Indian Patents. 264299:METHOD OF DRUG FORMULATION BASED ON INCREASING THE AFFINITY OF CRYSTALLINE MICROPARTICLE SURFACES FOR ACTIVE AGENTS

Title of Invention	METHOD OF DRUG FORMULATION BASED ON INCREASING THE AFFINITY OF CRYSTALLINE MICROPARTICLE SURFACES FOR ACTIVE AGENTS
Abstract	Methods are provided for coating crystalline microparticles with an active agent by altering the surface properties of the microparticles in order to facilitate favorable association on the microparticle by the active agent. Type of surface properties that are altered by the disclosed methods include by electrostatic properties, hydrophobic properties and hydrogen bonding properties.

Full Text	The persent application claims the benfit under 35 U.S.C. 119(e) to united states provisional application no. 60/717,524, filed on september 14, 2005, and united states provissional serial no 60/744,882m, filed on april 14, 2006,................................. We Claim: 1. A method of coating a preformed crystalline microparticle in suspension with an active agent comprising; i) adjusting the energetic interaction between the active agent and the crystalline microparticle independent of solvent removal; and ii) adsorbing the active agent onto the surface of the microparticle. 2. The method of claim 1 further comprising the step of removing or exchanging the solvent. 3. The method of claim 2 wherein the step of removing or exchanging the solvent is without substantial effect on the interaction between active agent and microparticle. 4. The method of claim 1 wherein said adjusting step comprises modifying the surface properties of the microparticle. 5. The method of claim 4 wherein modification of the surface properties of the microparticle comprises altering solution conditions. 6. The method of claim 5 wherein altering solution conditions comprises changing the pH. 7. The method of claim 6 further comprising the step of dissolving the active agent in a fluid phase of the suspension of microparticles and subsequently changing the pH of the fluid phase. 8. The method of claim 7 wherein the pH is changed prior to or after the addition of active agent. 9. The method of claim 5 wherein modification of the surface properties of the microparticle comprises altering the polarity of the solution. 10. The method of claim 5 wherein modification of the surface properties of the microparticle comprises addition of monovalent or multivalent ions. 11. The method of claim 5 wherein modification of the surface properties of the microparticle comprises chemical derivatization of the microparticle. 12. The method of claim 4 wherein the surface properties comprise electrostatic properties. 13. The method of claim 4 wherein the surface properties comprise hydrophobic properties. 14. The method of claim 4 wherein the surface properties comprise hydrogen bonding properties. 15. The method of claim 1 wherein the microparticle is porous and has interior surfaces accessible to the bulk fluid of the solution. 16. The method of claim 1 wherein the microparticle comprises a diketopiperazine. 17. The method of claim 16 wherein the diketopiperazine is fumaryl diketopiperazine. 18. The method of claim 1 wherein the method of coating produces a monolayer of active agent on the microparticle surface. 19. The method of claim 18 wherein the monolayer is continuous. 20. The method of claim 18 or 19 wherein the active agent in the monolayer has a preferred orientation. 21. The method of claim 1 wherein the active agent is insulin or an insulin analog. 22. A method of coating a pre-formed crystalline microparticle in suspension with insulin comprising: i) adjusting the energetic interaction between the active agent and the crystalline microparticle independent of solvent removal; and ii) absorbing the insulin onto the surface of the microparticles. 23. A method for coating a preformed crystalline microparticle with insulin in a suspension, said method comprising the steps in the sequence set forth of: i) dissolving said insulin in a solvent, wherein said insulin comprises insulin, an insulin analog or combinations thereof; ii) obtaining a preformed crystalline diketopiperazine microparticle wherein said preformed crystalline diketopiperazine microparticle does not comprise an active agent; iii) altering suspension conditions in said preformed crystalline diketopiperazine microparticle suspension wherein said altering step modifies a surface property of said crystalline microparticle; iv) forming a suspension comprising said surface-modified preformed crystalline diketopiperazine microparticle, said insulin, and said solvent wherein said altering step has modified the energetic interaction between said insulin and said crystalline microparticle; then v) adsorbing said active agent onto a surface of said crystalline microparticle to provide a coating of said active agent on said crystalline microparticle without removing solvent from said suspension and wherein said altering step causes said adsorption of insulin onto a surface of said crystalline microparticle; and vi) removing or exchanging said solvent after said adsorbing step.

Full Text

The persent application claims the benfit under 35 U.S.C. 119(e) to united states provisional application no. 60/717,524, filed on september 14, 2005, and united states provissional serial no 60/744,882m, filed on april 14, 2006,.................................

We Claim:
1. A method of coating a preformed crystalline microparticle in suspension
with an active agent comprising; i) adjusting the energetic interaction between
the active agent and the crystalline microparticle independent of solvent
removal; and ii) adsorbing the active agent onto the surface of the microparticle.
2. The method of claim 1 further comprising the step of removing or
exchanging the solvent.
3. The method of claim 2 wherein the step of removing or exchanging the
solvent is without substantial effect on the interaction between active agent and
microparticle.
4. The method of claim 1 wherein said adjusting step comprises modifying
the surface properties of the microparticle.
5. The method of claim 4 wherein modification of the surface properties of
the microparticle comprises altering solution conditions.
6. The method of claim 5 wherein altering solution conditions comprises changing the pH.
7. The method of claim 6 further comprising the step of dissolving the active agent in a fluid phase of the suspension of microparticles and subsequently changing the pH of the fluid phase.

8. The method of claim 7 wherein the pH is changed prior to or after the addition of active agent.
9. The method of claim 5 wherein modification of the surface properties of the microparticle comprises altering the polarity of the solution.
10. The method of claim 5 wherein modification of the surface properties of the microparticle comprises addition of monovalent or multivalent ions.
11. The method of claim 5 wherein modification of the surface properties of the microparticle comprises chemical derivatization of the microparticle.
12. The method of claim 4 wherein the surface properties comprise electrostatic properties.
13. The method of claim 4 wherein the surface properties comprise hydrophobic properties.
14. The method of claim 4 wherein the surface properties comprise hydrogen bonding properties.
15. The method of claim 1 wherein the microparticle is porous and has interior surfaces accessible to the bulk fluid of the solution.
16. The method of claim 1 wherein the microparticle comprises a diketopiperazine.
17. The method of claim 16 wherein the diketopiperazine is fumaryl diketopiperazine.

18. The method of claim 1 wherein the method of coating produces a monolayer of active agent on the microparticle surface.
19. The method of claim 18 wherein the monolayer is continuous.
20. The method of claim 18 or 19 wherein the active agent in the monolayer has a preferred orientation.
21. The method of claim 1 wherein the active agent is insulin or an insulin analog.
22. A method of coating a pre-formed crystalline microparticle in suspension with insulin comprising: i) adjusting the energetic interaction between the active agent and the crystalline microparticle independent of solvent removal; and ii) absorbing the insulin onto the surface of the microparticles.
23. A method for coating a preformed crystalline microparticle with insulin in a suspension, said method comprising the steps in the sequence set forth of:
i) dissolving said insulin in a solvent, wherein said insulin comprises
insulin, an insulin analog or combinations thereof; ii) obtaining a preformed crystalline diketopiperazine microparticle
wherein said preformed crystalline diketopiperazine microparticle
does not comprise an active agent; iii) altering suspension conditions in said preformed crystalline
diketopiperazine microparticle suspension wherein said altering step
modifies a surface property of said crystalline microparticle;

iv) forming a suspension comprising said surface-modified preformed crystalline diketopiperazine microparticle, said insulin, and said solvent wherein said altering step has modified the energetic interaction between said insulin and said crystalline microparticle; then
v) adsorbing said active agent onto a surface of said crystalline microparticle to provide a coating of said active agent on said crystalline microparticle without removing solvent from said suspension and wherein said altering step causes said adsorption of insulin onto a surface of said crystalline microparticle; and vi) removing or exchanging said solvent after said adsorbing step.

Documents:

1920-delnp-2008-Abstract-(11-09-2014).pdf

1920-DELNP-2008-Claims-(11-09-2009).pdf

1920-delnp-2008-Correspondence Others-(11-09-2014).pdf

1920-delnp-2008-Correspondence Others-(20-04-2012).pdf

1920-delnp-2008-Correspondence Others-(27-03-2014).pdf

1920-delnp-2008-Correspondence Others-(30-11-2012).pdf

1920-DELNP-2008-Correspondence-Others-(11-09-2009).pdf

1920-delnp-2008-Drawings-(11-09-2014).pdf

1920-delnp-2008-form-13-(11-09-2009).pdf

1920-DELNP-2008-Form-18-(11-09-2009).pdf

1920-delnp-2008-Form-2-(11-09-2014).pdf

1920-delnp-2008-Form-3 -(30-11-2012)0059.pdf

1920-delnp-2008-Form-3-(11-09-2014).pdf

1920-delnp-2008-Form-3-(20-04-2012).pdf

1920-delnp-2008-Form-3-(27-03-2014).pdf

1920-delnp-2008-GPA-(11-09-2014).pdf

1920-delnp-2008-Petition-137-(11-09-2014).pdf

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Patent Number

264299

Indian Patent Application Number

1920/DELNP/2008

PG Journal Number

52/2014

Publication Date

26-Dec-2014

Grant Date

19-Dec-2014

Date of Filing

05-Mar-2008

Name of Patentee

MANNKIND CORPORATION

Applicant Address

28903 North Avenue Paine Valencia CA 91355 USA

Inventors:

#	Inventor's Name	Inventor's Address
1	OBERG, Keith, A.	25850 El Gato Place Valencia CA 91355 USA

PCT International Classification Number

A61K 9/16

PCT International Application Number

PCT/US2006/036034

PCT International Filing date

2006-09-14

PCT Conventions:

#	PCT Application Number	Date of Convention	Priority Country
1	60/717,524	2005-09-14	U.S.A.
2	60/744,882	2006-04-14	U.S.A.