Title of Invention

AN ORAL IMMEDIATE RELEASE FORMULATION AND A METHOD OF PREPARING THE SAME

Abstract The present invention relates to an immediate release formulation with enhanced bio−availability comprising a solid homogeneous and thermostable solution of a poorly water−soluble biologically active substance, characterised in that said solid solution comprises: a) the active substance in an amount of between 10 and 50% of the total weight of the formulation, b) a non−ionic hydrophilic surfactant ingredient, which is in the liquid form between 15° and 30°C, in an amount of between 20% and 70 % of the total weight of the formulation and c) a pharmaceutically acceptable organic polymer or mixture of polymers, which polymer or mixture of polymers is in a liquid form above 60°C and in a solid form below 30°C, in an amount of between 5% and 70% of the total weight of the formulation, and d) optionally comprises a disintegrating agent in an amount of between 1% and 10% of the total weight of the formulation. The invention further relates to active substances formulated into the above form and methods for producing the formulation
Full Text

The present invention relates to an oral immediate release formulation with enhanced bio-availability and a method of preparing the same. More in particular the invention relates to a solid solution formulation of a poorly soluble active substance for which the bio-availability is strongly enhanced.
Solid solution formulations, which normally are in the form of gelatine capsules, are known in the art. EP 0001822 describes pharmaceutical formulations in the form of hard gelatine capsules filled with a liquid excipient which contains the active substance and which solidifies into a solid composition or into a thixotropic gel. US 4,795,643 discloses a solid solution formulation with a delayed release of the active substance. The delayed release is caused by the use of special polymers such as acrylate polymers or etherified celluloses.
Various active substances have a very poor solubility in water. When these active substances are administered to the body, they often have a poor bio-availability due to the poor solubility in the digestive fluid. In order to solve this problem several methods were developed, such as micronization, inclusion in cyclodextrines, the use of inert water-soluble carriers, the use of solid dispersions (WO 00/00179), or nanocrystalline or amorphous forms of an active substance.
The effect of the above mentioned methods on the bio-availability often depends on the properties of the active substance. Further the dosage forms developed until now have often drawbacks, such as poor thermodynamic stability, critical or difficult production processes or poor batch-to-batch reproducibility.
It is the objective of the present invention to provide an oral formulation for a poorly soluble active substance with a significant increase in bio-availability compared with said active substance in a traditionally formulated form. It is a further objective of the present invention to provide a formulation which can be prepared using normal formulation procedures and equipment, so that no large investments are necessary.
This objective can be achieved, according to the present invention, by an oral immediate release formulation with enhanced bio-availability comprising a solid homogeneous and thermodynamically stable solution of a poorly water-soluble biologically active substance, characterized in that said solid solution comprises—

a) the active substance in an amount of up to 50% of the total weight of the formulation,
b) a non-ionic hydrophilic surfactant ingredient, which is in the liquid form between 15° and 30°C, in an amount of between 20% and 70 % of the total weight of the formulation and
c) a pharmaceutical^ acceptable organic polymer or mixture of polymers, which polymer or mixture of polymers is in a liquid form above 60°C and in a solid form below 30°C, in an amount of between 5% and 70% of the total weight of the formulation, and
d) optionally comprises a disintegrating agent in an amount of between 1% and 10% of the total weight of the formulation.
The following definitions are provided to facilitate understanding of certain terms
used within the framework of the present application.
Immediate release refers to a release of at least 75 % of the drug in a dissolved form
from the dosage form within 90 minutes.
Thermodynamically stable refers to the absence of significant physical or chemical
changes of the product that might affect the quality of the product during storage for a
period up to 5 years under ambient conditions.
With poorly water-soluble is meant that the aqueous solubility of the active substance
is less than 1 in 1000. This means that according to the pharmacopoeial definitions
substances that are categorised as "very slightly soluble", "practically insoluble" and
"insoluble" are included in this definition (USP 24/NF 19, page 10; January 2000).
The term non-ionic hydrophilic surfactant refers to those amphiphilic substances that
are soluble in water (they have higher HLB values), posses surface activity and are
not ionised in aqueous solutions (H. Auterhoff, Worterbuch der Pharmazie,
Wissenschafliche Verlagsgesellschaft GmbH, Stuttgart 1981, page 192).
With HLB value is meant a value on a scale from 0 to 20, that is assigned to each
surfactant based on the relative proportions of the hydrophilic and hydrophobic part
of the molecule. Oil soluble surfactants have low HLB values, whereas water soluble
surfactants have higher HLB values.
The HLB value is calculated as:
HLB = 20{1-Mo/M) In which M is the molecular weight of the molecule and M0 is the molecular weight of the hydrophobic part of the molecule.

The ratio between the active substance in the formulation and the non-ionic hydrophilic surfactant is between 1 : 0.75 and 1 : 5, preferably between 1 : 1.5 and 1 : 4 and most preferred is 1 : 3. The ratio between the non-ionic hydrophilic surfactant and the pharmaceutical^ acceptable polymer or mixture of polymers is between 1 : 4 and 1 : 0.05, preferably between 1 : 1.5 and 1 : 0.1 and most preferred is approximately 1 : 0.75.
The non-ionic hydrophilic surfactant ingredient is preferably selected from the group consisting of polyoxyethylene glycol sorbitan fatty acid esters (polysorbates) and non hydrogentated polyoxyethylene castor oil derivatives, said surfactants having a hydrophilic-lipophilic balance (HLB) value of between 14 and 16. Polyoxyethylene glycol polysorbates are commercially available from ICI Inc., and are known under the trademark Tween®. For the present invention Tween® 40, Tween® 60 or Tween® 80 are preferred. The most preferred compound is Tween® 80. Non hydrogenated polyoxyethylene castor oil derivatives are commercially available from the BASF Corporation under the trademark Cremophor®. The most preferred compound for the present invention is Cremophor® EL.
In one embodiment the pharmaceutical^ acceptable organic polymer or mixture of polymers is consisting for a major part of polyethylene glycol (PEG) or a mixture of polyethylene glycols. PEGs are condensation polymers of ethylene oxide, commercially available from Union Carbide Corporation under the trade name Carbowax®. Preferred PEG:s are those with a moiecuiar weight of between 1000 and 50000 Daltons. More preferred are PEG'S having a molecular weight between 4000 and 10000 Daltons. The most preferred PEG has a molecular weight of about 6000 Daltons.
In a further embodiment of the invention the pharmaceutical^ acceptable organic polymer or mixture of polymers is consisting for a major part of polyvinyl pyrrolidone (PVP) or a mixture of poyvinyl pyrrolidones, commercially available from BASF under the trademark Kollidon® having approximate molecular weights of 2500 up to 3000000 Daltons.
In an even further embodiment of the invention the pharmaceutical^ acceptable organic polymer or mixture of polymers is consisting for a major part of polyvinyl alcohol (PVA) or a mixture of polyvinyl alcohols, commercially available from Shin-

Etsu Chemical Co under the trademark Poval® having approximate molecular weights of 30000 up to 200000 Daltons.
The formulation optionally comprises a disintegrating agent in an amount of between 1% and 10% of the total weight of the formulation. Normally a disintegration agent is not necessary, but in some cases it may be advantageous to add a small amount of such an agent in order to increase the dissolution of the formulation because of swelling and to increase the water transport into the formulation when contacting the dissolution media. An example of a disintegrating agent is Primojel®, commercially available from Penwest Pharmaceuticals. Other disintegrating agents that can be used are Ac-di-Sol®, commercially available from FMC, Kollidon CL®, commercially available from BASF or Polyplasdone XL®, commercially available from ISP.
An especially preferred dosage form for the above formulation consists of a hard gelatin capsule into which the homogeneous melt mixture is filled and allowed to solidify in situ.
Another dosage form composition is made by filling the melt mixture into soft, elastic gelatin capsules or by forming molded tablets, e.g. by filling the melt mixture into tablet molds, or shaping partially solidified melt mixtures into tablet shapes, like it is performed by the melt extrusion process of Knoll AG, Ludwigshafen, BRD.
The active substances that can be formulated according to the present invention is a virtually limitless list. As already stated above, the active substances to be formulated are poorly soluble in water and the invention provides an enhancement of the dissolution properties of said active substances, so that they become more soluble in the substantially aqueous system of the human digestive tract. The active substance is normally used in an amount between about 0.1 and 50% by weight, preferably in an amount between 1 and 50% by weight and more preferably in an amount between about 10 and 50% by weight.
A class of active substances which are poorly soluble in water and for which the present invention is especially useful are the substances described in EP0733642 with the general formula

wherein:
Ri is a selected from the group consisting of (Ci-C6)alkoxy(C1-C6)alkyl which may
be substituted by a (d-CeJalkoxy, phenyKd-CeJ-alkyl and phenyloxy-(CrC6)-
alkyl wherein the phenyigroup may be substituted with (C1-C6)aikyl, (CrC6)alkoxy
or halogen, and naphtyKd-CeJ-alkyl,
R2and R3 are both independently hydrogen or halogen,
R4 is a biolabile ester forming group,
M is a metal ion, preferably a bivalent metal ion,
n is 1, 2 or 3.
(CrC4)-alkyl is defined as a straight or branched alkyl group consisting of between 1 and 4 carbon atoms. (Ci-C4)-alkoxy is defined as a straight or branched alkoxy group consisting of between 1 and 4 carbon atoms.
Therefore the present invention is also related to a solid solution formulation as described above of a poorly water soluble compound of formula I. M is preferably a Li+, Mg2+, Zn2+ or a Ca2* ion and most preferrably a Ca2+ ion, R1 is preferably phenylethyl, R2 and R3are preferably hydrogen and R4 is preferably ethyl. The preferred compound is the calcium salt of 1H-1-Benzazepine-1 -acetic acid, 3-[[[1-[2-(ethoxycarbonyl)-4-phenylbutyl]cyclopentyl]carbonyi]amino]-2,3,4,5-tetrahydro-2-oxo-. The most preferred compound is said compound in its 3S,2'R form. This compound is referred to as Compound S-Ca; The corresponding acid (1H-1-Benzazepine-1-acetic acid, 3-[[[1-[2-(ethoxycarbonyl)-4-phenylbutyl]cyclopenty!]carbonyl]amino]-2l3,4,5-tetrahydro-2-oxo-) is referred to as Compound S-H and the corresponding S-a-methylbenzylamine salt is referred to as Compound S-Mba.
The formulation described above can be prepared using conventional formulation procedures and equipment. Therefore it is another aspect of the present invention to

provide a method of preparing a formulation as described above, characterized in that a) the non-ionic hydrophiiic surfactant ingredient is mixed with the pharmaceutical^ acceptable organic polymer or mixture of polymers at between 50-100 °C, preferably between 60 and 70°C, b) the active ingredient is added and dissolved at said temperature, c) the resulting mixture is optionally filled into a capsule and d) resulting mixture is solidified at room temperature.
Alternatively the non-ionic hydrophiiic surfactant ingredient, the pharmaceutically acceptable organic polymer or mixture of polymers and the active substances are mixed together and heated to a temperature of between 50 and 100 °C, preferably between 60 and 70 °C until a clear solution is obtained, optionally followed by filling of the solution into a capsule.
The following examples are only intended to further illustrate the invention, in more detail, and therefore these example are not deemed to restrict the scope of the invention in any way.
EXAMPLES.
Example 1. Effect of type and quantity of surfactant on release.
PREPARATION OF THE FORMULATIONS.
The non-ionic hydrophiiic surfactant, Tween 80 or Cremophor EL is heated together
with a hydrohilic polymer, PEG 6000 up to a temperature above 60 °C . The active
substance is added and dissolved in the melt at said temperature. The resulting
solution is filled into capsule size 0 (zero). The solution solidifies in the capsule at
room temperature.
Increasing quantities of a surfactant together with a poorly water soluble active
substance and the hydropholic polymer were composed. The compositions are given
in Table 1 for liquid filled capsules which contain 50 mg active substance. The effect
of the amount and the effect of type of surfactant on the release of the active
substance from the liquid filled capsule was determined.


IN-VITRO DISSOLUTION TESTING Dissolution system.
Dissolution testing of the liquid filled capsules is performed in artificial gastrointestinal fluids of 37 °C using USP II apparatus using a paddle speed of 100 rpm and a sinker for each capsule The dissolution is tested in a sequential range of increasing pH of the medium starting with 400 ml pH 2, prepared from 400 ml 0.01 N hydrochloric acid. One hour after starting the dissolution 15 ml of the medium is withdrawn and the pH of the buffer is changed into pH 4.5 by adding 88.5 ml 0.05 N glacial acetic acid and 211.5 ml 0.05 N sodium acetate solution. After 30 minutes 5 m! of the medium is withdrawn and the pH of the buffer is changed into pH 6.S by-adding 180 ml 0.2 N disodium hydrogen phosphate and 120 ml 0.2 N potassium dihydrogen phosphate. After XA hours 5 ml of the medium is withdrawn and the dissolution test is stopped.
Chromatographic system.
A high-performance liquid chromatographic system equipped with a thermostated column compartment, UV-absorbance detector with adjustable wavelength and integrating system is used. The analytical column (length 3 cm, internal diameter 3 mm) is a C18-modified silica, preferably Inertsil® ODS-3 column, particle size 3 jim. The mobile phase consists of a degassed mixture of 350 ml of water containing 800 mg of ammonium acetate and 800 (il of trifluoracetic acid and 650 ml of acetonitriL The flow rate is 0.5 ml/min. The column temperature is 40 °C. The injection volume is

5 jxl and the wavelenght of the UV absorbance detector is 236 nm. For external standardisation 0.12 mg of Compound S-Mba RS is dissolved in 1 ml mobile phase. The quantity of dissolved Compound S-H, expressed in percent relative to the label claim, is given by the equation 1;

Equation 1 Calculation of the quantity dissolved Compound S-H.
in which: Ist = peak area of Compound S-H in the standard chromatogram;
lsa = peak area of Compound S-H in the sample chromatogram; Vst = dilution volume of the standard solution, in ml (= 50 ml); Vsa = dilution volume of the sample solution, in ml (= 400, 700 and
1000 ml);
mst = weighed quantity of Compound S-Mba RS, in mg;
C = purity of Compound S-Mba RS, in % m/m;
LC = label claim of the analysed capsule, expressed as
Compound S-H. 0.8152= ratio between the molecular masses of the Compound S-H
and Compound S-Mba.
The dissolution results of the formulations A, B, C and D (see Table 1), containing Tween 80 as surfactant as determined by the above mentioned HPLC method are given in Figure 1 (♦ = 0%, ■ = 12%; A = 24% and • = 48% Tween 80). The dissolution results of the formulations E, F and G (see Table 1) containing Cremophor EL as surfactant are given in Figure 2 ( ♦ = 0%; ■ = 12%; A = 24% and
•= 48% Chremophor EL).
From the results given in Figure 1 and Figure 2 it is clear that the release of the active substance from liquid filled capsules is determined by the amount of hydrophilic surfactant used in the composition. The amount of released active substance increases with increasing amounts of surfactant.
More specifically it can be seen that the release of the active substance in pH 2 (release data during the first 60 minutes of the dissolution test) is determined by the amount of surfactant in the composition. The pH change from 2 into 4.5 (release data

during the next 30 minutes) improves the release of the active substance from the compositions which contain the hydrophiiic surfactant at a low level. At the end of the pH 5 period it is observed that the active substance is completely dissolved when the composition contains at least 12 % surfactant Cremophor EL or 24 % Tween 80. Finally the pH change from 4.5 into 6.8 does not influence the release data anymore. The active substance remains completely dissolved when using at least 12 % Cremophor EL or 24 % Tween 80.
Example 2. Effect of type of hydrophiiic polymer on release.
The hydrophiiic polymer in the liquid filled capsules can be a polyethylene glycol product. The influence of the molecular weight of this polymer on the dissolution is tested in the compositions shown in Table 2. The formulations were prepared as described in Example 1.
Table 2. Composition with different types of poly ethylene glycol, (n.a. = not
applicable)

Dissolution testing is performed was described in Example 1. The dissolution results of the composition with Tween 80 and with different types of polyethylene glycol is given in Figure 3 (♦ =PEG 4000; ■ = PEG 6000; A = PEG 50000). It is clearly shown that the active substance release from the composition containing PEG 4000 and PEG 50000 is comparable but in comparison with PEG 6000 delayed, however without being sustained release formulations.
The most preferred hydrophiiic polymer is PEG 6000 because PEG 4000 will cause sooner leakage from the capsules due to its lower melting point On the other hand PEG 50000 is difficult to handle because of the relatively high viscosity of this material in the molten phase.
The influence of the type of hydrophiiic polymer is also demonstrated with capsule formulations containing Cremophor EL as surfactant. The surfactant Tween 80 of the previous examples, composition D, H and J is exchanged with the same amount of Cremophor EL The dissolution test is carried out as described previously. The

dissolution results of liquid filled capsules containing 48 % Cremophor EL are given in Figure 4 ( ♦ =PEG 4000; ■ = PEG 6000; A = PEG 50000). Figure 4 clearly shows that the active substance release from liquid filled capsules containing the hydrophiiic polymers PEG 4000 and PEG 50000 is comparable but delayed in comparison with PEG 6000. The formulations can, however, not be regarded to be sustained release formulations.
Example 3. Effect of different cations on the release of the active substance,
The most preferred Ca2+ ion in the formula of the active substance is replaced by several other metal ions like Mg2+, Na+ and LP. These active substances are formulated according to composition D in Table 1. This means the formulations contain 16 % active substance, 48 % Tween 80 and 36 % PEG 6000. The preparation of the formulations is in accordance with the method described for Example 1. The dissolution results of the active substance with the Ca2+, Mg2\ Na+
or LP ion are given Figure 5. ( • = Ca2+, 0 = Mg2+, = Na+ or A = LP). From the dissolution results it can be seen that said cations do not affect the release of the active substance. The profiles in pH 2, pH 4.5 and pH 6.8 are comparable.
Example 4. Bio-availability study.
A cross-over study in 15 male subjects is performed to test the bio-availability of the liquid filled hard gelatin capsule. Compound S-Ca (Formulation I and III) or Compound S-H (Formulation II) is used as the drug substance. The subjects are administrated with the following formulations: (I) 2 x 103.7 mg compound S-Ca (corresponding to 100 mg compound S-H) liquid filled in hard gelatin capsule prepared according to Example 1 with the composition D, (II) 2 x 100 mg compound S-H in hard gelatin capsule as a 25 % m/m powder blend on tricalcium phosphate, (III) 8 x 25 mg plain tablet, consisting of 25.94 mg Compound S-Ca (corresponding to 25 mg compound S-H), 172 mg of micro crystalline cellulose PH101, 172 mg of mannitol-25, 8 mg of hydroxy propyl methyl cellulose E5, 20 mg of sodium starch glycolate and 2 mg of sodium stearyl fumarate. From the mean plasma levels shown in Figure 6 the results as given in Table 3 are obtained.


The results from Table 3 indicate that the bio-availability of the drug substance from the liquid filled hard gelatin capsule containing 103.7 mg of Compound S Ca, 311 mg Tween 80 and 234 mg polyethylene glycol 6000 improves with 80 % in comparison with the bio-availability of formulation III in which the Compound S-H is adsorbed on tricalcium phosphate as a 25 % m/m powder blend and with 20 % in comparison with the plain tablet of Compound S-Ca.



We Claim:
1. An oral immediate release formulation with enhanced bio-availability comprising a solid homogeneous and thermodynamically stable solution of a poorly water 5 soluble biologically active substance, characterised in that said solid solution comprises:

wherein:
R is a selected from the group consisting of (CpCe)) alkoxy ((Ci-C6) which may be substituted by a (C1-C6)alkoxy5 phenyl-((C1-C6)-alkyl and phenyloxy-(C1-C6)- alkyl wherein the phenylgroup may be substituted with (C1-C6)alkyl, (C1-C6) alkoxy halogen, and naphtyl-(C1-C6)-alkyl,
R2 and R3 are both independently hydrogen or halogen,
R4 is a biolabile ester forming group,
M is a metal ion, preferably a bivalent metal ion.
n is 1, 2 or 3;
A is CH2, O or S;
in an amount of between up to 50% of the total weight of the formulation,

b) a non-ionic hydrophilic surfactant ingredient, which is in the liquid form between 15° and 30°C, in an amount of between 20% and 70 % of the total weight of the formulation and
c) a pharmaceutically acceptable organic polymer or mixture of polymers, which polymer or mixture of polymers is in a liquid form above 60°C and in a solid form
below 30°C, in an amount of between 5 % and 70% of the total weight of the formulation, and
d) optionally comprises a disintegrating agent in an amount of between 1% and
10% of the total weight of the formulation.
2. An oral immediate release formulation with enhanced bio-availability comprising a solid homogeneous and thermodynamic ally stable solution of a poorly water- soluble biologically active substance, characterised in that said solid solution comprises:
a) a compound of the general formula wherein:

R is a selected from the group consisting of (Q-Q) alkoxyl (C1-C6) alkyl which may be substituted by a (Ci-C6) alkoxy, phenyl-(C]-C6)-alkyl and phenyloxy-(Ci-C6) alkyl wherein the phenyl group may be substituted with (C1-C6)alkyl, (C1-C6) alkoxy
or halogen, and naphtyl- (Ci-C6)-alkyl,
R2 and R3 are both independently hydrogen or halogen,
R4 is a biolabile ester forming group,
M is a metal ion, preferably a bivalent metal ion.
n is 1, 2 or 3;
A is CH2, O or S;
in an amount of between up to 50% of the total weight of the formulation,
b) a non-ionic hydrophilic surfactant ingredient, which is in the liquid form between 15° and 30°C, in an amount of between 20% and 70 % of the total weight of the formulation and
c) a pharmaceutically acceptable organic polymer or mixture of polymers, which polymer or mixture of polymers is in a liquid form above 60°C and in a solid form below 30°C, in an amount of between 5 % and 70% of the total weight of the formulation, and
d) optionally comprises a disintegrating agent in an amount of between 1% and 10% of the total weight of the formulation.
3. The oral immediate release formulation according to claims 1 or 2, wherein the ratio between the active substance and the non-ionic hydrophilic surfactant ingredient is between 1 : 0.75 and 1 : 5 and the ratio between the surfactant and

the pharmaceutically acceptable organic polymer or mixture of polymers is between 1: 4 and 1: 0.05.
4. The oral immediate release formulation according to claim 3, wherein the ratio between the surfactant and the pharmaceutically acceptable organic polymer or mixture of polymers is between 1 : 1.5 and 1 : 0.1.
5. The immediate release formulation according to claims 1-4, wherein the non-ionic hydrophilic surfactant ingredient is selected from the group consisting of polyoxyethylene glycol sorbitan fatty acid esters (polysorbates) and non hydrogenated polyoxyethylene castor oil derivatives, said non-ionic hydrophilic surfactant having a hydrophilic-lipophilic balance (HLB) value of between 14 and 16.
6. The immediate release formulation according to claim 5, wherin non-ionic hydrophilic surfactant ingredient is Tween®, preferably Tween® 80 or Chremophor EL.
7. The immediate release formulation according to claims 1 - 6, wherein the pharmaceutically acceptable organic polymer is a polyethylene glycol or amixture of polyethylene glycols, each with a molecular weight of between 1000 and 50000 Daltons, preferably between 4000 and 10000 Daltons.
*

8. The immediate release formulation according to claims 1-6, wherin the pharmaceutically acceptable organic polymer is a polyvinyl pyrrolidon or a mixture of polyvinyl pyrrolidons with molecular weight range of 2500 up to 3000000 Daltons or a polyvinyl alcohol or a mixture of polyvinyl alcohols with molecular weight range of 30000 up to 200000 Daltons.
9, The immediate release formulation according to claim 1-8 wherein M in the
general formula (1) is calcium in its 2+ form.
10. The immediate release formulation according to claims 1-9, wherin said
poorly water-soluble active substance is the calcium salt of IH—1-Benzaze-
pine-1-acetic acid, 3-[[[l-[2-(ethoxycarbonyl)4-
phenylbutyl]cyclopentyl]carbonyl-amino]-2, 3,4, 5-tetrahydro-2-oxo-,
preferably in its 3S,2'R form.
11 . The immediate release formulation according to claims 1-10 contained in a hard gelatine or soft gelatine capsule.
12. A method of preparing a formulation according to claims 1-11, characterized in that a) the non-ionic hydrophilic surfactant ingredient is mixed with the pharmaceutically acceptable organic polymer or mixture of polymers at between
50-100°C,

b) the compound of the general formula (I) is added and dissolved at said
temperature,
c) the resulting mixture is optionally filled into a capsule and
d) the resulting mixture is solidified at room temperature.
13. The method of preparing a formulation according to claims 1-11, wherein (a) the non-ionic hydrophilic surfactant ingredient is mixed with the pharmaceutically acceptable organic polymer or mixture of polymers and the compound of the general formula (I) at between 50-100°C,
b) the resulting mixture is optionally filled into a capsule and
c) the resulting mixture is solidified at room temperature.


Documents:

1769-chenp-2004-abstract.pdf

1769-chenp-2004-claims filed.pdf

1769-chenp-2004-claims granted.pdf

1769-chenp-2004-correspondnece-others.pdf

1769-chenp-2004-correspondnece-po.pdf

1769-chenp-2004-description(complete)filed.pdf

1769-chenp-2004-description(complete)granted.pdf

1769-chenp-2004-drawings.pdf

1769-chenp-2004-form 1.pdf

1769-chenp-2004-form 26.pdf

1769-chenp-2004-form 3.pdf

1769-chenp-2004-form 5.pdf

1769-chenp-2004-other documents.pdf

1769-chenp-2004-pct.pdf


Patent Number 212242
Indian Patent Application Number 1769/CHENP/2004
PG Journal Number 07/2008
Publication Date 15-Feb-2008
Grant Date 26-Nov-2007
Date of Filing 09-Aug-2004
Name of Patentee M/S. SOLVAY PHARMACEUTICALS B.V
Applicant Address C.J. van Houtenlaan 36, NL-1381 CP Weesp
Inventors:
# Inventor's Name Inventor's Address
1 GORISSEN, Henricus, R.M C.J. van Houtenlaan 36, NL-1381 CP Weesp
PCT International Classification Number A61K 9/48
PCT International Application Number PCT/EP2003/050014
PCT International Filing date 2003-02-11
PCT Conventions:
# PCT Application Number Date of Convention Priority Country
1 02075623.5 2002-02-14 EUROPEAN UNION