Controlled releasing composition

• US 20110244043A1
• Filed: 12/10/2009
• Published: 10/06/2011
• Est. Priority Date: 12/10/2008
• Status: Active Grant

• Current Assignee: Jianjian Xu, Manzhi Ding, Shiliang Wang
• Original Assignee: Jianjian Xu, Manzhi Ding, Shiliang Wang
• Inventors: Ding, Manzhi, Wang, Shiliang, Xu, Jianjian
• Granted Patent: US 9,498,431 B2
• Time in Patent Office: Days
• US Class Current: 424/484
• CPC Class Codes: A61K 2300/00 Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
• CPC Class Codes: A61K 31/167 having the nitrogen of a carboxamide group directly attached to the aromatic ring, e.g. lidocaine, paracetamol
• CPC Class Codes: A61K 31/365 Lactones
• CPC Class Codes: A61K 31/505 Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
• CPC Class Codes: A61K 31/513 having oxo groups directly attached to the heterocyclic ring, e.g. cytosine
• CPC Class Codes: A61K 31/519 ortho- or peri-condensed with heterocyclic rings
• CPC Class Codes: A61K 31/573 substituted in position 21, e.g. cortisone, dexamethasone, prednisone or aldosterone
• CPC Class Codes: A61K 31/7036 having at least one amino group directly attached to the carbocyclic ring, e.g. streptomycin, gentamycin, amikacin, validamycin, fortimicins
• CPC Class Codes: A61K 31/704 attached to a condensed carbocyclic ring system, e.g. sennosides, thiocolchicosides, escin, daunorubicin digitoxin A61K31/7048
• CPC Class Codes: A61K 31/7048 having oxygen as a ring hetero atom, e.g. leucoglucosan, hesperidin, erythromycin, nystatin , digitoxin or digoxin
• CPC Class Codes: A61K 33/243 Platinum; Compounds thereof
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61K 9/0024 Solid, semi-solid or solidifying implants, which are implanted or injected in body tissue compositions for intravenous administration, normal injectable solutions or dispersions for, e.g. subcutaneous administration A61K9/0019; brain implants A61K9/0085; (coated) prostheses, catheters or stents A61L
• CPC Class Codes: A61K 9/1647 Polyesters, e.g. poly(lactide-co-glycolide)
• CPC Class Codes: A61K 9/1652 Polysaccharides, e.g. alginate, cellulose derivatives; Cyclodextrin homeopathic globules A61K9/1623
• CPC Class Codes: A61K 9/1664 Compounds of unknown constitution, e.g. material from plants or animals oils, fats, waxes, shellac A61K9/1617
• CPC Class Codes: A61K 9/204 Polyesters, e.g. poly(lactide-co-glycolide)
• CPC Class Codes: A61P 1/02 Stomatological preparations, e.g. drugs for caries, aphtae, periodontitis
• CPC Class Codes: A61P 1/08 for nausea, cinetosis or vertigo; Antiemetics
• CPC Class Codes: A61P 1/10 Laxatives
• CPC Class Codes: A61P 1/12 : Antidiarrhoeals
• CPC Class Codes: A61P 1/14 : Prodigestives, e.g. acids, enzymes, appetite stimulants, antidyspeptics, tonics, antiflatulents
• CPC Class Codes: A61P 1/16 : for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
• CPC Class Codes: A61P 1/18 : for pancreatic disorders, e.g. pancreatic enzymes
• CPC Class Codes: A61P 11/00 : Drugs for disorders of the respiratory system
• CPC Class Codes: A61P 11/02 : Nasal agents, e.g. decongestants
• CPC Class Codes: A61P 11/04 : for throat disorders
• CPC Class Codes: A61P 11/06 : Antiasthmatics
• CPC Class Codes: A61P 13/02 : of urine or of the urinary tract, e.g. urine acidifiers
• CPC Class Codes: A61P 13/08 : of the prostate
• CPC Class Codes: A61P 13/10 : of the bladder
• CPC Class Codes: A61P 13/12 : of the kidneys
• CPC Class Codes: A61P 15/00 : Drugs for genital or sexual disorders for disorders of sex hormones A61P5/24; Contraceptives
• CPC Class Codes: A61P 15/02 : for disorders of the vagina
• CPC Class Codes: A61P 15/08 : for gonadal disorders or for enhancing fertility, e.g. inducers of ovulation or of spermatogenesis
• CPC Class Codes: A61P 15/10 : for impotence
• CPC Class Codes: A61P 15/12 : for climacteric disorders
• CPC Class Codes: A61P 17/00 : Drugs for dermatological disorders
• CPC Class Codes: A61P 17/02 : for treating wounds, ulcers, burns, scars, keloids, or the like
• CPC Class Codes: A61P 17/04 : Antipruritics
• CPC Class Codes: A61P 17/06 : Antipsoriatics
• CPC Class Codes: A61P 17/08 : Antiseborrheics
• CPC Class Codes: A61P 17/12 : Keratolytics, e.g. wart or anti-corn preparations
• CPC Class Codes: A61P 17/14 : for baldness or alopecia
• CPC Class Codes: A61P 17/16 : Emollients or protectives, e.g. against radiation
• CPC Class Codes: A61P 19/02 : for joint disorders, e.g. arthritis, arthrosis
• CPC Class Codes: A61P 19/04 : for non-specific disorders of the connective tissue
• CPC Class Codes: A61P 19/06 : Antigout agents, e.g. antihyperuricemic or uricosuric agents
• CPC Class Codes: A61P 19/08 : for bone diseases, e.g. rachitism, Paget's disease
• CPC Class Codes: A61P 19/10 : for osteoporosis
• CPC Class Codes: A61P 21/00 : Drugs for disorders of the muscular or neuromuscular system
• CPC Class Codes: A61P 21/02 : Muscle relaxants, e.g. for tetanus or cramps
• CPC Class Codes: A61P 21/04 : for myasthenia gravis
• CPC Class Codes: A61P 23/02 : Local anaesthetics
• CPC Class Codes: A61P 25/00 : Drugs for disorders of the nervous system
• CPC Class Codes: A61P 25/04 : Centrally acting analgesics, e.g. opioids
• CPC Class Codes: A61P 25/08 : Antiepileptics; Anticonvulsants
• CPC Class Codes: A61P 25/16 : Anti-Parkinson drugs
• CPC Class Codes: A61P 25/20 : Hypnotics; Sedatives
• CPC Class Codes: A61P 25/22 : Anxiolytics
• CPC Class Codes: A61P 25/24 : Antidepressants
• CPC Class Codes: A61P 25/28 : for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
• CPC Class Codes: A61P 25/34 : Tobacco-abuse
• CPC Class Codes: A61P 27/02 : Ophthalmic agents
• CPC Class Codes: A61P 27/14 : Decongestants or antiallergics
• CPC Class Codes: A61P 29/00 : Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• CPC Class Codes: A61P 3/00 : Drugs for disorders of the metabolism of the blood or the extracellular fluid A61P7/00
• CPC Class Codes: A61P 3/04 : Anorexiants; Antiobesity agents
• CPC Class Codes: A61P 3/06 : Antihyperlipidemics
• CPC Class Codes: A61P 3/10 : for hyperglycaemia, e.g. antidiabetics
• CPC Class Codes: A61P 3/14 : for calcium homeostasis vitamin D A61P3/02; parathyroid hormones A61P5/18; calcitonin A61P5/22; osteoporosis A61P19/10; bone metastasis A61P35/04
• CPC Class Codes: A61P 31/00 : Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
• CPC Class Codes: A61P 31/04 : Antibacterial agents
• CPC Class Codes: A61P 31/06 : for tuberculosis
• CPC Class Codes: A61P 31/10 : Antimycotics
• CPC Class Codes: A61P 31/12 : Antivirals
• CPC Class Codes: A61P 31/16 : for influenza or rhinoviruses
• CPC Class Codes: A61P 31/18 : for HIV
• CPC Class Codes: A61P 31/22 : for herpes viruses
• CPC Class Codes: A61P 35/00 : Antineoplastic agents
• CPC Class Codes: A61P 35/02 : specific for leukemia
• CPC Class Codes: A61P 35/04 : specific for metastasis
• CPC Class Codes: A61P 37/00 : Drugs for immunological or allergic disorders
• CPC Class Codes: A61P 37/04 : Immunostimulants
• CPC Class Codes: A61P 37/06 : Immunosuppressants, e.g. drugs for graft rejection
• CPC Class Codes: A61P 37/08 : Antiallergic agents antiasthmatic agents A61P11/06; ophthalmic antiallergics A61P27/14
• CPC Class Codes: A61P 5/00 : Drugs for disorders of the endocrine system
• CPC Class Codes: A61P 5/06 : of the anterior pituitary hormones, e.g. TSH, ACTH, FSH, LH, PRL, GH
• CPC Class Codes: A61P 5/10 : of the posterior pituitary hormones, e.g. oxytocin, ADH
• CPC Class Codes: A61P 5/14 : of the thyroid hormones, e.g. T3, T4
• CPC Class Codes: A61P 5/18 : of the parathyroid hormones
• CPC Class Codes: A61P 5/24 : of the sex hormones
• CPC Class Codes: A61P 5/26 : Androgens
• CPC Class Codes: A61P 5/30 : Oestrogens
• CPC Class Codes: A61P 5/48 : of the pancreatic hormones
• CPC Class Codes: A61P 7/02 : Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
• CPC Class Codes: A61P 7/04 : Antihaemorrhagics; Procoagulants; Haemostatic agents; Antifibrinolytic agents
• CPC Class Codes: A61P 7/06 : Antianaemics
• CPC Class Codes: A61P 7/10 : Antioedematous agents; Diuretics
• CPC Class Codes: A61P 9/00 : Drugs for disorders of the cardiovascular system
• CPC Class Codes: A61P 9/02 : Non-specific cardiovascular stimulants, e.g. drugs for syncope, antihypotensives
• CPC Class Codes: A61P 9/04 : Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
• CPC Class Codes: A61P 9/06 : Antiarrhythmics
• CPC Class Codes: A61P 9/08 : Vasodilators for multiple indications
• CPC Class Codes: A61P 9/10 : for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
• CPC Class Codes: A61P 9/12 : Antihypertensives
• CPC Class Codes: A61P 9/14 : Vasoprotectives; Antihaemorrhoidals; Drugs for varicose therapy; Capillary stabilisers
• CPC Class Codes: Y02A 50/30 : Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Abstract

A controlled releasing composition comprising a plurality of microparticles and a matrix as well as the preparation method thereof is disclosed. The plurality of microparticles comprise a first material and the matrix comprises a second material. The melting temperature of the first material is higher than the melting temperature of the second material.

Claims

1. A controlled release composition comprising a plurality of microparticles operably linked to a matrix, wherein:

the plurality of microparticles comprises a first material and a first active agent;

the matrix comprises a second material;

the first material comprises an initial melting temperature T_H;

the second material comprises a complete melting temperature T_L;

Δ

T=T_H−

T_L; and

Δ

T>

0.

2. The controlled release composition of claim 1, wherein the first material or the second material is a polymer or a non-polymeric organic compound.

3. The controlled release composition of claim 2, wherein the first material and the second material are either a polymer or a non-polymeric organic compound.

4. The controlled release composition of claim 2, wherein the first material is a polymer and the second material is a non-polymeric organic compound.

5. The controlled release composition of claim 2, wherein the first material is a non-polymeric organic compound and the second material is a polymer.

6. The controlled release composition of claim 2, wherein the first material is a combination of a polymer and a non-polymeric organic compound.

7. The controlled release composition of claim 2, wherein the second material is a combination of a polymer and a non-polymeric organic compound.

8. The controlled release composition of claim 1, wherein the first material or the second material comprises a polymer formed by at least one monomer independently selected from the group consisting of:

L-lactic acid, saccharide, ethylene glycol oxalate, p-dioxanone, ε

-caprolactone, ethylcyanoacrylate, butylcyanoacrylate, β

-hydroxybutyrate, 3-hydroxybutyrate, 4-hydroxyvalerate, 1,3-bis(carboxyphenoxy)propane, sebacic acid, D-glucose, acetate of glucose, glucose substituted with hydroxyl groups, glycolic acid, ε

-caprolacton, 1,4-dioxan-2-one, sebacic anhydride, dodecanoic anhydride, ethylene glycol, oxyethylene, 1,3-bis(carboxyphenoxy)propane, 3-hydroxyvalerate, caprolactone, methyl methacrylate, gelatin, isoleucine, leucine, alanine, asparagine, lysine, methionine, aspartic acid, cysteine, tryptophan, valine, glycine, proline, serine, tyrosine, arginine, histidine, phenylalanine, glutamic acid, threonine, glutamine, adenine, guanine, thymine, cytosine, and dimethyl siloxane.

9. The controlled release composition of claim 1, wherein the first material or the second material is independently selected from the group consisting of poly(L-lactic acid), dextran, poly(ethylene glycol oxalate), poly(p-dioxanone-co-ε

-caprolactone), poly(ethylcyanoacrylate), poly(butylcyanoacrylate), poly (β

-hydroxybutyrate), poly(3-hydroxybutyrate-co-4-hydroxyvalerate), poly(1,3-bis(carboxyphenoxy)propane-co-sebacic acid), cholesterol, cellulose acetate, hydroxypropyl methyl cellulose phthalate, zein, poly(L-lactic-co-glycolic acid), poly(ε

-caprolacton), poly(1,4-dioxan-2-one), poly(sebacic anhydride), poly(dodecanoic anhydride), poly(ethylene glycol), polyoxyethylene, stearic acid, stearyl alcohol;

ethylene glycol palmitostearate, cetyl esters wax, poly(1,3-bis(carboxyphenoxy)propane-co-sebacic acid), poly(3-hydroxybutyrate-co-3-hydroxyvalerate), Carnauba wax, ethylcellulose, octadecanol, polycaprolactone, poly(methyl methacrylate), poly(gelatin), and silicone rubber.

10. The controlled release composition of claim 1, wherein the first material is selected from the group consisting of:

(i) a combination of poly(L-lactic acid) and at least one compound selected from the group consisting of;

dextran, poly(ethylene glycol oxalate), poly(p-dioxanone-co-ε

-caprolactone), poly(ethylcyanoacrylate), poly(butylcyanoacrylate), poly (β

-hydroxybutyrate), poly(3-hydroxybutyrate-co-4-hydroxyvalerate), poly(1,3-bis(carboxyphenoxy)propane-co-sebacic acid), cholesterol, cellulose acetate, hydroxypropyl methyl cellulose phthalate, and zein;

(ii) a combination of poly(ethylene glycol oxalate) and at least one compound selected from the group consisting of;

dextran, poly(p-dioxanone-co-c-caprolactone), poly(ethylcyanoacrylate), poly(butylcyanoacrylate), poly (β

-hydroxybutyrate), poly(3-hydroxybutyrate-co-4-hydroxyvalerate), poly(1,3-bis(carboxyphenoxy)propane-co-sebacic acid), cholesterol, cellulose acetate, hydroxypropyl methyl cellulose phthalate, and zein;

(iii) a combination of poly(β

-hydroxybutyrate) and at least one compound selected from the group consisting of;

dextran, poly(p-dioxanone-co-ε

-caprolactone), poly(ethylcyanoacrylate), poly(butylcyanoacrylate), poly(3-hydroxybutyrate-co-4-hydroxyvalerate), poly(1,3-bis(carboxyphenoxy)propane-co-sebacic acid), cholesterol, cellulose acetate, hydroxypropyl methyl cellulose phthalate, and zein;

(iv) a combination of poly(1,3-bis(carboxyphenoxy)propane-co-sebacic acid) and at least one compound selected from the group consisting of;

dextran, poly(p-dioxanone-co-ε

-caprolactone), poly(ethylcyanoacrylate), poly(3-hydroxybutyrate-co-4-hydroxyvalerate), cholesterol, cellulose acetate, hydroxypropyl methyl cellulose phthalate, and zein;

(v) a combination of poly(butylcyanoacrylate) and at least one compound selected from the group consisting of;

dextran, poly(p-dioxanone-co-ε

-caprolactone), poly(ethylcyanoacrylate), poly(3-hydroxybutyrate-co-4-hydroxyvalerate), poly(1,3-bis(carboxyphenoxy)propane-co-sebacic acid), cholesterol, cellulose acetate, hydroxypropyl methyl cellulose phthalate, and zein; and

(vi) a combination of (i), (ii), (iii), (iv), or (v).

11. The controlled release composition of claim 1, wherein the second material is selected from the group consisting of:

(i) a combination of poly(L-lactic-co-glycolic acid) and at least one compound selected from the group consisting of;

poly(ε

-caprolacton), poly(1,4-dioxan-2-one), poly(sebacic anhydride), poly(dodecanoic anhydride), poly(ethylene glycol), polyoxyethylene, stearic acid, stearyl alcohol;

ethylene glycol palmitostearate, cetyl esters wax, poly(1,3-bis(carboxyphenoxy)propane-co-sebacic acid), and poly(3-hydroxybutyrate-co-3-hydroxyvalerate);

(ii) a combination of poly(ε

-caprolacton) and at least one compound selected from the group consisting of;

poly(1,4-dioxan-2-one), poly(sebacic anhydride), poly(dodecanoic anhydride), poly(ethylene glycol), polyoxyethylene, stearic acid, stearyl alcohol;

ethylene glycol palmitostearate, cetyl esters wax, poly(1,3-bis(carboxyphenoxy)propane-co-sebacic acid), and poly(3-hydroxybutyrate-co-3-hydroxyvalerate);

(iii) a combination of poly(1,4-dioxan-2-one) and at least one compound selected from the group consisting of;

poly(sebacic anhydride), poly(dodecanoic anhydride), poly(ethylene glycol), polyoxyethylene, stearic acid, stearyl alcohol;

ethylene glycol palmitostearate, cetyl esters wax, poly(1,3-bis(carboxyphenoxy)propane-co-sebacic acid), and poly(3-hydroxybutyrate-co-3-hydroxyvalerate); and

(iv) a combination of poly(sebacic anhydride) and at least one compound selected from the group consisting of;

poly(dodecanoic anhydride), poly(ethylene glycol), polyoxyethylene, stearic acid, stearyl alcohol;

ethylene glycol palmitostearate, cetyl esters wax, poly(1,3-bis(carboxyphenoxy)propane-co-sebacic acid), and poly(3-hydroxybutyrate-co-3-hydroxyvalerate); and

(v) a combination of (i), (ii), (iii), or (iv).

12. The controlled release composition of claim 1, wherein the first material and the second material is a pair of materials selected from the group consisting of:

poly(L-lactic acid) and poly(L-lactic-co-glycolic acid);

poly(L-lactic acid) and poly(ε

-caprolacton);

poly(L-lactic acid) and poly(1,4-dioxan-2-one);

poly(L-lactic acid) and poly(sebacic anhydride);

poly(L-lactic acid) and poly(dodecanoic anhydride);

poly(L-lactic acid) and poly(1,3-bis(carboxyphenoxy)propane-co-sebacic acid);

poly(1,3-bis(carboxyphenoxy)propane-co-sebacic acid) and poly(L-lactic-co-glycolic acid);

poly(1,3-bis(carboxyphenoxy)propane-co-sebacic acid) and poly(ε

-caprolacton);

poly(1,3-bis(carboxyphenoxy)propane-co-sebacic acid) and poly(1,4-dioxan-2-one);

poly(butylcyanoacrylate) and poly(L-lactic-co-glycolic acid);

poly(butylcyanoacrylate) and poly(1,3-bis(carboxyphenoxy)propane-co-sebacic acid);

poly(ethylcyanoacrylate) and poly(L-lactic-co-glycolic acid);

poly(ethylcyanoacrylate) and poly(1,3-bis(carboxyphenoxy)propane-co-sebacic acid);

poly(ethylene glycol oxalate) and poly(L-lactic-co-glycolic acid);

poly(ethylene glycol oxalate) and poly(ε

-caprolacton);

poly(ethylene glycol oxalate) and poly(1,4-dioxan-2-one);

poly(ethylene glycol oxalate) and poly(sebacic anhydride);

poly(ethylene glycol oxalate) and poly(dodecanoic anhydride);

poly(ethylene glycol oxalate) and poly(1,3-bis(carboxyphenoxy)propane-co-sebacic acid);

dextran and poly(butylcyanoacrylate);

dextran and poly(ethylcyanoacrylate);

dextran and poly(L-lactic acid);

dextran and poly(L-lactic-co-glycolic acid);

dextran and poly(1,3-bis(carboxyphenoxy)propane-co-sebacic acid);

dextran and poly(sebacic anhydride);

cellulose acetate and poly(L-lactic acid);

cellulose acetate and poly(butylcyanoacrylate);

cellulose acetate and poly(L-lactic-co-glycolic acid);

cellulose acetate and poly(sebacic anhydride); and

cellulose acetate and poly(dodecanoic anhydride);

Carnauba wax and poly(lactide-co-glycolide);

ethylcellulose and octadecanol;

Carnauba wax and polycaprolactone;

poly(methyl methacrylate) and poly(L-lactide);

poly(lactide-co-glycolide) and poly(gelatin);

silicone rubber and poly(L-lactide);

ethylcellulose and a combination of poly(L-lactic-co-glycolic acid) and poly(ethylene glycol);

a combination of poly(L-lactic acid) and dextran and a combination of poly(L-lactic-co-glycolic acid) and poly(ethylene glycol); and

dextran and a combination of poly(L-lactide) and poly(L-lactic-co-glycolic acid).

13. The controlled release composition of claim 1, wherein Δ

T≧

about 2°

C.

14. The controlled release composition of claim 1, wherein Δ

T≧

about 5°

C.

15. The controlled release composition of claim 1, wherein Δ

T≧

about 10°

C.

20. The controlled release composition of claim 1, wherein the first material is a biodegradable material.

21. The controlled release composition of claim 1, wherein the second material is a biodegradable material.

22. The controlled release composition of claim 21, wherein the second material degrades faster than the first material.

23. The controlled release composition of claim 22, wherein the first material and the second material is a pair of materials selected from the group consisting of:

poly (L-lactide acid) and poly(lactide-co-glycolide acid).

24. The controlled release composition of claim 1, wherein the first active agent or the second active agent is independently selected from the group consisting of:

local anesthetics, antiepileptic drugs and anticonvulsants, anti-alzheimer'"'"'s disease drugs, analgesics, antipodagric, anti-hypertensive drugs, antiarrhythmic drugs, diuretic drugs, drugs for treating liver diseases, drugs for treating pancreatic diseases, antihistamine drugs, anti-allergic drugs, glucocorticoid drugs, sex hormone drugs and contraceptive drugs, hypoglycemic drugs, anti-osteoporosis drugs, antibiotics, sulfonamides, quinolones, and other synthetic antibacterial drugs, antituberculous drugs, antiviral drugs, anti-neoplasm drugs, immunomodulators, and cosmetically active agents.

25. The controlled release composition of claim 1, wherein the microparticles comprise a weight percentage of about 2% to about 98% of the first material, and about 2% to about 98% of the first active agent.

26. The controlled release composition of claim 1, wherein the microparticles further comprise a first additive.

27. The controlled release composition of claim 26, wherein the weight percentage of the first additive in the microparticles ranges from about 0% to about 30%.

28. The controlled release composition of claim 1, wherein at least one of the plurality of the microparticles further comprises a coating.

29. The controlled release composition of claim 1, wherein the matrix further comprises a second active agent.

30. The controlled release composition of claim 29, wherein the weight percentage of the second active agent in the controlled release composition ranges from about 0% to about 70%.

31. The controlled release composition of claim 1, wherein the matrix further comprises a second additive.

32. The controlled release composition of claim 31, wherein the weight percentage of the second additive in the controlled release composition ranges from about 0% to about 30%.

33. The controlled release composition of claim 1, wherein controlled release composition comprises about 1% to about 95% of the microparticles.

34. The controlled release composition of claim 1, wherein the plurality of microparticles are uniformly distributed or embedded in the matrix.

35. The controlled release composition of claim 1, wherein the plurality of microparticles are distributed or embedded in the matrix in accordance with a pre-determined pattern.

36. The controlled release composition of claim 1, wherein controlled release composition comprises a coating.

37. The controlled release composition of claim 1, wherein at least one of the microparticles is of a size ranging from 1 μ

m to about 5000 μ

m.

41. The controlled release composition of claim 1, wherein the controlled release composition is a pharmaceutical composition.

42. The controlled release composition of claim 1, wherein the controlled release composition is an implantable pharmaceutical composition.

16-19. -19. (canceled)

38-40. -40. (canceled)

43. A method for making a controlled release composition comprising a plurality of microparticles operably linked to a matrix, comprising the steps of:

preparing a plurality of microparticles comprising a first material and a first active agent; and

applying the plurality of microparticles to a matrix-forming composition, thereby forming the controlled release composition comprising a second material, wherein;

the first material comprises an initial melting temperature T_H;

the second material comprises a complete melting temperature T_L;

Δ

T=T_H−

T_L; and

Δ

T>

0.

44-54. -54. (canceled)

55. A method of treating a condition in a subject, comprising administering to the subject a controlled release composition, wherein:

the controlled release composition comprising a plurality of microparticles operably linked to a matrix;

the plurality of microparticles comprises a first material and a first active agent;

the matrix comprises a second material;

the first material comprises an initial melting temperature T_H;

the second material comprises a complete melting temperature T_L;

Δ

T=T_H−

T_L; and

Δ

T>

0.

56-63. -63. (canceled)