Pharmaceutical compositions comprising monoterpenes

• US 8,507,734 B2
• Filed: 03/03/2011
• Issued: 08/13/2013
• Est. Priority Date: 03/03/2010
• Status: Active Grant

• Current Assignee: University of Southern California
• Original Assignee: Neonc Technologies Inc.
• Inventors: Chen, Thomas, Levin, Daniel, Puppali, Satish
• Primary Examiner(s): Richter, Johann R
• Assistant Examiner(s): Bakshi, Pancham
• Application Number:
  US13/040,059
• Publication Number:
  US 20110280860A1
• Time in Patent Office: 894 Days
• Field of Search: 568/875, 568/854, 556/437
• US Class Current: 568/854
• CPC Class Codes: A61K 31/045 Hydroxy compounds, e.g. alcohols; Salts thereof, e.g. alcoholates
• CPC Class Codes: A61K 31/4188 condensed with other heterocyclic ring systems, e.g. biotin, sorbinil
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61N 5/10 X-ray therapy; Gamma-ray therapy; Particle-irradiation therapy A61N5/01 takes precedence
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: C07B 2200/07 Optical isomers
• CPC Class Codes: C07C 201/12 by reactions not involving the formation of nitro groups
• CPC Class Codes: C07C 201/16 Separation; Purification; Stabilisation; Use of additives
• CPC Class Codes: C07C 205/57 having nitro groups and carboxyl groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton
• CPC Class Codes: C07C 2601/16 the ring being unsaturated
• CPC Class Codes: C07C 29/78 by condensation or crystallisation
• CPC Class Codes: C07C 29/86 by liquid-liquid treatment
• CPC Class Codes: C07C 29/88 by treatment giving rise to a chemical modification of at least one compound chemisorption C07C29/76
• CPC Class Codes: C07C 29/92 by a consecutive conversion and reconstruction
• CPC Class Codes: C07C 33/14 containing six-membered rings
• CPC Class Codes: C07C 67/14 from carboxylic acid halides
• CPC Class Codes: C07C 69/76 Esters of carboxylic acids having a carboxyl group bound to a carbon atom of a six-membered aromatic ring
• CPC Class Codes: C07C 69/92 with etherified hydroxyl groups

Abstract

The present invention provides a process for purifying a monoterpene or sesquiterpene having a purity greater than about 98.5% (w/w). The process comprises the steps of derivatizing the monoterpene (or sesquiterpene) to produce a monoterpene (or sesquiterpene) derivative, separating the monoterpene (or sesquiterpene) derivative, and releasing the monoterpene (or sesquiterpene) from the derivative. Also encompassed by the scope of the present invention is a pharmaceutical composition comprising a monoterpene (or sesquiterpene) having a purity greater than about 98.5% (w/w). The purified monoterpene can be used to treat a disease such as cancer. The present monoterpene (or sesquiterpene) may be administered alone, or may be co-administered with radiation or other therapeutic agents, such as chemotherapeutic agents.

Claims

1. A process for purifying (S)-perillyl alcohol comprising the steps of:

(a) derivatizing a mixture comprising (S)-perillyl alcohol to form a perillyl alcohol derivative, wherein the perillyl alcohol derivative is a benzoate ester and has at least one property that allows it to be separated from the mixture;

(b) separating the perillyl alcohol derivative from the mixture using the property for separation;

(c) releasing the (S)-perillyl alcohol from the perillyl alcohol derivative from step (b); and

,

(d) isolating the (S)-perillyl alcohol from step (c),

wherein the (S)-perillyl alcohol has a purity of greater than 98.5% (w/w).

2. The process of claim 1, wherein the property of the perillyl alcohol derivative is to form crystals, and wherein the separation in step (b) is through crystallization.

3. The process of claim 1, wherein the separation in step (b) is through chromatography.

4. The process of claim 1, wherein the benzoate ester is 3,5-dinitrobenzoate ester.

5. The process of claim 1, wherein the mixture further comprises natural-product-derived or other impurities.

6. (S)-perillyl alcohol having a purity of greater than 98.5% (w/w).

7. The (S)-perillyl alcohol of claim 6, wherein the (S)-perillyl alcohol is in a pharmaceutical composition, and wherein the (S)-perillyl alcohol in the pharmaceutical composition ranges from about 0.1% (w/w) to about 100% (w/w).

8. The (S)-perillyl alcohol of claim 6, wherein the (S)-perillyl alcohol is in a pharmaceutical composition, and wherein the pharmaceutical composition also comprises a chemotherapeutic agent.

9. The (S)-perillyl alcohol of claim 8, wherein the chemotherapeutic agent is selected from the group consisting of a DNA alkylating agent, a topoisomerase inhibitor, an endoplasmic reticulum stress inducing agent, a platinum compound, an antimetabolite, an enzyme inhibitor, a receptor antagonist, and a therapeutic antibody.

10. The (S)-perillyl alcohol of claim 8, wherein the chemotherapeutic agent is dimethyl-celecoxib (DMC), irinotecan (CPT-11), temozolomide or rolipram.

11. The (S)-perillyl alcohol of claim 7, wherein the pharmaceutical composition is administered before, during or after radiation.

12. The (S)-perillyl alcohol of claim 7, wherein the pharmaceutical composition is administered before, during or after the administration of a chemotherapeutic agent.

13. The (S)-perillyl alcohol of claim 7, wherein the pharmaceutical composition is administered by inhalation, intranasally, orally, intravenously, subcutaneously or intramuscularly.

14. The (S)-perillyl alcohol of claim 6, wherein the purity is chiral purity.

15. An article of manufacture comprising (S)-perillyl alcohol formulated for intranasal administration, and a device for intranasal administration of the (S)-perillyl alcohol, wherein the (S)-perillyl alcohol has a purity of greater than 98.5% (w/w).

16. The article of manufacture of claim 15, wherein the article of manufacture is a kit.

17. The article of manufacture of claim 15, wherein the device is an intranasal spray device, an atomizer, a nebulizer, a metered dose inhaler (MDI), a pressurized dose inhaler, an insufflator, an intranasal inhaler, a nasal spray bottle, a unit dose container, a pump, a dropper, a squeeze bottle, or a bi-directional device.

18. The article of manufacture of claim 15, further comprising printed matter, wherein the printed matter states the (S)-perillyl alcohol is to be used to treat glioblastoma cancer.

19. The article of manufacture of claim 18, wherein the printed matter further states the (S)-perillyl alcohol is to be administered alone, or administered in combination with radiation, surgery or chemotherapeutic agents.