WO2002007772A2

WO2002007772A2 - Improved oral dosage formulations

Info

Publication number: WO2002007772A2
Application number: PCT/US2001/021860
Authority: WO
Inventors: Michael L. Cappola; George W. Gereg; Susan Way
Original assignee: Boehringer Ingelheim Pharmaceuticals, Inc.
Priority date: 2000-07-24
Filing date: 2001-07-11
Publication date: 2002-01-31
Also published as: US20020031544A1; JP2004504360A; WO2002007772A3; MXPA02012909A; CA2415131A1; EP1305050A2; US6565880B2

Abstract

A formulation comprising, and process for preparing, improved oral dosage forms of 1-(5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl)-3-[4-(2-morpholin-4-yl-ethoxy)-naphthalen-1-yl]-urea, a chemical entity with anti-inflammatory properties. Granulation of 1-(5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl)-3-[4-(2-morpholin-4-yl-ethoxy)-naphthalen-1-yl]-urea within specified ranges provides improved dissolution of 1-(5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl)-3-[4-(2-morpholin-4-yl-ethoxy)-naphthalen-1-yl]-urea and oral bioavailability, as well as content uniformity. Incorporation into the formulation of an aqueous soluble inclusion compound capable of forming a complex with 1-(5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl)-3-[4-(2-morpholin-4-yl-ethoxy)-naphthalen-1-yl]-urea, such as beta-cyclodextrin provides enhanced stability of 1-(5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl)-3-[4-(2-morpholin-4-yl-ethoxy)-naphthalen-1-yl]-urea, in particular in highly ionic environments. Chipping and disintegration of tablets containing more than about 10 % betacyclodextin can be prevented by applying a polymeric coat to the surface of the tablet at a temperature below 40 °C.

Description

IMPROVED ORAL DOSAGE FORMULATIONS OF l-(5-TERT-BUTYL-2-P- TOLYL-2H-PYRAZOL-3-YLV3-[4-f2-MORPHOLIN-4-YL-ETHOXY)-

NAPHTHALEN-1-YL -UREA

BACKGROUND OF THE INVENTION

1. ^' Field of the Invention

The present invention relates to unique oral dosage formulations of l-(5-

tert-butyl-2-p-tolyl-2H-pyrazol-3-yl)-3-[4-(2-morpholin-4-yl-ethoxy)-naphthalen-l-yl]-

urea, a pharmacological agent exhibiting novel anti-inflammatory activity. More

particularly, the present invention relates to oral dosage formulations of l-(5-tert-butyl-2-

p-tolyl-2H-pyrazol-3 -y l)-3 - [4-(2-morpholin-4-yl-ethoxy)-naphthalen- 1 -yl] -urea that

provide enhanced stability of the compound in ionic environments, improved solubility,

and/or improved oral bioavailability, and are produced using unique process conditions.

2. Background of the Related Art

l-(5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl)-3-[4-(2-morpholin-4-yl-ethoxy)- naphthalen-l-yl]-urea (hereinafter, "BIRB 796") is disclosed in commonly assigned co-

pending PCT Application No. PCT/US99/29165, herein incorporated by reference, as

possessing unexpectedly significant inhibitory activity with respect to promflarnmatory

cytokines, such as tumor necrosis factor (TNF) and interleukin-1 (IL-1). BIRB 796 has

implications for the treatment of numerous disease states including arthritis, psoriasis and

Crohn's disease. While having many advantageous pharmacological properties, BIRB 796

has been found to possess certain less than desirable pharmaceutical properties, including

poor aqueous solubility, poor powder flow properties, and a tendency to discolor in the

presence of light.

At least seven polymorphs of BIRB 796 have been isolated (the melt point

of the drug is about 152°C and the pKa about 6.1). The polymorphs generally exist in the form of elongated needles. BIRB 796 is relatively poorly soluble in physiological

environments. The solubility of polymorphic BIRB 796 drug substance (Form IV) has been determined to be about 0.5 ug/ml at pH 7.4 and about 10 mg/ml at pH 2.0.

BIRB 796 may be administered by the many routes of administration

known in the art, including, but not limited to, orally, intravenously, intraperitoneally,

intramuscularly, subcutaneously, bucally, rectally, aurally, ocularly, transdermally, etc. A

preferred route of administration is oral administration by way of, for example, tablets,

capsules, caplets, troches, lozenges, powder, cachets, solutions and suspensions. Core

tablets may be prepared by addition of excipient, binder, disintegrant, lubricant and so on,

as would be understood by one of ordinary skill in the art. Core tablets containing BIRB

796 may be subjected to surface coating with a main coating agent such as, but not limited to, hydroxypropylmethylcellulose, hydroxymethylcellulose, hydroxypropyl cellulose and

the like. Formulations have been prepared which deliver doses from 0.5 mg to 300 mg.

, The present inventors have recently discovered that the solubility of BIRB

796 is adversely diminished when in the presence of ionic solutions. Increasing ionic

strength has been found to result in an overall decrease in the dissolution of BIRB 796. As

the various parts of the human (and other mammalian) intestinal tract show considerable

variability in ionic strength (typically ranging from I = 0.15 - 0.40 M), and as the ionic

strength of the intestinal tract may be significantly affected by intake of certain pharmaceutical products and foodstuffs, this variability of the solubility of BIRB 796 with

ionic strength may have significant adverse impacts on the overall bioavailability of BIRB

796.

BIRB 796 formulations have also been discovered to be plagued with less

than desirable adherency characteristics. Formulations containing BIRB 796 have been

found to suffer from the tendency of materials to stick to compression dies and/or punch

faces, as well as to stick to powder conduits, filling tubes, and other processing chambers.

Within conventional ranges, increases in the amount of lubricant in the formulation have

not been found to be adequate to resolve the problem.

There is a need therefore for formulations of BIRB 796 with improved

solubility and diminished adherency characteristics, which provide better oral

bioavailability of the drug as well as allow for efficient preparation of dosage forms. SUMMARY OF THE INVENTION

The present invention discloses formulations of BIRB 796, and processes

for. manufacturing such BIRB 796 formulations, that provide for improved solubilization

and/or bioavailability of BIRB 796, and which display improved flow characteristics. In

particular, advantageous oral dosage formulations of BIRB 796 are provided.

It has been discovered by the present inventors that the flow properties of

BIRB 796 drug substance may be significantly improved (adherence to surfaces reduced),

by granulation of the material followed by milling of the dried granules in such a manner

so as to form a granular composition of BIRB 796 within a defined range of granule sizes -

- such that the portion of granules which do not pass through a 1000 micron sieve do not account for more than about 5 percent by weight of the total granules, the amount that do

not pass through a 250 micron sieve does not account for more than about 60 percent by

weight, and the portion of granules which pass through a 63 micron sieve do not account

for more than about 20 percent by weight. Such granular compositions of BIRB 796 have

been obtained using a cone mill set at various rpms with a 1000 micron rasp or grate

screen. Manual milling through a 1000 micron screen, followed by a 700 micron screen

has also been found capable of producing such acceptable sieve patterns.

Surprisingly, it has been determined by the present inventor that BIRB 796

solubility is peculiarly affected by the ionicity of its attendant milieu. In particular,

aqueous solubility of BIRB 796 has been found to significantly decrease as the ionic strength of its milieu increases. Decreased dissolution has been found to affect overall » bioavailability of drugs.

» Presented with numerous possibilities for protecting BIRB 796 from ionic

interaction, the present inventor has discovered (after numerous failed attempts) a

relatively cheap and effective alteration in formulation that may be made that significantly

improves BIRB 796 dissolution in ionic solutions. Such improved formulation includes a

pharmaceutically non-toxic, aqueous-soluble, inclusion compound (preferably polymeric

in form) that is capable of forming a complex with BIRB 796 via manufacture by wet or dry granulation and in its aqueous state so as to protect BIRB 796 from interaction with

ionic species. By inclusion compound it is meant a compound capable of forming a cage structure with an unrelated molecule so as to form a well-defined addition structure (the

cage structure being formed by one or more molecules of inclusion compound). A

preferred inclusion compound of the present invention contains amylose moieties. A

particularly preferred inclusion compound is cyclodextrin. A particularly preferred

cyclodextrin is β-cyclodextrin.

When employing beta-cyclodextrin in combination with BIRB 796 to

protect against ion-induced diminishment of BIRB 796 solubilization, it is preferred that

the beta-cyclodextrin:BIRB 796 weight ratio be at least about 1, more preferably to be at

least about 2, and yet more preferably to be at least about 3. Such mixtures have been

found to significantly enhance the dissolution of BIRB 796 in aqueous solutions, with the

higher beta-cyclodextrin composition generally providing a better overall effect. Unexpectedly, it further has been discovered that standard techniques for

application of coating material to core tablets need to be altered when the core tablet

contains significant amounts of a cyclodextrin (greater than about 10%). While coatings

are conventionally applied at temperatures of 40°C or above, it has been found that when a

compression (i.e. tablets and the like) contains cyclodextrins that the coating temperature

must be kept below 40°C in order to prevent chipping and ultimately disintegration of the

compression. Such chipping and disintegration problem is particularly noted when the

core tablet contains substantial amounts bf cyclodextrin (> about 40%), In particular,

coatings applied to compressions (such as core tablets) containing beta-cyclodextrin need to be applied at temperatures below 40°C, more preferably below 39°C, temperatures

above 40°C causing chipping and disintegration of the compression.

The addition of cyclodextrin inclusion compounds to the BIRB 796 oral

formulation was seen to improve the average total plasma concentration of BIRB 796 (in

dogs) over a twelve hour period (AUC₀._π), as well as the maximum plasma concentration

(C_max) attained as compared to formulations containing lactose. The time to maximum

concentration (T_max) was also seen to be reduced as compared to lactose formulations

lacking cyclodextrin.

One aspect of the present invention consists of a pharmaceutical oral

dosage form comprsing: (a) a pharmaceutically effective dose of BIRB 796; and (b) a

pharmaceutically non-toxic amount of an aqueous soluble inclusion compound that is capable of forming a complex with BIRB 796 in its aqueous state so as to substantially

protect BIRB 796 from interaction with ionic species.

, In another embodiment of the present invention, there is disclosed

pharmaceutical tablet comprising: (a) a homogenous core comprising granulated BIRB

796 and a cyclodextrin; and (b) a coating completely covering said homogenous core

which comprises any suitable coating, and preferably a water dispersible

pharmaceutically-acceptable polymer coating, or the like.

In yet another embodiment of the present invention, there is disclosed a

pharmaceutical tablet comprising: (a) between about 0.1 to about 35% by weight granulated BIRB 796; (b) between about 25 to about 50% by weight binding agent; (c)

between about 3 to about 40% by weight disintegrant; and (d) between about 25 to about

60% by weight soluble granulation aid.

BRIEF DESCRIPTION OF THE DRAWINGS

The above description, as well as further objects, features and advantages of

the present invention will be more fully understood with reference to the following

detailed description when taken in conjunction with the accompanying drawings, wherein:

Fig. 1 is a graph of the solubility (μg/ml) of BIRB 796 versus ionic strength

at pH 2 of an aqueous HC1/KC1 solution (lower curve) and aqueous phosphate solution

(upper curve). Fig. 2 is a graph of the solubility (μg/ml) of BIRB 796 versus ionic strength

at pH 7.4 of an aqueous phosphate solution.

_f Fig. 3α is a graph of the percentage of 100 mg of BIRB 796 dissolved in an

aqueous phosphate solution at pH 2 (37°C) at ionic strength I = 0.25 for formulations

containing 3.7 parts lactose to 1 part BIRB 796 (lower curve), 2 parts beta-cyclodextrin to

1 part BIRB 796 and 1.7 parts lactose (middle curve), and 3 parts beta-cyclodextrin to 1

part BIRB 796 and 0.7 parts lactose (uppermost curve).

Fig. 3 b is a graph of the percentage of 100 mg of BIRB 796 dissolved in an

aqueous phosphate solution at pH 2 (37°C) at ionic strength I = 0.50 for formulations containing 3.7 parts lactose to 1 part BIRB 796 (lower curve), 2 parts beta-cyclodextrin to

part BIRB 796 and 0.7 parts lactose (uppermost curve).

Fig. 4α is a graph of the percentage of 100 mg of BIRB 796 dissolved in an

aqueous HC1/KC1 solution at pH 2 (37°C) at ionic strength I = 0.25 for formulations

part BIRB 796 and 0.7 parts lactose (uppermost curve).

Fig. 4b is a graph of the percentage of 100 mg of BIRB 796 dissolved in an

aqueous HC1/KC1 solution at pH 2 (37°C) at ionic strength I = 0.50 for formulations

containing 3.7 parts lactose to 1 part BIRB 796 (lower curve), 2 parts beta-cyclodextrin to 1 part BIRB 796 and 1.7 parts lactose (middle curve), and 3 parts beta-cyclodextrin to 1

part BIRB 796 and 0.7 parts lactose (uppermost curve).

_t Fig. 5 is a graph of mean BIRB 796 plasma concentration after oral

administration of a 100 mg BIRB 796 tablet containing 1 part BIRB 796 to 3.7 parts

lactose (lower curve), and administration of a 100 mg BIRB 796 tablet containing 1 part

BIRB 796 to 2 parts beta-cyclodextrin and 1.7 parts of lactose (upper curve).

DETAILED DESCRIPTION OF THE INVENTION

The present invention overcomes many of the problems associated with the

less than desirable solubility and handling characteristics of BIRB 796. The present

invention provides novel formulations of BIRB 796 that improve the solubility and bioavailabilty of BIRB 796 in oral dosage forms, as well as its powder flow properties

related to manufacture.

Dissolution performance is an important consideration in any oral

formulation. Formulation, however, must also take into account the need for economically

practicable methods to produce a wide range of oral potencies that are physiochemically

stable. Further, components of any formulation must possess satisfactory processing

properties. As a drug substance, BIRB 796 is a fine powder with poor flow characteristics

making it less than desirable with respect to processing. BIRB 796 is also a poorly soluble

crystalline material. The present invention provides for the economical production and processing of physiochemically stable oral dosage forms of BIRB 796 with improved

bioavailability.

In order to improve both the flow characteristics and dissolution rate of

BIRB 796, both wet and dry granulation of BIRB 796 crystals were investigated and both

found successful. Due to enhanced performance, wet granulation was chosen. Wet

granulations (after drying) were subsequently milled in an oscillating mill with a 700

micron screέn. It was found that formulations incorporating such granules had the

tendency to stick to the tablet die/punch and flow tubes. Increases in lubricant level in the

formulation within conventional tablet lubricant ranges, from 0.75% to 0.125%, was not

sufficient to correct the problem.

Cone milling of the BIRB 796 granules prepared by wet granulation was subsequently attempted in order to reduce dusting and to gain more control over the

homogeneity of the granules produced. A cone mill with various micron rasp or grate

screens was employed. It was found that a cone mill having a raised area for grating the

granulation significantly reduced dusting. The rotor speed of the mill and rasp screen size

were repeatedly adjusted to produce different particle size distributions. Such granulations

were then tested to determine acceptable sieve patterns with respect to granulations

exhibiting good solubility, good bulk flow, acceptable content uniformity and no evidence

of powder or tablet sticking.

While several rasp screen mesh sizes were investigated, with adjustment of

rotor speed, cone milling with a 1000 micron rasp screen was found capable of producing granules of appropriate particle size distribution insuring good content uniformity. This

devised procedure insured acceptable dissolution results with BIRB 796 as well as resulted

in a material which did not suffer from sticking problems.

BIRB 796 granules having a defined distribution range of granule sizes

were found to provide both substantial improvements in BIRB 796 uniformity as well as

to possess insubstantial sticking properties with respect to process apparatus materials.

Acceptable sieve patterns suggest that to effectuate pharmaceutically acceptable

improvement in content uniformity, the portion of granules that do not pass through a 1000 micron sieve should not account for more than about 5 percent by weight of the total granules, the amount that do not pass through a 250 micron sieve should not account for

more than about 60 percent by weight, and the portion of granules which pass through a 63 micron sieve should not account for more than about 20 percent by weight. Such

acceptable sieve patterns does not take into account drug dusting due to inappropriate

milling techniques (drug dusting can not be measured by sieve analysis as the small

particles mostly likely are in the 1 - 5 micron size and adhere to the larger granules by

static charge). Representative examples of acceptable sieve patterns are set forth in Table

1 below:

Table 1 Acceptable Sieve Patterns For Granulated BIRB 796

As would be understood by one of ordinary skill in the art, rotor speeds (as

well as the duration of milling) useful for producing such acceptable distributions differ

substantially between models of cone mills, as well as with the rasp screen size selected.

Such selections are well within the skill of one of ordinary skill in the art. Of course, other

milling methods known in the art may also be used to produce such a granule distribution.

For example, successive manual milling through a 1000 micron and then 700 screen was

used to produce BIRB 796 granule distributions coming within the above defined

acceptable sieve pattern range. Wet milling of granulation prior to drying is another

technique that may be utilized to produce such granule distribution. Unexpectedly, the present inventors have discovered that BIRB 796

solubility is adversely affected by highly ionic aqueous solutions. Fig. 1 demonstrates that

with respect to a HCI/KCl aqueous solution at pH 2 (upper curve), and an aqueous solution

containing phosphate (lower curve), as the ionic strength of the solution increases the

solubility of BIRB 796 decreases. Similarly, as shown in Fig. 2, the solubility of BIRB

796 in phosphate buffer at pH 7.4 decreases nearly linearly as the ionic strength of the

solution increases. The decrease in BIRB 796 solubility therefore is observed at

physiological relevant pH values. The decrease in aqueous solubility of the drug may have

profound effects on dosage form performance.

The present inventors have discovered that by incorporating a

pharmaceutically non-toxic, aqueous-soluble inclusion compound (preferably polymeric in

form) that is capable of forming a complex with BIRB 796 in its aqueous state (and

preferably also in its solid state), that the solubility of BIRB 796 can be significantly

enhanced, in particular in highly ionic solutions. Among the numerous inclusion

compound-BIRB 796 combinations attempted, it has been discovered that compounds

comprising amylose moieties are unexpectedly useful in aiding dissolution of BIRB 796.

A particularly preferred inclusion compound is cyclodextrin. Among the cyclodextrins

employed, β-cyclodextrin has been found to be particularly advantageous.

It is preferred (but not required) that beta-cyclodextrin be incorporated into

a BIRB formulation in an amount (weight basis) at least about that of BIRB 796, more

preferably approximately twice that of BIRB 796, and yet more preferably approximately three times that of BIRB 796. When beta-cyclodextrin is used with BIRB 796 to form

tablets, it has been found that a generally lower compressional force (than that with

matching lactose formulas) should be used to assure tablet disintegration.

In order to evaluate the effect of ionic strength on the dissolution of BIRB

796 from tablets with/without aqueous soluble BIRB 796 inclusion compounds, studies

were conducted with formulations containing lactose and different amounts of beta-

cyclodextrin.

Figs. 3a and 3b illustrate in graphic form the effect of beta-cyclodextrin on

BIRB 796 solubility (as a percent of 100 mg of BIRB 796 dissolved) in an aqueous

phosphate solution at pH 2 (37°C) at ionic strengths I = 0.25 M (Fig. 3a) and I = 0.50 M (Fig. 3b), for formulations containing 3.7 parts lactose to 1 part BIRB 796 (lower curve), 2

parts beta-cyclodextrin (BCD) to 1 part BIRB 796 and 1.7 parts lactose (middle curve),

and 3 parts beta-cyclodextrin to 1 part BIRB 796 and 0.7 parts lactose (uppermost curve).

The data evidences that in all cases dissolution was lowest with the lactose formulation as

compared to formulations containing cyclodextrin (1(BIRB 796):3 (BCD) > 1:2 > lactose)

at both ionic strengths. Increasing ionic strength resulted in an overall decrease in the

dissolution of the tablets. It is hypothesized that beta-cyclodextrin reduces the impact of

the ionic strength of the medium by complexing the BIRB 796 such that it does not ^•

interact with the ionic species.

Figs. 4a and 4b illustrate in graphic form the effect of beta-cyclodextrin on

the dissolution of a 100 mg BIRB 796 tablet dissolved in an aqueous HCI/KCl solution at pH 2 (37°C) at ionic strengths I = 0.25 M (Fig. 4a) and I = 0.05 M (Fig. 4b) for

formulations containing 3.7 parts lactose to 1 part BIRB 796 (lower curve), 2 parts beta-

cyclodextrin to 1 part BIRB 796 and 1.7 parts lactose (middle curve), and 3 parts beta-

cyclodextrin to 1 part BIRB 796 and 0.7 parts lactose (uppermost curve). The same trends

in dissolution behavior as seen with the aqueous phosphate solution of Figs. 3a and 3b

were observed with the HCI/KCl aqueous solution (pH 2) with rank order of dissolution

being: three parts beta-cyclodextrin to one part BIRB 796 (uppermost curve) > two parts

beta-cyclodextrin to one part BIRB 796 (middle curve) > 3.7 parts lactose to one part

BIRB 796 (lower curve). As in the aqueous phosphate solution of Figs. 3a and 3b, the

maximum amount dissolved in 60 minutes was not impacted significantly by ionic

strength for any of the formulations.

The effect of beta-cyclodextrin on BIRB 796 solubility (as a percent of 100

mg of BIRB 796 dissolved) in an aqueous phosphate solution at pH 2 (37°C) and an

aqueous HCI/KCl solution at pH 2 (37°C) was also determined at the relatively low ionic

strength I = 0.12 M. With respect to the aqueous phosphate solution, beta-cyclodextrin

was found overall to improve dissolution over a sixty-minute time frame, although

statistical significance (p < .05) was not discerned at any one point. With respect to the

aqueous HCI/KCl solution, on the other hand, while beta-cyclodextrin was found to

improve dissolution over most of the first ten minutes after initial exposure of the tablet to

the solution, beta-cyclodextrin incorporation was seen to reduce dissolution of the BIRB

796 for the next 50 minutes. It is believed that such decrease is artifactual due to a

common ion effect (chloride) as ionic strength was controlled by addition of NaCl in all cases (such effect being substantially unimportant at the higher ionic strengths tested in the

aqueous HCI/KCl solutions).

, The initial rate of dissolution (mg/min) as a function of ionic strength for

the representative solutions and formulations tested is set forth below in Table 2:

Table 2 Effect of ionic strength on initial rates of dissolution of BIRB 796 tablets (100 mg

Such data suggests that beta-cyclodextrin affords protection from bulk solvent properties

that may adversely effect on dosage form performance, and adversely impact on overall

bioavailability as various parts of the intestinal tract show considerable variability of ionic

strength, ranging from I = 0.15 to 0.40 M.

To evaluate differences in in vivo performance of BIRB 796-lactose test

formulations versus BIRB 796-beta-cyclodextrin test formulations, a relative

bioavailability study was conducted in dogs. Six dogs (approximately 10 kilograms each)

were dosed in a crossover fashion with 100 mg test tablets containing either lactose or beta-cyclodextrin. The composition of the tablets used in the study are set forth below in

Table 3:

Table 3

Composition of Tablets Evaluated in Dog Bioavailability Studies

Blood samples were taken over time to determine pharmacokinetic

parameters. Fig. 5 sets for in graphical form mean BIRB 796 plasma concentration after

oral administration of a 100 mg BIRB 796 tablet containing 1 part BIRB 796 to 3.7 parts

BIRB 796 to 2 parts beta-cyclodextrin to 1.7 parts lactose (upper curve).

The addition of beta-cyclodextrin to the BIRB 796 oral formulation was

seen to improve the average plasma concentration of BIRB 796 over a twelve hour period

(AUC₀.₁₂) (by a factor of about 1.58), as well as the maximum plasma concentration (C_max)

(by a factor of about 1.62) attained as compared to lactose. The time to maximum concentration (T_max) was also seen to be reduced as compared to lactose formulations (i.e.,

lacking cyclodextrin). Measured values for such parameters are set forth in Table 4 below:

Table 4- BIRB 796 Pharmacokinetic Parameters Following Oral Administration To Dogs

While beta-cyclodextrin has been seen to offer unexpected improvement in

BIRB 796 dissolution and bioavailability, surprisingly it noted during experimental work that core tablets containing cyclodextrins could not be coated under the same conditions as

lactose-based formulas, due to tablet chipping and disintegration when the coating was

applied. After investigating several possible parameters which might relate to such effect,

it was determined that temperature is a critical control variable. Coating was able to be

performed using the same coating solution/process/equipment as that for lactose-based

formulas only when low temperature coating was performed. As product temperatures

moved above 40°C during coating, tablets containing substantial amounts of beta-

cyclodextrin (> about 40%) were seen to disintegrate to the point until no tablet integrity

was left. Product temperatures above 40°C especially with larger tablets (e.g., 12 mm

tablets) create chipping and crumbling problems. However, when process temperatures

were less than about 40°C, more preferably less than about 39°C, acceptably coated tablets

could be produced, displaying adequate coating hardness and thickness. Preferred coating temperatures overcoming in most cases such problems are: (1) inlet air temperature

between about 30 to about 40 °C; (2) preheat core tablets between 35 - 39 °C; (3) product

temperature between about 25 to about 39 °C; and (4) final product temperature between

about 35 to about 39 °C (in each case 1 - 4, a target, and particularly preferred temperature

is about 35 °C).

In the preparation of oral dosage forms containing BIRB 796, use may be

made of a "common blend" approach in which several potencies of tablets are prepared

using different weights of the same blend. The blend may be used to make a number of

oral dosage forms including tablets, filled hard gelatin capsules (of different sizes and/or

net fills), caplets, powder papers, cachets, granules, etc.

It has been discovered that BIRB 796 may lead to discoloration of a core

tablet in which it is contained when that core tablet is exposed to light or heat. It has been

found that such coloration can be prevented by coating the BIRB 796 core tablet in

particular with a light/heat absorbing coating, preferably a water dispersible

pharmaceutically-acceptable polymer, or incorporation of a light/heat absorbing material

into the core tablet. Tablet coatings preferably comprise 2 - 3%, more preferably about

2.5%, by weight of the BIRB 796 tablet. Masking of the color change may also be used to

create a pharmaceutically acceptable dosage form, as for example, mixing dry colorants

(including yellow no. 10 iron oxide lake) into the formulation.

BIRB 796 has been found to be pharmaceutically compatible with a

number of compounds including hydrous lactose monohydrate, beta-cyclodextrin, povidone, microcrystalline cellulose, pre-gelatinized starch, sodium starch glycolate, t colloidal silicon dioxide, and magnesium stearate. A preferred tablet formulation of BIRB

796 includes a soluble granulation aid (such as lactose monohydrate), a binding agent,

preferably a granulating binding agent (such as povidone) and/or dry binding agent (such

as microcrystalline cellulose), one or more disintegrants (such as pre-gelatinized starch and

sodium starch glycolate), a flow aid (such as colloidal silicon dioxide), and a lubricant

(such as magnesium stearate). It is preferred in order to produce a BIRB 796 tablet with a

pharmaceutically adequate dissolution rate and compaction profile that the soluble

granulation aid(s) comprise between 40 to 50% of the tablet weight, the dry binding agent(s) comprise between 30 to 50% of the tablet weight, the disintegrant(s) comprise

between 5 - 40% of the tablet weight, the flow aid(s) comprise between 0.25 to 1 % of the

tablet weight, and the lubricant(s) comprise between 0.5 to 1% of the tablet weight.

Buffering agents may also be added (typically comprising less than 1% of the total tablet

weight). Depending on the size and dimensions of the core tablet pharmaceutically useful

tablets have been found to made from such compositions using compressional forces

between about 0.5 KN to about 12 KN.

Example 1 - BIRB 796B Tablet Production

BIRB 796, lactose monohydrate, and povidone were dry mixed in a drum

mixer for 5 minutes. The resulting dry mix was then granulated in a shear mixer with

water. The wet granulation was then spread onto stainless steel trays and dried in an oven at 40 - 50°C to an LOD of 2%. The dried granules were then milled through an 18 mesh

(1mm) screen in cone mill.

, Microcrystalline cellulose, pre-gelatinized starch, sodium starch glycolate,

and colloidal silicon dioxide were then screened through an 18 mesh (1 mm) screen into

the milled granules and the resulting mixture mixed in a drum mixer for 12 minutes at

approximately 30 rpm. Magnesium stearate, a lubricant, was then pre-blended with some

of the mixed blend, screened through an 18 mesh screen and returned to the drum to be

mixed an additional 4 minutes under the same conditions. The resulting blend was then

tabletted using tablet tooling and adjusting the tablet weight for the appropriate potency.

After the blend was compressed into core tablets, the tablets were film coated. Tablets were coated to a weight increase of 2 - 3%.

Example 2 - BIRB 796 Tablet Production

BIRB 796 was solubilized in a pH 2, phosphate buffer to prepare a spray

solution. Lactose monohydrate and povidone K30 were mixed and heated with low

fluidization in a small fluid bed granulator (Uniglatt). The drug solution was sprayed onto

the mixed powders in the fluid bed granulator. A rinse solution of buffer followed by

purified water was used to minimize drug loss. The granulation was dried in the same unit

to an LOD of 2% (Mettler LJ16 tester).

The dried granules were then milled in a cone mill with an 18 mesh (1 mm)

grate screen at low speed. Microcrystalline cellulose, pre-gelatinized starch, sodium starch glycolate, and colloidal silicon dioxide were then screened through an 18 mesh screen into

the milled granules and the resultant mixture mixed in a drum mixer for approximately 12

minutes at 30 rpm. Magnesium stearate, a lubricant, was then pre-blended with some of

» the mixed blend, screened through an 18 mesh screen and returned to the drum to be

mixed an additional 4 minutes under the same conditions. The blend was then tabletted,

and coated to a weight increase of about 2 to about 3%,

Several blends may be prepared, one for the highest potency manufactured

(300mg), one "common blend" for the high potency dosages (20, 25, 50, 100 and 200mg), one for the low potency 5mg dosage, and one "common blend" for the lowest potencies

manufactured (0.5, 1.25 and 2.5 mg). Tablets may be prepared from the respective

common blend using tablet tooling and adjusting the tablet weight for the appropriate

potency. After the blend is compressed into tablets, the tablets may be film coated.

Tablets may be coated to a weight increase of about 2 to about 3%, preferably about 2.5%.

While the invention has been described with respect to preferred

embodiments, those skilled in the art will readily appreciate that various changes and/or

modifications can be made to the invention without departing from the spirit or scope of

the invention as defined by the appended claims. All documents cited herein are

incorporated in their entirety herein.

Claims

WHAT IS CLAIMED IS:

1. A pharmaceutical oral dosage form comprising:

(a) a pharmaceutically effective amount of l-(5-tert-butyl-2-p-

tolyl-2H-pyrazol-3-yl)-3-[4-(2-morpholin-4-yl-ethoxy)-naphthalen-l-yl]-urea;

(b) a pharmaceutically non-toxic amount of an aqueous soluble

inclusion compound that is capable of forming a complex with l-(5-tert-butyl-2-p-tolyl- 2H-pyrazol-3-yl)-3-[4-(2-morpholin-4-yl-ethoxy)-naphthalen-l-yl]-urea in its aqueous

state so as to substantially protect l-(5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl)-3-[4-(2- morpholin-4-yl-ethoxy)-naphthalen-l-yl]-urea from interaction with ionic species.

2. The pharmaceutical oral dosage form of Claim 1 which is a tablet.

3. The pharmaceutical oral dosage form of Claim 1 which is a capsule.

4. The pharmaceutical oral dosage form of Claim 1 which is a caplet.

5. The pharmaceutical oral dosage form of Claim 1 which is a troche.

6. The pharmaceutical oral dosage form of Claim 1 , which is a powder

paper.

7. The pharmaceutical oral dosage form of Claim 1 which is a cachet.

8. The pharmaceutical oral dosage form of Claim 1 wherein said

aqueous soluble inclusion compound contains amylose moieties.

9. The pharmaceutical oral dosage form of Claim 1 wherein said

aqueous soluble inclusion compound is a cyclodextrin.

10. The pharmaceutical oral dosage form of Claim 1 wherein said

aqueous soluble inclusion compound is beta-cyclodextrin.

11. . A pharmaceutical tablet comprising:

(a) a homogenous core comprising granulated l-(5-tert-butyl-2-p-

tolyl-2H-pyrazol-3-yl)-3-[4-(2-morpholin-4-yl-ethoxy)-naphthalen-l-yl]-urea and a

cyclodextrin;

(b) a coating completely covering said homogenous core which

comprises a water dispersible pharmaceutically-acceptable polymer.

11. A pharmaceutical tablet comprising: (a) a homogenous core comprising granulated l-(5-tert-butyl-2-p-

cyclodextrin;

(b) a coating completely covering said homogenous core which

comprises a water dispersible pharmaceutically-acceptable polymer.

12. A pharmaceutical tablet comprising:

(a) granulated l-(5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl)-3-[4-(2-

morpholin-4-yl-ethoxy)-naphthalen- 1 -yl] -urea;

(b) at least about 25% lactose.

13. A pharmaceutical tablet comprising:

(a) between 0.1 to 35% by weight granulated l-(5-tert-butyl-2-p-

tolyl-2H-pyrazol-3-yl)-3-[4-(2-morpholin-4-yl-ethoxy)-naphthalen-l-yl]-urea;

(b) between 25 to 50% by weight binding agent;

(c) between 3 to 40% by weight disintegrant; and

(d) between 25 to 60% by weight soluble granulation aid.

14. The pharmaceutical tablet of Claim 12 further comprising 0.25 to

1% flow aid.

15. A granular composition of l-(5-tert-butyl-2-p-tolyl-2H-pyrazol-3-

yl)-3-[4-(2-morpholin-4-yl-ethoxy)-naphthalen-l-yl]-urea containing granules

dimensioned such that the portion of granules which do not pass through a 1000 micron

sieve do not account for more than about 5 percent by weight of the granules, the portion

of granules that do not pass through a 250 micron sieve does not account for more than

about 60 percent by weight, and the portion of granules that pass through a 63 micron

sieve do not account for more than 20 percent by weight.

16. A pharmaceutical dosage form containing the 1 -(5-tert-butyl-2-p- tolyl-2H-pyrazol-3-yl)-3-[4-(2-morpholin-4-yl-ethoxy)-naphthalen-l-yl]-urea granular composition as asserted in Claim 1.

17. A pharmaceutical dosage form comprising a core compression

comprising at least about 40% betacyclodextrin and a water-soluble polymeric coating

substantially covering said core compression.

18. A pharmaceutical dosage form comprising l-(5-tert-butyl-2-p-tolyl-

2H-pyrazol-3-yl)-3-[4-(2-morpholin-4-yl-ethoxy)-naphthalen-l-yl]-urea and a colorant,

said colorant being capable of masking any color change due to the l-(5-tert-butyl-2-p-

tolyl-2H-pyrazol-3-yl)-3-[4-(2-morpholin-4-yl-ethoxy)-naphthalen-l-yl]-urea when such is

exposed for more than twenty-four hours of ambient light.

19. A pharmaceutical dosage form comprising l-(5-tert-butyl-2-p-tolyl-

I

» tolyl-2H-pyrazol-3-yl)-3-[4-(2-morpholin-4-yl-ethoxy)-naphthalen-l-yl]-urea when such is

exposed to a 70% humidity level for more than 24 hours

20. A method for coating a compression containing more than about 10%

betacylcodextrin, said method comprising:

obtaining a compression containing more than about 10% betacyclodextrin;

coating said compression with a polymeric material at a temperature below

40°C.

21. A pharmaceutical tablet comprising :

(a) a homogenous core comprising granulated l-(5-tert-butyl-2-p-

tolyl-2H-pyrazol-3-yl)-3-[4-(2-morpholin-4-yl-ethoxy)-naphthalen- 1 -yl]-urea and a

cyclodextrin;

(b) a coating completely covering said homogenous core which

comprises a water dispersible pharmaceutically-acceptable polymer.