Title of Invention

"A PROCESS FOR MAKING TABLETS OF A POORLY COMPRESSIBLE DRUG BY DIRECT COMPRESSION AND A BINDER COMPOSITION"

Abstract The present invention relates to a process for making tablets of a poorly compressible drug by direct compression, which comprises providing a binder composition which is made by spray drying an aqueous dispersion of a copolymer of 60 wt% polyvinylpyrrolidone (PVP) and 40% vinyl acetate (VA), having a defined glass transition temperature (Tg) at about 106°C, and an effective amount of 5 - 15 wt. % of a plasticizer which is an organic ester or polyol therewith to reduce the Tg of said copolymer by at least 20°C, admixing said binder composition and 50 - 90 wt. % of said drug, and forming a tablet thereof by direct compression having a predetermined hardness and friability, and at an acceptable compression force.
Full Text The present invention relates to a process for making tablets of a poorly compressible drug by direct compression and a binder composition.
BACKGROUND OF THE INVENTION
1. Field of the Invention
This invention relates to direct compression of poorly compressible drugs, and, more particularly, to a new and improved binder composition for such drugs, which enables mixtures thereof to be processed into drug tablets of desired hardness and friability by direct compression, and at an acceptable compression force.
2. Description of the Prior .Art
Poorly compressible drugs such as naproxen and acetaminophen are currently made into tablets by wet granulation. However, it would be advantageous to provide a method of forming tablets of such drugs by direct compression, which is a more commercially advantageous process.

SUMMARY OF THE INVENTION
Tablets of a poorly compressible drug are made by direct compression using a binder composition which is a mixture of a polymer, e.g. a copolymer of polyvinylpyrrolidone (PVP) and vinyl acetate (VA), hydroxypropyl cellulose, hydroxypropyl methyl cellulose and polyvinylpyrrolidone, having a defined glass transition temperature (Tg), and an effective amount of a plasticizer therewith, to reduce the Tg of said copolymer by at least 10°C. The binder composition and drug are admixed, and formed into a tablet by direct compression at an acceptable compression force. The resultant tablet has an advantageous hardness and friability.
The preferred copolymer is 60 wt. % PVP and 40% VA having a Tg of 106°C, and the plasticizer reduces the Tg of this copolymer by at least 20°C when present in admixture therewith in an amount of about 1-25 wt. %, preferably 5-15%. Representative plasticizers include polyethylene glycol, triethyl citrate, acetylated fatty acid glycerides, castor oil, dibutyl phthalate, diethyl phthalate, dibutyl sebacate, glycerol, glycerol monostearate, glyceryl triacetate, polyoxyethylene/polyoxypropylene copolymers and propylene glycol. Preferred plasticizers are organic esters and-polyols, for example, triethyl citrate and polyethylene glycol.
In general, the binder composition is a free-flowing powder having an average particle size of about 30-90 u.
A typical poorly compressible drug in the invention is naproxen or acetaminophen.
The process of the invention is carried out by direct compression of the admixture of about 1-25wt. % of the binder composition and at least 50%, preferably 50-90 wt. % of the drug, the rest being other excipients. Direct compression at about 3000-7000 Ibs. provides a tablet having a hardness of at least about 8 Kp, generally 8-20 Kp, and a friability of about less than 3%, preferably 1-3%.
DETAILED DESCRIPTION OF THE INVENTION
The invention will now be illustrated in more detail by reference to the following examples.
The test for efficacy of selected polymer and plasticizer is described in the following Example 1, wherein an aqueous dispersion of the components is prepared, mixed well, and dried on a substrate. Then the glass tansition temperature Tg is determined and compared to a control (without plasticizer). The criteria for efficacy is a reduction in Tg (with plasticizer) by at least 10°C.
EXAMPLE 1
Aqueous dispersions of a binder composition of PVP/VA copolymer (60:40 by wt.) and plasticizer were spray dried in a laboratory scale spray dryer. The resultant powders were collected in a plastic bag. The glass transition temperature for each composition was determined and compared to copolymer without plasticizer (control). The results are shown in Table 1 below.
TABLE 1

(Table Removed)
* polyethylene glycol ** triethyl citrate
The data in Table 1 demonstrates that the plasticizer reduced the Tg of
the copolymer by at least 10°C, and up to 27°C.
EXAMPLE 2
Free flowing powders of a binder composition of PVP/VA (60:40) plasticized with added PEG 4000 (5 and 10% w/w) or Methyl citrate (TEC) (5 and 10% w/w), having a particle size of 30µ, and a poorly compressible drug (acetaminophen) were prepared at a wt. ratio of 75:25 drug:binder composition. Then 0.5% silica and 0.5% lubricant were added and the mixture was compressed at a compression force of (Ibs) 3000, 5000 or 7000. The hardness and friability values of the resultant tablets are shown in Table 2 below.
TABLE 2

(Table Removed)
The data in Table 2 demonstrates that the drug tablet plasticized with PEG or TEC had a hardness value of 13.9 to 26.1 kP, as compared to only 5 to 7.4 kP for the control. Also friability was reduced from 3-9% for control (copolymer without plasticizer) to only 0.27 to 0.64% with added plasticizer.
EXAMPLE 3
The properties of the binder compositions of the invention were determined and compared to the copolymer itself as a control. The test powders were prepared in laboratory apparatus (composition A) or in a production minor spray dryer (51 x 5') using a rotary wheel atomizer with and without an air broom device (composition B). These copolymers were used as controls, or admixed with plasticizer (composition C) and (composition D). Drying was carried out at an inlet temperature of 150°C, an outlet temperature of 80°C and a feed temperature of 50°C. The results are given in Table 3 below.
TABLE 3

(Table Removed)
The results in Table 3 show that the binder compositions C and D reduced the Tg of the control copolymers A or B by > 20°C, decreased the particle size of the copolymer powders.
EXAMPLE 4
Typical formulations of binder composition and drug ready for direct compression into tablets are given in Table 4 below.
TABLE 4

(Table Removed)
* The presence of amorphous silica as processing aid eases the formation of tablets by direct compression, generally in an amount of 0.1-10% of the composition, preferably 0.1-5%, and most preferably 0.05-3%"."Suitable silica is available from Cabosil as M-5P, surface area 200 + 15 m2/g, and HS-5, surface area 325 + 25 m2/g.
EXAMPLE 5
Table 5 below shows the hardness and friability properties of tablets obtained by direct compression of the formulations of Example 4 at various compression forces.
TABLE 5 ,

(Table Removed)
The results in Table 5 show that the binder compositions of the invention provide hard tablets with low friability, even with a high amount of drug (77%) present in the tablet.
EXAMPLE 6
Tablets can be prepared as above using hydroxypropyl cellulose, hydroxypropyl methyl cellulose and polyvinylpyrrolidone as the polymer component in the binder composition. Similar results are obtained.
EXAMPLE 7
Tablets can be prepared as above using the following as plasticizers: polyethylene glycol, triethyl citrate, acetylated fatty acid glycerides, castor oil, dibutyl phthalate, diethyl phthalate, dibutyl sebacate, glycerol, glycerol monostearate, glyceryl triacetate, polyoxyethylene/polyoxypropylene copolymers and propylene glycol. Similar results are obtained.
While the invention has been described with particular reference to certain embodiments thereof, it will be understood that changes and modifications may be made which are within the skill of the art. Accordingly, it is intended to be bound only by the following claims, in which:








WE CLAIM:
1. A process for making tablets of a poorly compressible drug by direct compression, which comprises providing a binder composition which is made by spray drying an aqueous dispersion of a copolymer of 60 wt% polyvinylpyrrolidone (PVP) and 40% vinyl acetate (VA), having a defined glass transition temperature (Tg) at about 106°C, and an effective amount of 5 -15 wt. % of a plasticizer which is an organic ester or polyol therewith to reduce the Tg of said copolymer by at least 20°C, admixing said binder composition and 50 - 90 wt. % of said drug, and forming a tablet thereof by direct compression having a predetermined hardness and friability, and at an acceptable compression force.
2. The process as claimed in claim 1 wherein said drug is naproxen or acetaminophen.
3. The process as claimed in claim 1 wherein the binder composition is a free-flowing powder having an average particle size of about 30-90 µ.
4. The process as claimed in claim 1 wherein said plasticizer is triethyl citrate.
5. The process as claimed in claim 1 wherein direct compression is carried out at 3000-7000 lbs. and the tablet has a hardness of at least about 8 kP and a friability of less than about 3.
6. The process as claimed in claim 5 wherein said tablet hardness is about 8-30 kP, and said friability is about 1-3.
7. The process as claimed in claim 1, wherein said binder composition for direct compression of poorly compressible drug comprises a free-flowing powder which is a spray dried aqueous dispersion of a copolymer of 60wt % polyvinylpyrrolidone (PVP) and 40 wt% vinyl acetate (VA) having a Tg of about 106°C, and an effective amount of 5-15 wt.% of a plasticizer which is an organic ester or polyols reduce the Tg of the polymer by at least 20°C.
8. The process as claimed in claim 7, wherein the particle size of the free-flowing is about 30-90µ.
9. The process as claimed in claim 7, wherein said plasticizer is triethyl citrate or polyethylene glycol.
10. The process as claimed in claim 7, wherein the spray drying is carried out in the presence of silica powder.
11. The process as claimed in claim 1, wherein a drug tablet is formulated.
12. The process as claimed in claim 11, wherein said drug is naproxen or acetaminophen.

Documents:

4732-DELNP-2005-Abstract-(02-07-2009).pdf

4732-DELNP-2005-Abstract-(10-05-2010).pdf

4732-delnp-2005-abstract.pdf

4732-delnp-2005-assignment.pdf

4732-DELNP-2005-Claims-(02-07-2009).pdf

4732-DELNP-2005-Claims-(10-05-2010).pdf

4732-delnp-2005-claims.pdf

4732-DELNP-2005-Correspondence-Others-(10-05-2010).pdf

4732-DELNP-2005-Correspondence-Others-(27-07-2009).pdf

4732-delnp-2005-correspondence-others.pdf

4732-DELNP-2005-Corresponence-Others-(02-07-2009).pdf

4732-DELNP-2005-Description (Complete)-(02-07-2009).pdf

4732-delnp-2005-description (complete).pdf

4732-DELNP-2005-Form-1-(02-07-2009).pdf

4732-delnp-2005-form-1.pdf

4732-delnp-2005-form-18.pdf

4732-DELNP-2005-Form-2-(02-07-2009).pdf

4732-delnp-2005-form-2.pdf

4732-DELNP-2005-Form-3-(27-07-2009).pdf

4732-delnp-2005-form-3.pdf

4732-delnp-2005-form-5.pdf

4732-DELNP-2005-GPA-(02-07-2009).pdf

4732-delnp-2005-gpa.pdf

4732-DELNP-2005-PCT-101.pdf

4732-delnp-2005-pct-210.pdf

4732-delnp-2005-pct-220.pdf

4732-delnp-2005-pct-237.pdf

4732-delnp-2005-pct-301.pdf

4732-delnp-2005-pct-304.pdf

4732-delnp-2005-pct-311.pdf

4732-delnp-2005-pct-401.pdf

4732-DELNP-2005-PCT-402.pdf

4732-delnp-2005-pct-409.pdf

4732-delnp-2005-pct-416.pdf

4732-DELNP-2005-Petition-137-(27-07-2009).pdf


Patent Number 246579
Indian Patent Application Number 4732/DELNP/2005
PG Journal Number 10/2011
Publication Date 11-Mar-2011
Grant Date 04-Mar-2011
Date of Filing 18-Oct-2005
Name of Patentee ISP INVESTMENTS INC.
Applicant Address 300 DELAWARE AVENUE, WILMINGTON, DE 19801, U.S.A.
Inventors:
# Inventor's Name Inventor's Address
1 RAMA HALDAR 1 PRINCE HENRY DRIVE, RANDOLPH, NJ 07869, U.S.A.
2 JOHN ZAMORA 52 HEATHER LANE, PARAMUS, NJ 07652, U.S.A.
3 DIPAN B. RAY 5 SOJOURNER WAY, OLD BRIDGE, NJ 08857, U.S.A.
4 WILLIAM DREFKO 625 CHESTNUT STREET, KEARNY, NJ 07032, U.S.A.
5 GREG DUBROWNY 38 HARTMANN AVENUE, GARFIELD, NJ 07026, U.S.A.
6 SIDNEY ETIENNE 205 BERGEN TPK., APT. #3B, RIDGEFIELD PARK, NJ 07660, U.S.A.
PCT International Classification Number A61K 9/20
PCT International Application Number PCT/US2004/010256
PCT International Filing date 2004-04-01
PCT Conventions:
# PCT Application Number Date of Convention Priority Country
1 60/468,001 2003-05-05 U.S.A.
2 10/641,878 2003-08-15 U.S.A.