Claims for Patent: 5,881,926

Summary for Patent: 5,881,926

Title:	Pharmaceutical compositions in semisolid form and a device for administration thereof
Abstract:	A pharmaceutical formulation in semisolid form useful for systemic treatment of an illness is disclosed, as well as a device for containing and measuring a unit dose of the formulation comprising a squeezable container having a cap with a spoon attached thereto and closure for resealing the squeezable container after use. A child proof closure useful for the device is also disclosed.
Inventor(s):	Ross; Malcolm Stewart Frank (Tel Aviv, IL)
Assignee:	Taro Pharmaceutical Industries, Ltd. (IL)
Application Number:	08/114,315
Patent Claims:	1. A non-spill delivery system for oral administration of a pharmaceutical agent, comprising: (a) a squeezable container having an outlet defining a flow channel; (b) a dispenser connected to the container comprising (i) a channel communicating with the outlet, (ii) an unvented channel closure device having a closed and an open position, the channel closure device comprising a spring biased step cylinder positioned in said dispenser with channel means which allows passage of a composition from inside the squeezable container when said spring biased step cylinder is pressed to compress the spring and which reseals the squeezable container when not pressed; and (iii) a tamper-evident seal of the channel closure device, and (c) at least one dose of a pharmaceutical composition, the composition being a semisolid material that is storage stable, and consists of mutually compatible components, the components comprising (i) an effective amount of an orally active pharmaceutical agent useful for systemic treatment, and (ii) a pharmaceutically acceptable vehicle, comprising a liquid base in an amount of about 45 weight-percent to about 95 weight-percent, the liquid base comprising a palatable solvent, selected from the group consisting of water, propylene glycol, polyethylene glycol, glycerin, and mixtures thereof, a thickening agent in an amount of about 1 weight-percent to about 55 weight-percent, the thickening agent selected from the group consisting of starch, modified starch, sodium carboxymethyl cellulose, microcrystalline cellulose, hydroxypropyl cellulose, other cellulose derivatives, acacia, tragacanth, pectin, gelatin, polyethylene glycol, and water-soluble carboxyvinyl polymers. the pharmaceutical composition having a Brookfield viscosity of about 2500 to about 70,000 cps at about 20.degree.-25.degree. C. at a spindle speed of 10-20 rpm, and a consistency which allows the composition to be squeezed by manual pressure through the channel. whereby in response to pressure on the container when the channel closure device is open, a predetermined unit dose of the pharmaceutical composition can be easily squeezed from the container into a receptacle, measured, and administered orally without spilling any of the composition from the container or the receptacle, the spring biased step cylinder being a rotatable spring biased step cylinder positioned in said dispenser, said rotatable spring biased step cylinder having channel means and an outside button, said dispenser being provided with a cavity which matches the size and shape of said button so that said button can fit into said cavity, whereby the channel means allows passage of a composition from inside the squeezable container when said rotatable spring biased step cylinder is depressed and said rotatable spring biased step cylinder can be depressed only when said button is aligned with said cavity, and in which the tamper-evident seal filter comprises a plastic covering over said cavity which prevents tampering with said device before use, and which is broken when the cylinder is depressed. 2. A non-spill delivery system for oral administration of a pharmaceutical agent, comprising: (a) a squeezable container having an outlet defining a flow channel; (b) a dispenser connected to the container comprising (i) a channel communicating with the outlet, (ii) an unvented channel closure device having a closed and an open position, the channel closure device comprising a spring biased step cylinder positioned in said dispenser with channel means which allows passage of a composition from inside the squeezable container when said spring biased step cylinder is pressed to compress the spring and which reseals the squeezable container when not pressed; and (iii) a tamper-evident seal of the channel closure device, and (c) at least one dose of a pharmaceutical composition, the composition being a semisolid material that is storage stable, and consists of mutually compatible components, the components comprising (i) an effective amount of an orally active pharmaceutical agent useful for systemic treatment, and (ii) a pharmaceutically acceptable vehicle, comprising a liquid base in an amount of about 45 weight-percent to about 95 weight-percent, the liquid base comprising a palatable solvent, selected from the group consisting of water, propylene glycol, polyethylene glycol, glycerin, and mixtures thereof; a thickening agent in an amount of about 1 weight-percent to about 55 weight-percent, the thickening agent selected from the group consisting of starch, modified starch, sodium carboxymethyl cellulose, microcrystalline celllose, hydroxypropyl cellulose. other cellulose derivatives, acacia, tratacanth, pectin, gelatin, polyethylene glycol, and water-soluble carboxyvinyl polymers. the pharmaceutical composition having a Brookfield viscosity of about 2500 to about 70,000 cps at about 20.degree.25.degree. C. at a spindle speed of 10-20 rpm, and a consistency which allows the composition to be squeezed by manual pressure through the channel, whereby in response to pressure on the container when the channel closure device is open, a predetermined unit dose of the pharmaceutical composition can be easily squeezed from the container into a receptacle, measured, and administered orally without spiing any of the composition from the container or the receptacle. 3. The device of claim 2 in which the spring biased step cylinder is a rotatable spring biased step cylinder positioned in said dispenser, said rotatable spring biased step cylinder having channel means and an outside button, said dispenser being provided with a cavity which matches the size and shape of said button so that said button can fit into said cavity, whereby the channel means allows passage of a composition from inside the squeezable container when said rotatable spring biased step cylinder is depressed and said rotatable spring biased step cylinder can be depressed only when said button is aligned with said cavity. 4. A non-spill delivery system for oral administration of a pharmaceutical agent, comprising: (a) a squeezable container having an outlet defining a flow channel having an internal diameter of from about 0.1 mmn to about 5 mm; (b) an unvented channel closure device adapted to be connected to the outlet, (c) a receptacle positioned to receive material dispensed from the channel; and (d) at least one dose of a pharmaceutical composition, the composition being a semisolid material that is storage stable, palatable, and consists of mutually compatible components, the components comprising (i) an effective amount of an orally active pharmaceutical agent useful for systemic treatment, and (ii) a pharmaceutically acceptable vehicle, comprising a liquid base, and a thickening agent selected from the group consisting of starch, sodium carboxymethyl cellulose, hydroxypropyl methyl cellulose, microcrystalline cellulose, tragacanth, acacia, pectin, gelatin, polyethylene glycol and carbomer, whereby the configuration of the container, closure device, and receptacle and the consistency of the formulation are selected so that in response to pressure on the container when the channel closure device is open, a predetermined unit dose of the pharmaceutical composition can be easily squeezed by manual pressure from the container through the channel into the receptacle, measured, and administered orally without spilling any of the composition from the container or the receptacle. 5. A system according to claim 4, wherein the receptacle is a measuring spoon connected to the channel, sized to hold a unit dose of the pharmaceutical composition. 6. The system of claim 4, wherein the receptacle is a spoon bowl attached to the dispenser. 7. The system of claim 4, wherein the liquid base is selected from water, propylene glycol, glycerin or a mixture thereof. 8. The system of claim 4 comprising multidoses of the pharmaceutical composition. 9. The system of claim 4, wherein the thickening agent is a cellulose derivative in an amount of about 2.4 to 3.3 weight % by volume. 10. The system of claim 4, wherein the thickening agent is a polyethylene glycol in an amount of about 72 to 85 weight % by volume or a mixture of polyethylene glycol in an amount of about 10 to 25 weight % by volume and a cellulose derivative in an amount of about 2.5 to 3.3 weight % by volume. 11. The system of claim 4 wherein, the pharmaceutical agent is selected from a member of the group consisting of an analgesic, non-steroidal anti-inflammatory, antihistamine, cough suppressant, expectorant, bronchodilator, anti-infective, CNS active drug, cardiovascular drug, antineoplastic, cholesterol-lowering drug, anti-emetic, vitamin, mineral supplement and fecal softener. 12. The system of claim 4, wherein the pharmaceutical agent is selected from a member of the group consisting of acetaminophen, aspirin, ibuprofen, diphenhydramine, dextromethorphan, guaifenesin, pseudoephedrine, carbidopa, levodopa, terfenadine, ranitidine, ciprofloxacin, triazolam, fluconazole, propranolol, acyclovir, fluoxetine, enalapril, diltiazem, lovastatin and a pharmaceutically acceptable salt or ester thereof. 13. A pharmaceutical delivery system comprising: (a) at least one dose of a storage stable, semisolid pharmaceutical composition comprising an effective amount of a pharmaceutical agent useful for systemic treatment in a pharmaceutically acceptable vehicle, the vehicle comprising a liquid base and a thickening agent in an amount effective to provide a Brookfield viscosity of about 2500 to 70,000 cps at about 25.degree. C. and a spindle speed of about 10 rpm; (b) a squeezable means for containing and dispensing substantially all of the pharmaceutical composition; (c) means for dispensing the composition connected to the container means, the dispenser means comprising; a channel communicating with the container means and having an internal diameter of from about 0.1 mm to about 5 mm tamper evident sealing means, means for reversibly sealing the channel, having sealed and open positions, opening the sealing means requiring at least two separate manipulations, (d) means for receiving a unit dose of the composition, whereby in response to pressure on the means for containing, when the sealing means is in the open position, a predetermined unit dose of the pharmaceutical composition can be easily squeezed into the receiving means, measured, and administered orally without spilling any of the composition from the containing means or the receiving means. 14. The system of claim 13, wherein the receptacle is a spoon bowl attached to the dispenser. 15. The system of claim 13, wherein the liquid base is selected from water, propylene glycol, glycerin or a mixture thereof. 16. The system of claim 13 comprising multidoses of the pharmaceutical composition. 17. The system of claim 13, wherein the thickening agent is selected from a member of the group consisting of starch, sodium carboxymethyl cellulose, hydroxypropyl methyl cellulose, microcrystalline cellulose, tragacanth, acacia, pectin, gelatin, polyethylene glycol and carbomer. 18. The system of claim 13, wherein the thickening agent is a cellulose derivative in an amount of about 2.4 to 3.3 weight % by volume. 19. The system of claim 13, wherein the thickening agent is a polyethylene glycol in an amount of about 72 to 85 weight % by volume or a mixture of polyethylene glycol in an amount of about 10 to 25 weight % by volume and a cellulose derivative in an amount of about 2.5 to 3.3 weight % by volume. 20. The system of claim 13, wherein the pharmaceutical agent is selected from a member of the group consisting of an analgesic, non-steroidal anti-inflammatory, antihistamine, cough suppressant, expectorant, bronchodilator, anti-infective, CNS active drug, cardiovascular drug, antineoplastic, cholesterol-lowering drug, anti-emetic, vitamin, mineral supplement and fecal softener. 21. The system of claim 13, wherein the pharmaceutical agent is selected from a member of the group consisting of acetaminophen, aspirin, ibuprofen, diphenhydramine, dextromethorphan, guaifenesin, pseudoephedrine, carbidopa, levodopa, propranolol, terfenadine, ranitidine, ciprofloxacin, triazolam, fluconazole, acyclovir, fluoxetine, enalapril, diltiazem, lovastatin and a pharmaceutically acceptable salt or ester thereof. 22. A non-spill delivery system for oral administration of a pharmaceutical agent, comprising: (a) a squeezable container having an outlet defining a flow channel; (b) a dispenser connected to the container comprising (i) a channel communicating with the outlet, (ii) an unvented channel closure device having a closed and an open position; and (iii) a tamper-evident seal of the channel closure device, and (c) at least one dose of a pharmaceutical composition, the composition being a semisolid material that is storage stable, and consists of mutually compatible components, the components comprising (i) an effective amount of an orally active pharmaceutical agent useful for systemic treatment, and (ii) a pharmaceutically acceptable vehicle, comprising a liquid base in an amount of about 45 weight-percent to about 95 weight-percent, the liquid base comprising a palatable solvent, selected from the group consisting of water, propylene glycol, polyethylene glycol, glycerin, and mixtures thereof, a thickening agent in an amount of about 1 weight-percent to about 55 weight-percent, the thickening agent selected from the group consisting of starch, modified starch, sodium carboxymethyl cellulose, microcrystalline cellulose, hydroxypropyl cellulose, other cellulose derivatives, acacia, tragacanth, pectin, gelatin, polyethylene glycol, and water-soluble carboxyvinyl polymers, the pharmaceutical composition having a Brookfield viscosity of about 2500 to about 70,000 cps at about 20.degree.-25.degree. C. at a spindle speed of 10-20 rpm, and a consistency which allows the composition to be squeezed by manual pressure through the channel, whereby in response to pressure on the container when the channel closure device is open, a predetermined unit dose of the pharmaceutical composition can be easily squeezed from the container into a receptacle, measured, and administered orally without spilling any of the composition from the container or the receptacle. 23. The system of claim 22, in which opening the channel closure device requires at least two separate manipulations, and breaks the tamper-evident seal the first time the closure device is opened. 24. A system according to claim 22 wherein the thickener is polyethylene glycol. 25. A system according to claim 22 wherein the composition further comprises hydrogenated glucose in an amount greater than about 6.5%. 26. A system according to claim 22 wherein the vehicle consists essentially of the liquid base, the thickening agent, and optionally sweetener, flavoring, preservative, buffer, and solubilizing agent. 27. A system according to claim 22 wherein the viscosity is between about 7500 and about 40,000 cps. 28. A system according to claim 22 wherein the container is a flexible tube. 29. The system of claim 2, in which the channel closure device comprises a valve positioned in said dispenser capable of allowing passage of a composition from inside the squeezable container when in the open position and resealing the squeezable container when in the closed position. 30. The device of claim 29, wherein the valve is rotatable. 31. The device of claim 29, wherein the valve is pivotable. 32. The system of claim 22, wherein the liquid base comprises propylene glycol and glycerin, and the thickening agent comprises a water soluble carboxyvinyl polymer. 33. The system of claim 32, wherein the concentration of propylene glycol and glycerin is about 29%, and the concentration of the carboxyvinyl polymer is up to about 1%. 34. The systern of claim 22, wherein the liquid base comprises glycerin and sorbitol, and the thickening agent comprises sodium carboxymethylcellulose and microcrystalline cellulose. 35. The system of claim 34 wherein the sorbitol is present as a solution of about 70% in water, the concentration of glycerin and sorbilol solution is about 40%, the concentration of the carboxymethylcellulose is about 2.4%, and the concentration of the microcrystalline cellulose is about 0.9%. 36. A non-spill delivery system for oral administration of a pharmaceutical agent, comprising: (a) a flexible packet that can be torn or cut to open a channel; and (b) a single dose of a pharmaceutical composition contained within the packet, the composition being a semisolid material that is storage stable, and consists of mutually compatible components, the components comprising (i) an effective amount of an orally active pharmaceutical agent useful for systemic treatment, and (ii) a pharmaceutically acceptable vehicle, comprising a liquid base, and a thickening agent, whereby when the packet is torn or cut open, and in response to pressure on the container, a single dose of the pharmaceutical composition can be easily squeezed from the container into the mouth of a patient and swallowed, without spilling any of the composition wherein the liquid base is in an amount of about 45 weight-percent to about 95 weight-percent, and comprises a palatable solvent selected from the group consisting of water, propylene glycol, polyethylene glycol, glycerin, and mixtures thereof, and the thickening agent is in an amount of about 1 weight-percent to about 55 weight-percent, and is selected from the group consisting of starch, modified starch, sodium carboxymethyl cellulose, microcrystalline cellulose, hydroxypropyl cellulose, other cellulose derivatives, acacia, tragacanth, pectin, gelatin, polyethylene glycol, and water-soluble carboxyvinyl polymers. 37. The system of claim 36, wherein the liquid base comprises propylene glycol and glycerin, and the thickening agent comprises a water soluble carboxyvinyl polymer. 38. The system of claim 37, wherein the concentration of propylene glycol and glycerin is about 29%, and the concentration of the carboxyvinyl polmer is up to about 1%. 39. The system of claim 36, wherein the liquid base comprises glycerin and sorbitol, and the thickening agent comprises sodium carboxymethylcellulose and microcrystalline cellulose. 40. The system of claim 39 wherein the sorbitol is present as a solution of about 70% in water, the concentration of glycerin and sorbitol solution is about 40%, the concentration of the carboxymethylcellulose is about 2.4%, and the concentration of the microcrystalline cellulose is about 0.9%. 41. A device for containing and measuring a unit dose of a pharmaceutical composition in semisolid form comprising a squeezable container for holding the pharmaceutical composition having an open neck and a cap suitable to fit on the neck of the squeezable container, a spoon having a shaft with channel means fixed in the cap so that the bowl-shaped end of the spoon projects outside the cap and the shaft projects into the cap and the channel means are in alignment with the open neck of the squeezable container and sealing means in said cap positioned to seal the container when the cap is fully closed and to provide space for the contents of the container to flow through the channel means into the spoon in response to pressure on the container when the cap is partially opened, whereby substantially all the contents of the squeezable container can be squeezed into the bowl-shaped end of the spoon and administered therefrom, said sealing means comprises a pin inside the channel means which projects into the cap so as to rest against the neck of the container and seal the container when the cap is fully closed due to compete engagement of the threads of the cap, but which allows for the passage of a composition from inside the squeezable container through the channel means to the spoon when the threads of the neck of the squeezable container and threads of the cap are only partially engaged, said pharmaceutical composition comprises an effective amount of an orally active pharmaceutical agent useful for systemic treatment in combination with a pharmaceutical acceptable vehicle comprising a thickening agent in an amount effective to provide a Brookfield viscosity of about 2500 to 70,000 cps at 25 degrees Celsius at a spindle speed of 10 rpm.