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Details for Patent: 6,355,258

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Details for Patent: 6,355,258

Title: Method for formulating spill resistant pharmaceutical compositions in semi-solid form
Abstract:A spill-resistant pharmaceutical formulation for oral administration from a squeezable container comprises a pharmaceutical agent in a suitable vehicle comprising a liquid base and a thickening agent, the formulation consisting of mutually compatible components and having the following proper ties: a viscosity within the range of about 7500 to about 12,500 cps using a Brookfield Viscometer with a `C` spindle with Helipath movement at a spindle speed of 20 rpm and 20-25.degree. C., a viscometric yield value of a semi-solid, a spill-resistant consistency permitting the composition to be squeezed by light manual pressure through a channel, to spread in a spoon bowl sufficiently quickly for accurate measurement, and to remain in the spoon bowl without spilling on spoon inversion, tilting at 90 degrees, and vibration, homogeneity such that the components do not separate under conditions of use, and a storage stability such that the foregoing properties are retained for at least two years shelf life. A method for producing a formulation for a spill-resistant pharmaceutical composition comprises combining a per-unit dose effective amount of a pharmaceutical agent with suitable vehicle components comprising a liquid base and a thickening agent and testing the formulation for acceptance criteria.
Inventor(s): Mehta; Rakesh (Nanuet, NY), Moros; Dan (Larchmont, NY)
Assignee: Taro Pharmaceutical Industries Ltd. (IL)
Filing Date:Apr 13, 2000
Application Number:09/548,927
Claims:1. A method for producing a spill-resistant pharmaceutical formulation, comprising combining a per-unit dose effective amount of a pharmaceutical agent with vehicle components comprising a liquid base and a thickening agent, testing the formulation for acceptance critera for a formulation that can be easily squeezed from a container into a receptacle, measure, and administered orally without spilling the composition from the container or the receptacle, and accepting a formulation that satisfies the acceptance criteria, the acceptance critera comprising:

viscosity within the range equivalent to 5000-45,000 cps using a Brookfield Viscometer with a `C` spindle with Helipath movement at 20 RPM and 20-25.degree. C.,

viscometric yield value of a semi-solid,

ease of administration comprising (a) extrudability under light manual squeezing from a squeezable container, and (b) spreadability in a spoon bowl measured by extruding the formulation into a spoon bowl and determining whether the material spreads to the edges of the spoon bowl sufficiently quickly for accurate measurement,

spill resistance in the spoon bowl during at least one test period comprising vibrations for at least about 30 seconds, inversion for at least about 20 seconds, and tilting for at least about one second, while monitoring whether the product spills from the spoon,

mutual compatibility of the components such that they do not separate, and

storage stability during storage for an extended period of time for at least one month.

2. A method according to claim 1, wherein the test spoon is plastic and the test period for vibrations is at least about one minute, the test period for inversion is at least about 30 seconds, and the test period for tilting is at least about 20 seconds.

3. A method according to claim 1, wherein the spreadability is such that the formulation spreads to the edge of the spoon within about five seconds.

4. A method according to claim 1, wherein the liquid base is in an amount of about 45 weight-percent to about 95 weight-percent, comprising 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 up to about 55 weight-percent, and is selected from the group consisting of starch, modified starch, sodium carboxymethyl cellulose in an amount of less than about 2%, microcrystalline cellulose, hydroxypropyl cellulose, other cellulose derivatives, acacia, tragacanth, pectin, gelatin, polyethylene glycol, and water-soluble carboxyvinyl polymers in a concentration of less than 1%.

5. A method according to claim 1, comprising testing a vehicle without the pharmaceutical agent for at least one of the acceptance criteria, combining the pharmaceutical agent with the vehicle, and then testing the formulation for all acceptance criteria.

6. The method according to claim 1, wherein the test spoon is plastic and the test period for vibrations is at least about thirty seconds, and the test period for inversion and for tilting is at least about 1 second.

7. A method according to claim 1, wherein the spreadability is at least as great as honey.

8. A method according to claim 1, further comprising varying the components and/or concentrations of theta liquid base, the thickening agent, and/or the pharmaceutical agent, to prepare a series of formulations.

9. method for producing a spill-resistant pharmaceutical formulation for oral administration from a squeezable container, comprising combining a per-unit dose effective amount of a pharmaceutical agent in a suitable vehicle comprising a liquid base and a thickening agent, testing the formulation for acceptance criteria for a formulation that can be by easily squeezed from the container into a receptacle, measured and administered orally without spilling the composition from the container or the receptacle, and accepting a formulation that satisfies the acceptance criteria, the formulation consisting of mutually compatible components and having the following properties:

an initial viscosity within the range of about 7,500 to about 12,500 cps using a Brookfield Viscometer with a "C" spindle with Helipath movement at a spindle speed of 20 rpm and 20-25.degree. C.,

a viscometric yield value of a semi-solid,

a spill resistant consistency permitting the composition to be squeezed by light manual pressure through a channel of about 1-1.5 mm, to spread in a spoon bowl sufficiently quickly for accurate measurement, and to remain in the spoon bowl without spilling for at least about one second and less than about 20 seconds on spoon tilting at 90 degrees, and for at least about 30 seconds upon spoon vibration at a frequency of about 120/minute, homogeneity such that the components do not separate under conditions of use, and a storage stability such that the foregoing properties are retained for at least three months of storage at elevated temperature, with viscosity remaining within a range of 50% less to 100% more than the initial viscosity,

wherein said thickening agent comprises components selected from the group consisting of cellulose derivatives in an amount of less than about 2 weight % by volume, and water-soluble cart oxyvinyl polymer in an amount less than 1 weight % by volume.

10. A method for producing a spill-resistant pharmaceutical formulation, comprising combining a per-unit dose effective amount of a pharmaceutical agent with vehicle components comprising a liquid base and a thickening agent, testing the formulation for acceptance criteria for a formulation that can be easily squeezed from a container into a receptacle, measured, and administered orally without spilling the composition from the container or the receptacle, and accepting a formulation that satisfies the acceptance criteria, the acceptance criteria comprising:

viscometric yield value of a semi-solid,

ease of administration comprising (a) extrudability under light manual squeezing from a squeezable container, and (b) spreadability in a spoon bowl measured by extruding the formulation into spoon bowl and determining whether the material spreads to the edges of the spoon bowl sufficiently quickly for accurate measurement,

spill resistance in the spoon bowl during at least one test period comprising vibrations for at least about 30 seconds, inversion for at least about 20 seconds, and tilting for at least about one second, while monitoring whether the product spills from the spoon,

mutual compatibility of the components such that they do not separate, storage stability during storage for an extended period of time for at least one month, and

wherein said thickening agent comprises components selected from the group consisting of celluose derivatives in an amount of less than about 2 weight % by volume, and water-soluble carboxyvinyl polymer in an amount less than 1 weight % by volume.

11. A method of testing a spill-resistant pharmaceutical formulation for acceptance criteria a formulation that can be easily squeezed from a container into a receptacle, measured, and administered orally without spilling the composition from the container or the receptacle, the testing comprising, without regard to order, the steps of:

combining per-unit dose effective amount of a pharmaceutical agent with vehicle components comprising a liquid base and a thickening agent,

measuring initial viscosity, to determine whether the viscosity is within the range equivalent to 5000-45,000 cps using a Brookfield Viscometer with a `C` spindle with Helipath movement at 20 RPM and 20-25.degree. C.,

measuring yield value,

extruding the formulation into a spoon from a container through a 1 to 5 mm orifice,

observing the spreading/leveling characteristic of the formulation in the spoon bowl,

measuring spill resistance of the formulation in a spoon bowl by

vibrating the spoon bowl for at least about 30 seconds,

inverting the spoon bowl for at least about 20 seconds, and/or

tilting the spoon bowl for at least about one second, and

monitoring whether the product spills from the spoon, and measuring viscosity after storing at elevated temperature for at lease one month.

12. A method of testing according to claim 11, further comprising determining the viscometric yield value is that of a semi-solid.

13. A method of testing according to claim 11, wherein the extruding comprises extruding under light manual squeezing from a squeezable container.

14. A method of testing according to claim 11, wherein the observing consists of determining spreadability in a spoon bowl measured by extruding the formulation into a spoon bowl and determining whether the material spreads to the edges of the spoon bowl sufficiently quickly for accurate measurement.

15. A method of testing according to claim 11, wherein the formulation does not start to spill until after about 30 seconds when vibrated at a frequency of about 2-8 per second, and an amplitude up to about 1 inch.

16. A method of testing according to claim 11, wherein the spill start time on spoon inversion is at least about 20-30 seconds for a plastic 8 ml spoon, longer than for a syrup, and within about 1-20 seconds on spoon tilting at 90 degrees.

17. A method of testing according to claim 11, further comprising determining mutual compatibility of the components such that they do not separate.

18. A method of testing according to claim 11, further comprising measuring storage stability during storage for at least one month.

19. A method of testing according to claim 11, wherein the viscosity is in the range equivalent to 7000-25,000 cps.

20. A method of testing according to claim 11, wherein the viscosity is in the range equivalent to 7000-12,500 cps.

21. A method according to claim 1, wherein the viscosity is in the range equivalent to 7000-25,000 cps.

22. A method according to claim 1, wherein the viscosity is in the range equivalent to 7000-12,500 cps.
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