Pharmaceutical formulation
View Patent ↗The present invention is directed to pharmaceutically acceptable polymeric compositions suitable for injection molding of single or multi-component pharmaceutical dosage forms comprising a plurality of drug substance containing sub-units, being capsule compartments and/or solid sub-units comprising a solid matrix of a polymer which contains a drug substance, the sub-units being connected together in the assembled dosage form by a weld between parts of the assembled dosage form.
1. A process for making a pharmaceutical dosage form comprising the steps of:
a) introducing simultaneously, and at substantially the same location, into an elongated hot melt extruder
a copolymer of methyl acrylate, methyl methacrylate and methacrylic acid, with a ratio of free carboxyl groups to esters groups of 1:10, and an average molecular weight of approximately 220,000, present in an amount of about 20 to 90% w/w, and
an excipient composition comprising:
i) a lubricant present in an amount of about 10 to about 25% w/w;
ii) at least one dissolution-modifying excipient selected from the group consisting of a swellable solid, disintegrant, non-reducing sugar, water soluble filler, wicking agent, and an inorganic salt present in an amount of about 2.5 to about 70% w/w; and
iii) a surfactant present in an amount of less than 5% w/w, and wherein the surfactant is selected from a block copolymer of ethylene oxide and propylene oxide, lecithin, sodium dioctyl sulfosuccinate, sodium dodecyl sulphate, polyoxyl 40 hydrogenated castor oil, polyoxyethylene sorbitan fatty acid ester, sorbitan fatty acid ester, polyethylene glycol, d-alpha-tocopheryl polyethylene glycol 1000 succinate, or a sucrose fatty acid ester, or combinations and mixtures thereof; and
optionally a plasticizer present in an amount of 0 to 10% w/w, and/or optionally a processing agent present in an amount of 0 to about 10% w/w;
b) mixing said copolymer and said excipient composition in the hot melt extruder to form a homogeneous composition, and ejecting the homogeneous composition in the form of a strand from the hot melt extruder though a die at a location remote from said same location at which the copolymer and said excipient composition are introduced;
c) cutting the strand into pellets;
d) introducing said pellets into an injection molder and forming capsule shells by injection molding.
2. The process according to claim 1 , in which the excipient composition comprises at least one dissolution modifying excipient which is a swellable solid selected from ethyl cellulose, cellulose acetate phthalate, hydroxypropyl cellulose, hydroxypropylmethyl cellulose, hydroxypropylmethyl cellulose phthalate, or other hydroxyalkylcellulose derivative; or combinations or mixtures thereof.
3. The process according to claim 1 , in which the surfactant is selected from sodium dodecyl sulphate or a block copolymer of ethylene oxide and propylene oxide.
4. The process according to claim 1 , in which the lubricant is selected from the group consisting of stearyl alcohol, glycerol monostearate (GMS), talc, magnesium stearate, silicon dioxide, amorphous silicic acid, and fumed silica; and combinations or mixtures thereof.
5. The process according to claim 1 , in which the hot melt extruder is maintained at a temperature not exceeding approximately 135° C.
6. The process according to claim 1 , in which the hot melt extruder is maintained at a temperature not lower than the copolymer and said excipient composition melting points.
7. The process according to claim 1 , in which the temperature in the hot melt extruder gradually increases along the length of the hot melt extruder, from said same location at which the copolymer and an excipient composition are introduced, to the die, the maximum temperature not exceeding approximately 135° C.
8. The process according to claim 1 , in which the hot melt extruder comprises an elongated barrel having first and second opposite ends, and twin screws within the barrel for propelling copolymer and said excipient composition along the length of the interior of the barrel, said substantially same location at which the copolymer and said excipient composition are introduced is located adjacent the first end of the barrel, and said die is located adjacent the second end of the barrel.
9. The process according to claim 1 , in which the injection molding of the thin-walled capsule compartments is carried using an injection molder having a barrel and a nozzle, while maintaining the injection molder barrel at a temperature in the range of about 120° C. to 140° C.
10. The process according to claim 1 , in which the injection molding of the thin-walled capsule compartments is carried out using an injection molder having a barrel and a nozzle, while maintaining the injection molder nozzle at a temperature in the range of about 140° C. to 190° C.
11. The process according to claim 1 , in which the injection molding of the thin-walled capsule compartments is carried out using an injection molder having a barrel and a nozzle, while maintaining the injection molder nozzle at a temperature of about 165 to 170° C.
12. The process according to claim 1 , in which the injection molding of the thin-walled capsule compartments is carried out using an injection molder having a barrel and a nozzle, while maintaining the injection molder barrel at a temperature in the range of about 120° C. to 140° C. and maintaining the injection molder nozzle at a temperature in the range of about 140° C. to 190° C.
13. The process according to claim 1 wherein the pharmaceutical dosage forms are assembled using said capsule shells as components of said dosage forms.
14. The process according to claim 13 wherein the said capsule shells of the assembled dosage form are connected together by at least one weld where adjacent parts of said shells are in contact.
15. The process according to claim 14 wherein the weld is produced by a thermal weld, an ultrasonic weld, an inductive weld, or an adhesive weld.