0.003 mg / kg. The method, use or composition according to claim 20, wherein the daily dose is 0.0007 to 0.003 mg / kg. The method, use or composition according to claim 20, wherein the daily dose is 0.0001 to 0.0007 mg / kg. The method, use or composition according to claim 20, wherein the daily dose is 0.00035 to 0.002 mg / kg. The compound of claim 16, 17, or 18, wherein the compound is provided in a unit dosage form of 5, 12.5, 25, 50 or 75 μg, administered twice daily or once a day for 50 μg. The method, use or composition administered. The pharmaceutical composition of the unit dosage form according to any one of claims 9 or 10 to 15, which is selected in the range of 5 to 125 μg per unit dose. The pharmaceutical composition of claim 26 comprising 5, 12.5, 25, 50 or 75 μg per unit dosage form. 28. A pharmaceutical composition according to any of claims 9, 10-15, or 26 or 27 for use as an active therapeutic substance. The pharmaceutical composition according to claim 9, 10 to 15, or 26 or 27 for use in the treatment and / or prevention of dementia. A method of treating and / or preventing dementia comprising administering to a patient an effective amount of a composition according to claim 29. Use of the pharmaceutical composition according to claim 29 in the manufacture of a medicament for the treatment and / or prevention of dementia.