U.S. patent application number 10/769008 was filed with the patent office on 2004-11-25 for ph triggered site specific targeted controlled drug delivery system for the treatment of cancer.
Invention is credited to Shefer, Adi, Shefer, Samuel.
Application Number | 20040234597 10/769008 |
Document ID | / |
Family ID | 32468803 |
Filed Date | 2004-11-25 |
United States Patent
Application |
20040234597 |
Kind Code |
A1 |
Shefer, Adi ; et
al. |
November 25, 2004 |
pH triggered site specific targeted controlled drug delivery system
for the treatment of cancer
Abstract
The present invention relates to a novel pH triggered, targeted
controlled release system. The controlled delivery system of the
present invention is substantially a free-flowing powder formed of
solid hydrophobic nanospheres comprising pharmaceutical active
ingredients that are encapsulated in pH sensitive microspheres. The
invention also relates to the processes for preparing the
compositions and processes for using same. The controlled release
system can be used to target and control the release of active
ingredients for treating a cellular proliferation disease or
tumors. The invention further pertains to pharmaceutical products
comprising the controlled release system of the present
invention.
Inventors: |
Shefer, Adi; (East
Brunswick, NJ) ; Shefer, Samuel; (East Brunswick,
NJ) |
Correspondence
Address: |
Diane Dunn McKay, Esq.
Mathews, Collins, Shepherd & McKay, P.A.
Suite 306
100 Thanet Circle
Princeton
NJ
08540
US
|
Family ID: |
32468803 |
Appl. No.: |
10/769008 |
Filed: |
January 30, 2004 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
10769008 |
Jan 30, 2004 |
|
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10315801 |
Dec 9, 2002 |
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Current U.S.
Class: |
424/468 |
Current CPC
Class: |
A61K 49/0404 20130101;
A61K 9/5084 20130101; B82Y 5/00 20130101; A61K 9/1635 20130101;
A61K 9/2077 20130101; A61K 9/5138 20130101; A61K 49/0485
20130101 |
Class at
Publication: |
424/468 |
International
Class: |
A61K 009/22 |
Claims
What is claimed is:
1. A controlled release composition comprising: a plurality of
solid nanospheres encapsulated in a microsphere formed of a pH
sensitive or salt sensitive matrix material, and a first active
agent incorporated into at least one of: the nanospheres or the
microsphere; wherein said first active agent is selected from the
group consisting of a cytotoxic agent, a chemotherapeutic agent, an
anti-oncology agent, a radionuclide, a nucleic acid, a protein, and
a biopharmaceutical.
2. The composition of claim 1 wherein said first pharmaceutical
active agent is incorporated into the nanospheres and a second
pharmaceutical active agent is incorporated into the microsphere
wherein said second active agent is selectively released upon
contact with an aqueous solution having a predetermined pH or
predetermined salt concentration.
3. The composition according to claim 1 wherein said microsphere
degrades or dissolves in an aqueous solution having a pH within the
range of about 3.5 to about 6.8.
4. The composition according to claim 1 wherein the microsphere
degrades or dissolves in an aqueous solution at a pH lower than
about 6.8.
5. The composition according to claim 1 wherein the microsphere
degrades or dissolves in an aqueous solution at pH lower than about
6.5.
6. The composition according to claim 1 wherein the microsphere
degrades or dissolves in an aqueous solution at a pH lower than
about 6.
7. The composition of claim 1 wherein said pH sensitive matrix is
relatively insoluble and impermeable at a normal physiological pH
of about 7.4, and is more soluble and permeable at an ambient pH at
or near cancerous tissue at a pH between about 3.5 and about
6.8.
8. The composition of claim 1 wherein said pH sensitive matrix
material is selected from the group consisting of: acrylate
polymers with amino substituents, acrylic acid esters,
polyacrylamides, phthalate derivatives and mixtures thereof.
9. The composition of claim 1 wherein said pH sensitive matrix
material is selected from the group consisting of: acid phthalate
of carbohydrate, amylose acetate phthalate, cellulose acetate
phthalate, cellulose ester phthalate, cellulose ether phthalate,
hydroxy propyl cellulose phthalate, hydroxypropyl ethylcellulose
phthalate, hydroxypropyl methyl cellulose phthalate, methyl
cellulose phthalate, polyvinyl acetate phthalate, polyvinyl acetate
hydrogen phthalate, sodium cellulose acetate phthalate, starch acid
phthalate, styrene-maleic acid dibutyl phthalate copolymer,
styrene-maleic acid polyvinyl acetate phthalate copolymer, styrene
and maleic acid copolymer, gelatin, gluten, shellac, salol,
keratin, keratin sandarac-tolu, ammoniated shellac, benzophenyl
salicylate, cellulose acetate trimellitate, cellulose acetate
blended with shellac, hydroxypropylmethyl cellulose acetate
succinate, oxidized cellulose, polyacrylic acid derivative, acrylic
acid and acrylic ester copolymers, methacrylic acid, methacrylic
acid ester, vinyl acetate, crotonic acid copolymer and mixtures
thereof.
10. The composition according to claim 1 wherein a first portion of
said plurality of nanospheres are adhered to a second portion of
said plurality of nanospheres with a pH sensitive matrix
material.
11. The composition according to claim 1 further comprising a
moisture sensitive material mixed with said pH sensitive or salt
sensitive material of said microsphere.
12. The composition according to claim 11 wherein said moisture
sensitive material is selected from the group consisting of
polyvinyl pyrrolidone, water soluble cellulose, polyvinyl alcohol,
ethylene maleic anhydride copolymer, methyl vinyl ether maleic
anhydride copolymer, polyethylene oxides, polyamide, polyester,
copolymers or homopolymers of acrylic acid, polyacrylic acid,
polystyrene acrylic acid copolymer, starch derivatives, polyvinyl
alcohol, acrylic acid copolymer, anionic polymer of methacrylic
acid and methacrylate, cationic polymer having dimethyl-aminoethyl
ammonium functional groups, hydroxyethyl cellulose, carboxymethyl
cellulose, hydroxymethyl cellulose, carboxymethyl cellulose,
hydroxypropyl carboxymethyl cellulose, hydroxypropyl methyl
carboxyethyl cellulose, hydroxypropyl carboxypropyl cellulose,
hydroxybutyl carboxymethyl cellulose, polysaccharide, hydrocolloid,
natural gum, protein, and mixtures thereof.
13. The composition of claim 1 wherein said solid nanospheres are
formed of a wax material having a melting point in the range of
between about 25.degree. C. and about 150.degree. C.
14. The composition of claim 13 wherein said wax material has a
penetration point of about 1 to about 10.
15. The composition of claim 13 wherein said wax material is
selected from the group consisting of: natural wax, synthetic wax,
regenerated wax, vegetable wax, animal wax, mineral wax, petroleum
wax, microcrystalline wax and mixtures thereof.
16. The composition of claim 13 wherein said wax comprises one or
more of carnauba wax, candelilla wax and beeswax.
17. The composition of claim 1 wherein said solid nanospheres are
formed of a fat material selected from the group consisting of:
hydrogenated castor oil, hydrogenated vegetable oil, hard fat,
glyceride, fatty acids, fatty acid derivative, lipid, steroid and
mixtures thereof.
18. The composition of claim 17 wherein said glyceride is selected
from the group consisting of: triglyceride, monoglyceride,
diglyceride, glyceryl monostearate, glycerol tristearate and
mixtures thereof.
19. The composition of claim 17 wherein said fatty acid derivative
is selected from the group consisting of: alcohol, ester,
anhydride, hydroxy fatty acid and prostaglandin.
20. The composition of claim 17 wherein said fat material is
selected from the group consisting of: lauric acid, physeteric
acid, myristoleic acid, palmitoleic acid, petroselinic acid, oleic
acid, isolauric acid, isomyristic acid, isopalmitic acid,
isostearic acid, isoprenoid,
12-(((7'-diethylaminocoumarin-3yl)carbonyl)methylamino)-octadecanoic
acid,
N-[12-(((7'-diethylaminocoumarin-3-yl)carbonyl)methyl-amino)octadec-
anoyl]-2-aminopalmitic acid, N succinyl-dioleoylphosphatidylethanol
amine, palmitoyl-homocysteine, digalactosyldiglyceride,
1,2-dioleoyl-sn-glycerol- ; 1,2-cdipalmitoyl-sn-3 succinylglycerol;
1,3-dipalmitoyl-2-succinylglycer- ol and mixtures thereof.
21. The composition of claim 17 wherein said fat material is
selected from the group consisting of: phospholipid, sphingolipid,
cholesterol, steroid derivative, terpene, tocopherol, stearlyamine,
vitamin and mixtures thereof.
22. The composition of claim 21 wherein said phospholipid is
selected fom the group consisting essentially of phosphatidic acid,
phosphatidyl choline, phosphatidyl ethanolamine,
phosphatidylglycerol, phosphatidylserine, phosphatidylinositol,
lysophosphatidyl derivative, cardiolipin, beta-acyl-y-alkyl
phospholipid, phosphatidylcholines, dioleoylphosphatidylcholine,
dimyristoylphosphatidylcholine, dipentadecanoylphosphatidylcholine,
dilauroylphosphatidylcholine, dipalmitoylphosphatidylcholine
(DPPC), distearoylphosphatidylcholine (DSPC),
diarachidoylphosphatidylcholine (DAPC), dibehenoylphosphatidylcho-
line (DBPC), ditricosanoylphosphatidylcholine (DTPC),
dilignoceroylphatidylcholine (DLPC), phosphatidylethanolamine,
dioleoylphosphatidylethanolamine,
1-hexadecyl-2-palmitoylglycerophosphoet- hanolamine, synthetic
phospholipids and mixtures thereof.
23. The composition of claim 21 wherein said steroid derivative is
selected from the group consisting of: cholesterol, cholesterol
sulfate, cholesterol hemisuccinate, 6-(5-cholesterol 3 beta-yloxy)
hexyl6-amino-6-deoxy-1-thio-alpha-D-galactopyranoside,
6-(5-cholesten-3 beta-tloxy)hexyl-6-amino-6-deoxyl-1-thio-alpha-D
mannopyranoside, cholesteryl(4'-trimethyl 35 ammonio)butanoate and
mixtures thereof.
24. The composition of claim 1, wherein said microsphere further
comprises a water sensitive material selected from the group
consisting of: natural oligomer, synthetic oligomer, natural
polymer, synthetic polymer and copolymer, starch, starch
derivative, oligosaccharide, polysaccharide, hydrocolloid, natural
gum, protein, cellulose, cellulose derivative and mixtures
thereof.
25. The composition of claim 1 further comprising a bioadhesive
material incorporated into said solid nanosphere or said
microsphere or in both said nanosphere and said microsphere.
26. The composition of claim 25 wherein said bioadhesive material
is a bioadhesive polymer.
27. The composition of claim 26 wherein said bioadhesive polymer is
selected from the group consisting of polyhyaluronic acids, casein,
gelatin, glutin, polyanhydrides, polyacrylic acid, alginate,
chitosan, poly(methyl methacrylates), poly(ethyl methacrylates),
poly (butyl methacrylate), poly(isobutyl methacrylate), poly(hexl
methacrylate), poly(isodecl methacrylate), poly(lauryl
methacrylate), poly(phenyl methacrylate), poly(methyl acrylate),
poly(isopropyl acrylate), poly(isobutyl acrylate), poly(octadecl
acrylate) and poly(fumaric-co-sebacic)acid.
28. The composition of claim 1 wherein said nanosphere further
comprises a ligand.
29. The composition of claim 1 wherein said nanosphere further
comprises a targeting material selected from the group comprising
lectin viral protein, bacterial protein, monoclonal antibody and
antibody fragment.
30. The composition of claim 1 wherein said first active agent is
selected from the group consisting of: cisplatin, camptothecin,
vinblastine, paclitaxel, fluorouracil, docetaxel, fluorourideine,
tiazofurin, doxorubicin, mechlorethamine, etoposide, mitomycin, and
bleomycin.
31. The composition of claim 1 wherein said nanospheres further
comprise a cationic surface active agent, anionic surface active
agent, a nonionic surface active agent or a zwitterionic surface
active agent.
32. The composition of claim 1 wherein said microsphere has a size
within the range of about 20 to about 100 microns.
33. The composition according to claim 1 wherein each of said
nanospheres has an average size within the range of about 0.01 to
about 5 microns.
34. The composition according to claim 1 wherein said first active
agent is incorporated in said microsphere and said nanospheres,
wherein said pH or salt sensitive material upon contact with an
aqueous solution releases said first active agent to provide a
burst and said first active agent is released continuously
thereafter for an extended period of time.
35. The composition according to claim 34 wherein the extended
period of time is within the range of about one day to about three
weeks.
36. The composition according to claim 2 wherein upon contact with
said solution said second pharmaceutical agent is released to
provide a burst and said first pharmaceutical agent is released
continuously thereafter for an extended period of time.
37. The composition according to claim 36 wherein the extended
period of time is within the range of about one day to about three
weeks.
38. A pharmaceutical composition comprising a physiologically
acceptable carrier, and a controlled release composition
comprising: a plurality of solid nanospheres encapsulated in a
microsphere formed of a pH sensitive or salt sensitive matrix
material, and an effective amount of first active agent
incorporated into at least one of: the nanospheres or the
microsphere; wherein said first active agent is selected from the
group consisting of a cytotoxic agent, a chemotherapeutic agent, an
anti-oncology agent, a radionuclide, a nucleic acid, a protein, and
a biopharmaceutical.
39. The pharmaceutical composition according to claim 38 in a
dosage form selected from the group consisting of powder, tablets,
capsules and injectable compositions.
40. An article comprising the composition of claim 1.
41. A method for selectively delivering an active substance to a
preselected environment comprising aministering a controlled
release composition to an environment, said composition comprising:
a plurality of solid nanospheres encapsulated in a microsphere
formed of a pH sensitive or salt sensitive matrix material, and a
first active agent incorporated into at least one of: the
nanospheres or the microsphere; wherein said first active agent is
selected from the group consisting of a cytotoxic agent, a
chemotherapeutic agent, an anti-oncology agent, a radionuclide, a
nucleic acid, a protein, and a biopharmaceutical.
42. The method of claim 41 wherein said environment is a mammal and
said preselected environment is a tumor.
43. The method of claim 42 wherein said pH sensitive matrix
material degrades or dissolves when the microsphere contacts a
solution having a pH in the range of about 3.5 to about 6.8.
44. The method of claim 43 wherein said pH sensitive material is
selected from the group consisting of: acid phthalate of
carbohydrate, amylose acetate phthalate, cellulose acetate
phthalate, cellulose ester phthalate, cellulose ether phthalate,
hydroxy propyl cellulose phthalate, hydroxypropyl ethylcellulose
phthalate, hydroxypropyl methyl cellulose phthalate, methyl
cellulose phthalate, polyvinyl acetate phthalate, polyvinyl acetate
hydrogen phthalate, sodium cellulose acetate phthalate, starch acid
phthalate, styrene-maleic acid dibutyl phthalate copolymer,
styrene-maleic acid polyvinyl acetate phthalate copolymer, styrene
and maleic acid copolymer, gelatin, gluten, shellac, salol,
keratin, keratin sandarac-tolu, ammoniated shellac, benzophenyl
salicylate, cellulose acetate trimellitate, cellulose acetate
blended with shellac, hydroxypropylmethyl cellulose acetate
succinate, oxidized cellulose, polyacrylic acid derivative, acrylic
acid and acrylic ester copolymers, methacrylic acid, methacrylic
acid ester, vinyl acetate, crotonic acid copolymer and mixtures
thereof.
45. The method of claim 42 wherein a first portion of said
plurality of nanospheres are adhered to a second portion of said
plurality of nanospheres with a pH sensitive or salt sensitive
matrix material.
46. The method of claim 42 further comprising a moisture sensitive
material mixed with said pH sensitive or salt sensitive material of
said microsphere.
47. The method of claim 42 wherein said active agent is selected
from the group consisting of: cisplatin, camptothecin, vinblastine,
paclitaxel, fluorouracil, docetaxel, fluorourideine, tiazofurin,
doxorubicin, mechlorethamine, etoposide, mitomycin, and
bleomycin.
48. The method of claim 42 further comprising a bioadhesive
material incorporated into said solid nanosphere or said
microsphere or in both said nanosphere and said microsphere.
49. The method of claim 48 wherein said bioadhesive material is a
bioadhesive polymer.
50. The method of claim 42 wherein said nanosphere further
comprises a ligand.
51. The method of claim 42 wherein said nanosphere comprises a
targeting material selected from the group consisting essentially
of lectin, viral protein, bacterial protein, monoclonal antibody
and antibody fragment.
52. A method for treating a host suffering from a cellular
proliferation disease comprising: administering to the host a
composition comprising a controlled release composition comprising
a plurality of solid nanospheres encapsulated in a microsphere
formed of a pH sensitive or salt sensitive matrix material, and a
first active agent incorporated into at least one of: the
nanospheres or the microsphere; wherein said first active agent is
selected from the group consisting of a cytotoxic agent, a
chemotherapeutic agent, an anti-oncology agent, a radionuclide, a
nucleic acid, a protein, and a biopharmaceutical.
53. A method for treating a mammal according to claim 52, wherein
the mammal has a solid tumor as a result of a cancer selected from
the group consisting of melanoma, colon cancer, prostate cancer,
lung cancer, pancreatic cancer, ovarioan cancer and breast cancer,
comprising: administering to the mammal an effective amount of a
controlled release composition comprising a plurality of solid
nanospheres encapsulated in a microsphere formed of a pH sensitive
or salt sensitive matrix material, and a first active agent
incorporated into at least one of: the nanospheres or the
microsphere; wherein said first active agent is selected from the
group consisting of a cytotoxic agent, a chemotherapeutic agent, an
anti-oncology agent, a radionuclide, a nucleic acid, a protein, and
a biopharmaceutical.
54. A process for producing a controlled release composition
comprising the steps of: heating a hydrophobic material to a
temperature above a melting point to form a hot melt; dissolving or
dispersing a first pharmaceutical active agent into the melt;
dissolving or dispersing a second active agent, and a pH sensitive
matrix material, in an aqueous phase and heating it to above the
melting temperature of the hydrophobic material; mixing the hot
melt with the aqueous phase to form a dispersion; high shear
homogenizing the dispersion at a temperature above the melting
temperature until a homogeneous fine dispersion is obtained;
cooling the dispersion to ambient temperature; and spray drying the
emulsified mixed suspension to form a dry powder composition.
Description
CROSS REFERENCE TO RELATED APPLICATION
[0001] This application is a continuation-in-part of U.S. patent
application Ser. No. 10/315,801, filed Dec. 9, 2002, entitled pH
Triggered Targeted Controlled Release Systems For The Delivery Of
Pharmaceutical Active Ingredients, the entirety of which is hereby
incorporated by reference into this application.
BACKGROUND OF THE INVENTION
[0002] 1. Field of the Invention
[0003] The present invention relates to a novel targeted controlled
drug delivery system for the treatment of patients afflicted with
oncological disorders, such as cancer tumors. More specifically,
the present invention relates to a site specific targeted
controlled drug delivery composition that comprises solid
hydrophobic nanospheres encapsulated in a pH sensitive microsphere
for treating cancer tumors.
[0004] 2. Description of the Related Art
[0005] Systemic chemotherapy is one of the most successful
treatments for cancer out of the current available treatment
strategies, including surgical resection and external beam
radiation therapy and has been successful in treating colon-rectum,
esophagus, liver, pancreas, kidney, and melanoma cancers. However,
efficacious systemic chemotherapeutic agents at the doses that
control tumor growth have high systemic toxicity and adverse side
effects such as vomiting, myelosuppression, cardiac toxicity,
pulmonary fibrosis, hepatobiliary toxicity, and others. These toxic
side effects are the limiting factor in determining the
concentration of the drug that can be prescribed to the patient and
as a result the doses that are administered may be insufficient to
completely kill the tumor cells and prevent their spreading and
regrowth. Poor solubility and low bioavailability of some of the
chemotherapeutic agents were also observed to reduce treatment
efficacy. For example, paclitaxel (taxol), a high molecular weight,
lipophilic deterpenoid isolated from the western yew, Taxus
brevifolia, is insoluble in water and needs to be administered
intravenously by dilution into saline of the drug dissolved or
suspended in polyoxyethylated castor oil.
[0006] Targeted controlled delivery of the chemotherapeutic agent
to the tumor site and the ability to maintain efficacious levels of
these agents at the target site over the duration of treatment has
long been the goal of the pharmaceutical industry. The aim in this
form of treatment is to deliver higher and more effective doses of
the chemotherapeutic agent to the tumor tissue without affecting
the surrounding healthy tissue. If successful, targeted delivery
provides a significant reduction in systemic toxicity, reduction of
the chemotherapeutic agent dose, and increased treatment
efficacy.
[0007] Liposomes have been widely used as delivery vehicles for
anti-cancer drugs. U.S. Pat. No. 6,426,086 discloses a serum of
liposomes that are pH-sensitive for controlled drug delivery. The
liposomes are complexed with a molecule comprising a
thermally-sensitive polymer showing lower critical solution
temperature behavior in aqueous solutions. The thermally-sensitive
polymer bears a hydrophobic substituent and a pH sensitive
substituent, wherein the hydrophobic substituent is less than 10 kD
and which pH sensitive substituent remains ionizable following the
covalent bonding to the thermally-sensitive polymer, and whose pH
sensitive does not depend on cleavage of the covalent bond to the
thermally-sensitive polymer. The limited stability of liposomes
both in terms of shelf life and after administration, their ability
to encapsulate only certain types of molecules, as well as their
rapid clearance from the blood have hampered the use of liposomes
as effective controlled drug delivery systems.
[0008] U.S. Pat. No. 6,602,524 discloses methods for treating
tumors comprising the administration of a drug loaded in
pH-sensitive microspheres wherein said pH-sensitive microspheres
comprise a cross-linked polymer gel comprising ethyl methacrylate,
diethyl aminoethyl methacrylate, and divinyl benzene. The
pH-sensitive microspheres have a swelling transition with the pH
range found in or near tumor tissue. When the microspheres swell,
the loaded drug is released into the microenvironment of the tumor
tissue. The microspheres are capable of effectively releasing a
loaded substance at a pre-determined pH. The major drawback of the
pH sensitive microspheres disclosed in U.S. Pat. No. 6,602,524 is
that the matrix structure created by the cross-linking of ethyl
methacrylate, diethyl aminoethyl methacrylate, and divinyl benzene
is most likely to facilitate the diffusion and premature release of
the chemotherapeutic agents, that are relatively small molecules,
before these microspheres reach the target site of the tumor.
Further protection of these molecules is needed to ensure that they
are sustained by microspheres until they reach the tumor site.
Also, at a pre-determined pH these microspheres quickly release the
drug and cannot provide prolonged release of these active agents
over an extended period of time.
[0009] The prior art of which applicant is aware does not set forth
a controlled release system for the effective treatment of patients
afflicted with oncological disorders, such as cancer tumors, that
effectively deliver and localize the therapeutic effect of
chemotherapeutic agents to the target site or the tumor tissue and
maintains efficacious levels of these agents at the target site for
the duration of treatment. Therefore, there remains a need for a
system and method of cancer treatment that overcomes the drawbacks
of the systems disclosed in the prior art and that effectively
deliver effective concentrations of chemotherapeutic agent
targeting only the tumor tissue while reducing the damage to
surrounding healthy tissue, and maintain efficacious levels of
these agents at the target site for the duration of treatment.
SUMMARY OF THE INVENTION
[0010] The present invention relates to an improved carrier system
for site-specific targeted controlled delivery of pharmaceutical
active ingredients onto cancer tumors and maintains efficacious
levels of these agents at the target site for the duration of
treatment. More particularly, the invention relates to a controlled
release system that comprises solid hydrophobic nanospheres
encapsulated in a pH sensitive microsphere for the treatment of
patients afflicted with oncological disorders, such as cancer
tumors. Pharmaceutical active ingredients can be incorporated in
the solid hydrophobic nanospheres, in the pH sensitive microsphere,
or in both the micro and nanospheres. The active ingredients and
the nanospheres are released from the microsphere at the pH range
typically found in the surrounding of tumor tissues. At the pH
range typically found in the surrounding of tumor tissues the
microsphere pH sensitive matrix materials dissolve or swell. The
dissolution or swelling of the matrix disrupts the microsphere
structure and facilitates the release of the nanospheres and the
active ingredients. The deposition of the nanospheres onto the
tumor tissue is improved by optimizing particle size to ensure
entrainment of the nanospheres within the target tissue and by
modifying the surface properties of the nanospheres to enhance
their affinity for a particular residue expressed on a cell surface
or enhance their affinity for a cell surface protein or receptor to
maximize interaction between the nanospheres and the tumor
tissue.
[0011] The present invention also pertains to solid hydrophobic
nanospheres encapsulated in a pH sensitive microsphere that can be
loaded with a pharmaceutical active ingredient useful in treating
cancerous cells. The microspheres are capable of effectively
releasing a pre-determined pH pharmaceutical active ingredients and
the nanospheres loaded with pharmaceutical active ingredients. The
nanospheres can be designed to release their incorporated
pharmaceutical active ingredients over an extended period of time
at a pH that is typically found in or near cancerous tissue.
[0012] The present invention also provides a method of treating
cancer tumors comprising administering an effective amount of
microspheres that are capable of enhancing the bioavailability of
the pharmaceutical active ingredient encapsulated in the solid
hydrophobic nanospheres and releasing the pharmaceutical active
ingredient over an extended period of time at a specified pH.
[0013] In one embodiment, the pH-sensitive microspheres of the
present invention swell and release the pharmaceutical active
ingredients and the solid hydrophobic nanospheres within a pH range
typically found in tumor tissue. The compositions and methods of
the present invention provide a novel treatment of cancer, which
specifically targets tumor tissue and reduces damage to surrounding
healthy tissue.
[0014] The pharmaceutical active ingredient encapsulated in the
controlled release system of the present invention include, but are
not limited to, cytotoxic agents, chemotherapeutic agents,
radionuclides, gene based drugs or gene based treatment modalities,
including the use of sense, antisense nucleotide sequences,
antigens, antibodies, ribozymes, as well as chimeric
oligonucleotides constructs for gene correction. The pharmaceutical
active ingredient may also include DNA or RNA fragments, which code
functionally active or inactive or conditionally inactivatable
proteins.
[0015] The invention further provides a method to effectively
deliver and localize the therapeutic effect of chemotherapeutic
agents to the target site or tumor tissue and maintain efficacious
levels of these agents at the target site for the duration of
treatment, that reduces the amount of adverse side effects such as
vomiting, myelosuppression, cardiac toxicity, pulmonary fibrosis,
hepatobiliary toxicity, and pericholangitis commonly associated
with other current non-invasive treatments.
[0016] A preferred embodiment of the present invention pertains to
a method of treating a tumor with the solid hydrophobic nanospheres
encapsulated in a pH sensitive microsphere which contain a selected
anti-tumor substance and injecting the microspheres in a blood
vessel suitable for carrying the microspheres to the tumor.
[0017] In one embodiment, the nanospheres of the present invention
are bioadhesive. Bioadhesive nanosphere can be created by
incorporating a bioadhesive material into the solid hydrophobic
matrix of the nanospheres, by incorporating a bioadhesive material
in the pH-sensitive microsphere matrix, or by using a bioadhesive
material in the nanosphere matrix in conjunction with a bioadhesive
material in the microsphere matrix.
[0018] The carrier system of the present invention is a
free-flowing powder formed of solid hydrophobic nanospheres
comprising various active ingredients that are encapsulated in a pH
sensitive microspheres, having the advantages of:
[0019] (i) protection of the pharmaceutical active ingredients,
during storage, or until they reach the target site;
[0020] (ii) pH triggered controlled release of a first
pharmaceutical active ingredient from the microspheres and of a
second pharmaceutical active ingredient from the nanospheres at the
pH range typically found in the surrounding of tumor tissues,
and,
[0021] (iii) site specific targeted delivery and enhanced
deposition of the nanospheres comprising pharmaceutical active
ingredients, onto the target tumor site;
[0022] (iv) enhanced bioavailability and efficacy of pharmaceutical
active ingredients encapsulated in the nanospheres; and
[0023] (v) prolonged release of pharmaceutical active ingredients
encapsulated in the nanospheres over an extended period of
time.
[0024] The invention also provides a method for producing the multi
component controlled release system of the present invention
including active ingredients that comprises the steps of:
[0025] (i) incorporating the pharmaceutical active ingredients into
solid hydrophobic nanospheres;
[0026] (ii) forming an aqueous mixture comprising of one or more
pharmaceutical active agents, the nanospheres, and pH sensitive
materials; and
[0027] (iii) spray drying the mixture to form a dry powder
composition.
[0028] The invention further provides a process for producing the
multi component controlled release system of the present invention
including the pharmaceutical active ingredients that comprises the
steps of:
[0029] (i) heating hydrophobic materials to a temperature above the
melting point of the materials to form a melt;
[0030] (ii) dissolving or dispersing a first pharmaceutical active
agent into the melt;
[0031] (iii) dissolving or dispersing a second pharmaceutical
active agent, pH sensitive material, and a targeting material, in
the aqueous phase;
[0032] (iv) heating the composition to above the melting
temperature of the hydrophobic materials;
[0033] (v) mixing the hot melt with the aqueous phase to form a
dispersion;
[0034] (vi) high shear homogenization of the dispersion at a
temperature above the melting temperature until a homogeneous fine
dispersion is obtained having a sphere size of from about 1 micron
to about 2 microns;
[0035] (vii) cooling the dispersion to ambient temperature; and
[0036] (viii) spray drying the emulsified mixed suspension to form
a dry powder composition.
[0037] The invention also provides pharmaceutical products
comprising the multi component controlled release system of the
present invention.
[0038] The invention will be more fully described by reference to
the following drawings:
BRIEF DESCRIPTION OF THE DRAWINGS
[0039] FIG. 1 is a schematic diagram of the pH sensitive
microspheres of the present invention
[0040] FIG. 2 is a schematic diagram of the release profile of
active ingredients from the controlled release system of the
present invention.
[0041] FIG. 3 is a schematic diagram of the nanospheres
encapsulated in the pH sensitive microsphere of the present
invention. The surface properties of the nanospheres (shown as
squiggly lines) can be altered to be bioadhesive, negatively
charged, or positively charged, depending on the intended target
site.
DETAILED DESCRIPTION
[0042] pH levels in human tumors are substantially and consistently
lower than that in normal tissue (Gerweck L. E. et al., "Cellular
pH gradient in tumor versus normal tissue: potential exploitation
for the treatment of cancer", Cancer Research 56, issue 6, pp.
1194-1198, 1996). Deborah M. P. et al. ("The Relationship between
Intracellular and Extracellular pH in Spontaneous Canine Tumors",
Clinical Cancer Research Vol. 6, pp. 2501-2505, 2000) have also
reported that the cellular uptake of chemotherapeutic drugs may be
dependent on the pH gradient between the intracellular and
extracellular compartments. Hence, pH-sensitive delivery systems
can be a useful route for tumor targeting. The pH difference
provides an exploitable avenue for targeting the chemotherapeutic
agent to the tumor site. Also, weakly acidic drug delivery systems,
which are relatively lipid soluble in their nonionized state have
been found to diffuse freely across the cell membrane and, upon
entering a relatively basic intracellular compartment, become
trapped and accumulate within a cell, leading to substantial
differences in the intracellular/extracellular drug distribution
between tumor and normal tissue for drugs exhibiting appropriate
pKas.
[0043] The present invention provides an improved pH triggered,
site-specific targeted controlled delivery system for the treatment
of patients afflicted with conditions associated with or mediated
by cell proliferation, e.g., oncological disorders, such as cancer
and tumors. The controlled delivery system of the present invention
comprises solid hydrophobic nanospheres encapsulated in a pH
sensitive microsphere, as shown in FIG. 1. Pharmaceutical active
ingredients useful in treating cancerous cells can be incorporated
in the solid hydrophobic nanospheres, in the pH sensitive
microsphere, or in both the microspheres and nanospheres. A first
pharmaceutical active ingredient can be incorporated in the
nanosphere and a second pharmaceutical active ingredient, which can
be the same or different from the first pharmaceutical active
ingredient, can be incorporated into the microsphere.
[0044] The compositions and methods of the present invention
provide a novel treatment of cell proliferation and the control of
cancer, specifically targeting tumor tissue thereby reducing damage
to surrounding tissue. The pH-sensitive microspheres of the present
invention swell or dissolve within a pH range typically found in
tumor tissue and effectively release the pharmaceutical active
ingredients from the microspheres and the solid hydrophobic
nanospheres comprising the same or different pharmaceutical active
ingredients onto the tumor site, as shown in FIG. 2. The
nanospheres can be designed to release their pharmaceutical active
ingredient over an extended period of time at a pH that is
typically found in or near cancerous tissue and maintain
efficacious levels of these agents at the target site for the
duration of treatment.
[0045] The deposition of the nanospheres onto the tumor tissue is
improved by optimizing particle size to ensure entrainment of the
nanospheres within the target tissue and by modifying the surface
properties of the nanospheres to enhance their affinity for a
particular residue expressed on a cell surface or enhance their
affinity for a cell surface protein or receptor to maximize
interaction between the nanospheres and the tumor tissue, as shown
in FIG. 3. With respect to the interaction between the nanospheres
and the target surface, various chemical groups and bioadhesive
materials can be incorporated in the nanospheres structure, for
improving interaction with the target surface. A cationic surface
active agent creates positively charged nanospheres; an anionic
surface active agent creates negatively charged nanospheres; a
nonionic surface active creates neutral charged nanospheres; and a
zwitterionic surface active agent creates variable charged
nanospheres.
[0046] In one embodiment, the nanospheres of the present invention
are bioadhesive. Bioadhesive nanosphere can be created by
incorporating a bioadhesive material into the solid hydrophobic
matrix of the nanospheres, by incorporating a bioadhesive material
in the pH sensitive microsphere matrix, or by using a bioadhesive
material in the nanosphere matrix in conjunction with bioadhesive
material in the microsphere matrix.
[0047] The term "spheres" is intended to describe solid,
substantially spherical particulates. It will be appreciated that
the term "sphere" includes other particle shapes that can be formed
in accordance with the teachings of the present invention.
[0048] The term "pH triggered release" is intended to mean that the
rate of release is dependent of or regulated by the pH of the
system surrounding media or environment.
[0049] The present invention also provides a method of treating
cancer tumors comprising administering an effective amount of
microspheres that are capable of enhancing the bioavailability of
the pharmaceutical active ingredient encapsulated in solid
hydrophobic nanospheres and release them over an extended period of
time at a specified pH. The term extended period of time at a
specified pH is intended to mean an extended release a selected pH
suitable for treating a cellular proliferation disease
characterized by the abnormal proliferation of cells, such as
cancer.
[0050] Frequent cancer tumor sites are the lung, colon, rectum,
breast, prostate, testicles, bladder, uterus, liver, pancreas,
ovary, head and neck and the like. Prevalent types of cancer
include leukemia, central nervous system cancers, brain cancer,
melanoma, lymphoma, erythro leukemia, uterine cancer, bone cancer
and head and neck cancer.
[0051] The pharmaceutical active ingredient encapsulated in the
controlled release system of the present invention include, but are
not limited to, cytotoxic agents, chemotherapeutic agents,
radionuclides, nucleic acids, hormones, proteins, secreted
proteins, and biopharmaceiticals including but not limited to
antibodies or antibody-engineered therapeutic entities, ligands,
receptors and mimetics thereof. Nucleic acids as used herein also
includes gene based drugs or gene based treatment modalities,
including the use of sense, and antisense nucleic acids, ribozymes,
as well as chimeric oligonucleotides constructs for gene
correction. Antigens, including protein antigens, are agents for
use in compositions of the present invention. Nucleic acids include
DNA or RNA fragments, which encode functionally active or inactive
or conditionally inactivatable proteins.
[0052] The invention further provides a method to effectively
deliver and localize the therapeutic effect of chemotherapeutic
agents to the target site or tumor tissue and maintain efficacious
levels of these agents at the target site for the duration of
treatment, that reduces the amount of adverse side effects such as
vomiting, myelosuppression, cardiac toxicity, pulmonary fibrosis,
hepatobiliary toxicity, and pericholangitis commonly associated
with other current non-invasive treatments.
[0053] A preferred embodiment of the present invention pertains to
a method of treating a tumor with the solid hydrophobic nanospheres
encapsulated in a pH sensitive microsphere which contain a selected
anti-tumor substance and injecting the microspheres in a blood
vessel suitable for carrying the microspheres to the tumor.
[0054] The multi-component controlled release system of the present
invention can comprise from about 1% to about 50% by weight
hydrophobic matrix, from about 1% to about 50% by weight pH
sensitive matrix, from about 0% to about 10% by weight targeting
materials, from about 0% to about 20% by weight surface active
agents, and from about 0.01% to about 50% by pharmaceutical weight
active ingredients. The hydrophobic matrix enhances bioavailability
and sustains the diffusion rate of the pharmaceutical active
ingredients, through the nanospheres and enables them to be
released onto the target site over an extended period of time. The
microsphere has an average sphere size in the range from about 0.1
micron to about 50 microns. The nanosphere has an average sphere
size in the range from about 0.001 micron to about 1 micron and has
a melting point in the range from about 30.degree. C. to about
90.degree. C. This linear dimension for any individual sphere
represents the length of the longest straight line joining two
points on the surface of the sphere.
[0055] Additional components can be added to the carrier system or
can be incorporated into the nanospheres, the microspheres, or both
the nano and micro spheres matrices. The controlled release system
of the present invention can readily include other pharmaceutical
active agents, including but are not limited to: anti-oxidants;
free radical scavengers; anti-microbial agents; antibacterial
agents; allergy inhibitors; anti-aging agents; antiseptics;
analgesics; anti-inflammatory agents; healing agents; inflammation
inhibitors; vasoconstrictors; vasodilators; wound healing
promoters; peptides, polypeptides and proteins; anti-fungal;
depilating agents; counterirritants; vitamins; amino acids and
their derivatives; herbal extracts; flavoids; chelating agents;
cell turnover enhancers; and nourishing agents. The additional
components are usually present in an amount from about 1% to about
20% by weight of the spheres.
[0056] The controlled release compositions of the present invention
can be easily processed into articles of predetermined generic
dimensions. Examples of articles include pharmaceutical doses,
diagnostics materials, implants including depots, imaging entities,
medical devices, and the like.
[0057] I. Matrix Materials for Forming the Nanospheres
[0058] Considerations in the selection of the matrix material
include good barrier properties to the active ingredients, low
toxicity and irritancy, stability, integrity, and high loading
capacity for the active agents of interest. Suitable wax materials
for the compositions and devices of the present invention are inert
nontoxic materials with a melting point range between about
25.degree. C. and about 150.degree. C. and penetration point of
about 1 to about 10. Examples of wax materials include natural
waxes, synthetic waxes and mixtures thereof. Suitable waxes also
include natural, regenerated, or synthetic food approved waxes
including animal waxes such as beeswax, vegetable waxes such as
carnauba, candelilla, sugar cane, rice bran, and bayberry wax,
mineral waxes such as petroleum waxes including paraffin and
microcrystalline wax, and mixtures thereof.
[0059] Other wax materials that are known to those skilled in the
art and suitable materials as described in "Industrial Waxes" Vol.
I and II, by Bennett F.A.I.C., published by Chemical Publishing
Company Inc., 1975 and Martindale, "The Extra Pharmacopoeia", The
Pharmaceutical Press, 28.sup.th Edition pp. 1063-1072, 1982 can be
used in the present invention.
[0060] Suitable fat materials and/or glyceride materials which can
be used as matrix materials for forming the nanospheres of the
present invention include, but are not limited to, the following
classes of lipids: mono-, di and triglycerides, phospholipids,
sphingolipids, cholesterol and steroid derivatives, terpenes and
vitamins.
[0061] The fat material of the present invention can be a glyceride
selected from monoglycerides, diglycerides, glyceryl monostearate,
glyceryl tristearate and mixtures thereof. Other fat materials
which can be used are hydrogenated palm oil, hydrogenated palm
kernel oil, hydrogenated peanut oil, hydrogenated rapeseed oil,
hydrogenated rice bran oil, hydrogenated soybean oil, hydrogenated
cottonseed oil, hydrogenated sunflower oil, partially hydrogenated
soybean oil, partially hydrogenated cottonseed oil, and mixtures
thereof.
[0062] Examples of solid fat materials, which can be used in the
present invention, include solid hydrogenated castor and vegetable
oils, hard fats, and mixtures thereof. Other fat materials which
can be used, include triglycerides of food grade purity, which can
be produced by synthesis or by isolation from natural sources.
Natural sources can include animal fat or vegetable oil, such as
soy oil, as a source of long chain triglycerides (LCT). Other
triglycerides suitable for use in the present invention are
composed of a majority of medium length fatty acids (C10-C18),
denoted medium chain triglycerides (MCT). The fatty acid moieties
of such triglycerides can be unsaturated or polyunsaturated and
mixtures of triglycerides having various fatty acid material.
[0063] Phospholipids which can be used include, but are not limited
to, phosphatidic acids, phosphatidyl cholines with both saturated
and unsaturated lipids, phosphatidyl ethanolamines,
phosphatidylglycerols, phosphatidylserines, phosphatidylinositols,
lysophosphatidyl derivatives, cardiolipin, and beta-acyl-y-alkyl
phospholipids. Examples of phospholipids include, but are not
limited to, phosphatidylcholines such as
dioleoylphosphatidylcholine, dimyristoylphosphatidylcholine,
dipentadecanoylphosphatidylcholine dilauroylphosphatidylcholine,
dipalmitoylphosphatidylcholine (DPPC),
distearoylphosphatidylcholine (DSPC),
diarachidoylphosphatidylcholine (DAPC), dibehenoylphosphatidylcho-
line (DBPC), ditricosanoylphosphatidylcholine (DTPC),
dilignoceroylphatidylcholine (DLPC); and phosphatidylethanolamines
such as dioleoylphosphatidylethanolamine or
1-hexadecyl-2-palmitoylglycerophos- phoethanolamine. Synthetic
phospholipids with asymmetric acyl chains (e.g., with one acyl
chain of 6 carbons and another acyl chain of 12 carbons) can also
be used.
[0064] Steroids which can be used include as fat materials, but are
not limited to, cholesterol, cholesterol sulfate, cholesterol
hemisuccinate, 6-(5-cholesterol 3 beta-yloxy)
hexyl6-amino-6-deoxy-1-thio-alpha-D-galact- opyranoside,
6-(5-cholesten-3 beta-tloxy)hexyl-6-amino-6-deoxyl-1-thio-alp- ha-D
mannopyranoside and cholesteryl)4'-trimethyl 35 ammonio)butanoate.
Additional lipid compounds as fat material which can be used
include tocopherol and derivatives, and oils and derivatized oils
such as stearlyamine.
[0065] The fat material can be fatty acids and derivatives thereof
which can include, but are not limited to, saturated and
unsaturated fatty acids, odd and even number fatty acids, cis and
trans isomers, and fatty acid derivatives including alcohols,
esters, anhydrides, hydroxy fatty acids and prostaglandins.
Saturated and unsaturated fatty acids that can be used include, but
are not limited to, molecules that have between 12 carbon atoms and
22 carbon atoms in either linear or branched form. Examples of
saturated fatty acids that can be used include, but are not limited
to, lauric, myristic, palmitic, and stearic acids. Examples of
unsaturated fatty acids that can be used include, but are not
limited to, lauric, physeteric, myristoleic, palmitoleic,
petroselinic, and oleic acids. Examples of branched fatty acids
that can be used include, but are not limited to, isolauric,
isomyristic, isopalmitic, and isostearic acids and isoprenoids.
Fatty acid derivatives include 12-(((7'-diethylaminocoum-
arin-3yl)carbonyl)methylamino)-octadecanoic acid;
N-[12-(((7'-diethylamino-
coumarin-3-yl)carbonyl)methyl-amino)octadecanoyl]-2-aminopalmitic
acid, N succinyl-dioleoylphosphatidylethanol amine and
palmitoyl-homocysteine; and/or combinations thereof. Mono, di and
triglycerides or derivatives thereof that can be used include, but
are not limited to, molecules that have fatty acids or mixtures of
fatty acids between 6 and 24 carbon atoms, digalactosyldiglyceride,
1,2-dioleoyl-sn-glycerol; 1,2-cdipalmitoyl-sn-3 succinylglycerol;
and 1,3-dipalmitoyl-2-succinylgly- cerol.
[0066] The nanospheres of the present invention can have a melting
point in the range from about 30.degree. C. to about 90.degree. C.,
preferably from about 40.degree. C. to about 90.degree. C. The
melting point of the spheres is typically a function of the carrier
matrix employed. Accordingly, preferred matrix materials have a
melting point in the range of about 50.degree. C. to about
80.degree. C., preferably from about 60.degree. C. to about
70.degree. C. It should be understood that it is the melting point
of the sphere rather than the melting point of the carrier matrix
that is important for use of the carrier system of the present
invention.
[0067] II. Materials for Forming a Microsphere Matrix
[0068] The microsphere can be composed of purely pH sensitive
materials or be comprised of a mixture of pH sensitive materials,
salt sensitive, water sensitive or bioadhesive materials.
[0069] pH Sensitive Materials
[0070] The pH-sensitive materials that are utilized to form the
microspheres of the present invention comprises any material or
structure that has the ability to maintain the integrity of the
microsphere at normal physiological pH, of about 7.4, until the
microspheres reach the pH found in or near cancerous tissue that is
more acidic than the surrounding normal tissues typically, between
about 3.5 and about 6.8. Suitable pH sensitive materials for
targeting the controlled delivery system of the present invention
to the tumor sites are materials that have a threshold pH of about
6.8 or less, alternatively those with threshold pH of about 6.5 or
less, and alternatively have threshold pH of about 6 or less.
[0071] The trigger pH is the threshold pH value or range of values
at which either above or below the trigger pH the pH-sensitive
material degrades, and/or dissolves. The microsphere can be formed
to be stable in solutions and then as the pH increases above the
trigger pH the microspheres are activated to swell or dissolve.
Likewise, microspheres can be formed to be stable in solutions and
as the pH drops below the trigger pH the microspheres are activated
to swell or dissolve. Once activated, the active ingredients and
the nanospheres are released.
[0072] In one embodiment a pH-sensitive trigger means is used such
that the microsphere is capable of becoming more permeable to water
and/or losing physical strength following triggering by a solution
of the desired pH, either above or below the trigger pH. In another
embodiment a pH-sensitive trigger means is used to hold together
two nanosphere portions. The trigger means is capable of losing its
adhesive quality or strength, such as to degrade or dissolve,
following triggering by a solution of the desired pH, either above
or below the trigger pH. The reduction in adhesion strength allows
the hydrostatic pressure inside the microsphere core to push apart
the nanospheres portions held together by the adhesive trigger
means, thereby releasing the contents of the nanospheres.
[0073] The pH-sensitive materials can be insoluble solids in acidic
or basic aqueous solutions, which dissolve, or degrade and
dissolve, as the pH of the solution is neutral. The pH-sensitive
materials can be insoluble solids in acidic or basic aqueous
solutions which dissolve, or degrade and dissolve, as the pH of the
solution rises above or drops below a trigger pH value.
[0074] Exemplary pH-sensitive materials include copolymers of
acrylate polymers with amino substituents, acrylic acid esters,
polyacrylamides, phthalate derivatives (i.e., compounds with
covalently attached phthalate moleties) such as acid phthalates of
carbohydrates, amylose acetate phthalate, cellulose acetate
phthalate, other cellulose ester phthalates, cellulose ether
phthalates, hydroxy propyl cellulose phthalate, hydroxypropyl
ethylcellulose phthalate, hydroxypropyl methyl cellulose phthalate,
methyl cellulose phthalate, polyvinyl acetate phthalate, polyvinyl
acetate hydrogen phthalate, sodium cellulose acetate phthalate,
starch acid phthalate, styrene-maleic acid dibutyl phthalate
copolymer, styrene-maleic acid polyvinyl acetate phthalate
copolymer, styrene and maleic acid copolymers, formalized gelatin,
gluten, shellac, salol, keratin, keratin sandarac-tolu, ammoniated
shellac, benzophenyl salicylate, cellulose acetate trimellitate,
cellulose acetate blended with shellac, hydroxypropylmethyl
cellulose acetate succinate, oxidized cellulose, polyacrylic acid
derivatives such as acrylic acid and acrylic ester copolymers,
methacrylic acid and esters thereof, vinyl acetate and crotonic
acid copolymers.
[0075] Examples of suitable pH sensitive polymers for use are the
Eudragit.RTM. polymers series from Rohm America Inc., a
wholly-owned subsidiary of Degussa-Huls Corporation, headquartered
in Piscataway, N.J., and an affiliate of Rohm GmbH of Darmstadt,
Germany. EUDRAGIT.RTM. L 30 D-55 and EUDRAGIT.RTM. L 100-55, pH
dependent anionic polymer that is soluble at pH above 5.5 and
insoluble blow pH 5. These polymers can be utilized for targeted
drug delivery in the duodenum. EUDRAGIT.RTM. L 100 pH dependent
anionic polymer that is soluble at pH above 6.0 for targeted drug
delivery in the jejunum. EUDRAGIT.RTM. S 100 pH dependent anionic
polymer that is soluble at pH above 7.0 for targeted drug delivery
in the ileum. EUDRAGIT.RTM. E 100 and EUDRAGIT.RTM. EPO, pH
dependent cationic polymer, soluble up to pH 5.0 and insoluble
above pH 5.0 dependent cationic polymer, soluble up to pH 5.0 and
insoluble above pH 5.0. Accordingly, suitable pH sensitive
materials degrade or dissolve when said pH sensitive microsphere
contacts a solution having a pH greater than about 5.
[0076] Additional pH-sensitive materials include poly functional
polymers containing multiple groups that become ionized as the pH
drops below their pKa. A sufficient quantity of these ionizable
groups must be incorporated in the polymer such that in aqueous
solutions having a pH below the pKa of the ionizable groups, the
polymer dissolves. These ionizable groups can be incorporated into
polymers as block copolymers, or can be pendent groups attached to
a polymer backbone, or can be a portion of a material used to
crosslink or connect polymer chains. Examples of such ionizable
groups include polyphosphene, vinyl pyridine, vinyl aniline,
polylysine, polyornithine, other proteins, and polymers with
substituents containing amino moieties.
[0077] pH-sensitive polymers which are relatively insoluble and
impermeable at the pH of the stomach, but which are more soluble
and permeable at the pH of the small intestine and colon include
polyacrylamides, phthalate derivatives such as acid phthalates of
carbohydrates, amylose acetate phthalate, cellulose acetate
phthalate, other cellulose ester phthalates, cellulose ether
phthalates, hydroxypropylcellulose phthalate,
hydroxypropylethylcellulose phthalate, hydroxypropylmethylcellulose
phthalate, methylcellulose phthalate, polyvinyl acetate phthalate,
polyvinyl acetate hydrogen phthalate, sodium cellulose acetate
phthalate, starch acid phthalate, styrene-maleic acid dibutyl
phthalate copolymer, styrene-maleic acid polyvinylacetate phthalate
copolymer, styrene and maleic acid copolymers, polyacrylic acid
derivatives such as acrylic acid and acrylic ester copolymers,
polymethacrylic acid and esters thereof, poly acrylic methacrylic
acid copolymers, shellac, and vinyl acetate and crotonic acid
copolymers.
[0078] Other pH-sensitive polymers include shellac; phthalate
derivatives, particularly cellulose acetate phthalate,
polyvinylacetate phthalate, and hydroxypropylmethylcellulose
phthalate; polyacrylic acid derivatives, particularly polymethyl
methacrylate blended with acrylic acid and acrylic ester
copolymers; and vinyl acetate and crotonic acid copolymers.
[0079] Anionic acrylic copolymers of methacrylic acid and
methylmethacrylate are also particularly useful coating materials
for delaying the release of compositions and devices until the
compositions and devices have moved to a position in the small
intestine which is distal to the duodenum. Copolymers of this type
are available from RohmPharma Corp, under the trade names
Eudragit-L.R.TM. and Eudragit-S.R.TM., are anionic copolymers of
methacrylic acid and methylmethacrylate. The ratio of free carboxyl
groups to the esters is approximately 1:1 in Eudragit-L.R.TM. and
approximately 1:2 in Eudragit-S.RT.TM.. Mixtures of
Eudragit-L.R.TM. and Eudragit-S.R.TM. can also be used.
[0080] The pH-sensitive and salt sensitive materials can be blended
with an inert water sensitive material. By inert is meant a
material that is not substantially affected by a change in pH or
salt concentration in the triggering range. By altering the
proportion of a pH-sensitive material to inert material the time
lag subsequent to triggering and prior to release can be
tailored.
[0081] In an embodiment of the present invention, the micro sphere
is formed of a pH sensitive material which is substantially
insoluble and impermeable at the pH of the stomach, and is more
soluble and permeable at the pH of the small intestine. Preferably,
the micro spheres are substantially insoluble and impermeable at pH
less than about 5.0, and water-soluble at pH greater than about
5.0. pH-sensitive polymers which are relatively insoluble and
impermeable at the pH of the stomach, but which are more soluble
and permeable at the pH of the small intestine and colon include
polyacrylamides, phthalate derivatives such as acid phthalates of
carbohydrates, amylose acetate phthalate, cellulose acetate
phthalate, other cellulose ester phthalates, cellulose ether
phthalates, hydroxypropylcellulose phthalate,
hydroxypropylethylcellulose phthalate, hydroxypropylmethylcellulose
phthalate, methylcellulose phthalate, polyvinyl acetate phthalate,
polyvinyl acetate hydrogen phthalate, sodium cellulose acetate
phthalate, starch acid phthalate, styrene-maleic acid dibutyl
phthalate copolymer, styrene-maleic acid polyvinylacetate phthalate
copolymer, styrene and maleic acid copolymers, polyacrylic acid
derivatives such as acrylic acid and acrylic ester copolymers,
polymethacrylic acid and esters thereof, poly acrylic methacrylic
acid copolymers, shellac, and vinyl acetate and crotonic acid
copolymers.
[0082] Suitable pH-sensitive polymers include shellac; phthalate
derivatives, particularly cellulose acetate phthalate,
polyvinylacetate phthalate, and hydroxypropylmethylcellulose
phthalate; polyacrylic acid derivatives, particularly polymethyl
methacrylate blended with acrylic acid and acrylic ester
copolymers; vinyl acetate; crotonic acid copolymers and
Eudragit.RTM. polymers series from Rohm America Inc.
[0083] Water Sensitive Materials
[0084] Water-sensitive materials can be mixed with the pH or salt
sensitive materials to form the microspheres of the present
invention. Suitable water sensitive materials comprise polyvinyl
pyrrolidone, water soluble celluloses, polyvinyl alcohol, ethylene
maleic anhydride copolymer, methyl vinyl ether maleic anhydride
copolymer, polyethylene oxides, water soluble polyamide or
polyester copolymers or homopolymers of acrylic acid such as
polyacrylic acid, polystyrene acrylic acid copolymers or starch
derivatives, polyvinyl alcohol, polysaccharides, hydrocolloids,
natural gums, proteins, and mixtures thereof. Examples of synthetic
water sensitive polymers which are useful for the invention include
polyvinyl pyrrolidone, water soluble celluloses, polyvinyl alcohol,
ethylene maleic anhydride copolymer, methylvinyl ether maleic
anhydride copolymer, acrylic acid copolymers, anionic polymers of
methacrylic acid and methacrylate, cationic polymers with
dimethyl-aminoethyl ammonium functional groups, polyethylene
oxides, water soluble polyamide or polyester.
[0085] Examples of water soluble hydroxyalkyl and carboxyalkyl
celluloses include hydroxyethyl and carboxymethyl cellulose,
hydroxyethyl and carboxyethyl cellulose, hydroxymethyl and
carboxymethyl cellulose, hydroxypropyl carboxymethyl cellulose,
hydroxypropyl methyl carboxyethyl cellulose, hydroxypropyl
carboxypropyl cellulose, hydroxybutyl carboxymethyl cellulose, and
the like. Also useful are alkali metal salts of these carboxyalkyl
celluloses, particularly and preferably the sodium and potassium
derivatives.
[0086] The polyvinyl alcohol useful in the practice of the
invention is partially and fully hydrolyzed polyvinyl acetate,
termed "polyvinyl alcohol" with polyvinyl acetate as hydrolyzed to
an extent, also termed degree of hydrolysis, of from about 75% up
to about 99%. Such materials are prepared by means of any of
Examples I-XIV of U.S. Pat. No. 5,051,222 issued on Sep. 24, 1991,
the specification for which is incorporated by reference
herein.
[0087] Polyvinyl alcohol useful for practice of the present
invention is Mowiol.RTM. 3-83, having a molecular weight of about
14,000 Da and degree of hydrolysis of about 83%, Mowiol.RTM. 3-98
and a fully hydrolyzed (98%) polyvinyl alcohol having a molecular
weight of 16,000 Da commercially available from Gehring-Montgomery,
Inc. of Warminister Pa. Other suitable polyvinyl alcohols are:
AIRVOL.RTM. 205, having a molecular weight of about 15,000-27,000
Da and degree of hydrolysis of about 88%, and VINEX.RTM. 1025,
having molecular weight of 15,000-27,000 Da degree of hydrolysis of
about 99% and commercially available from Air Products &
Chemicals, Inc. of Allentown, Pa.; ELVANOL.RTM. 51-05, having a
molecular weight of about 22,000-26,000 Da and degree of hydrolysis
of about 89% and commercially available from the Du Pont Company,
Polymer Products Department, Wilmington, Del.; ALCOTEX.RTM. 78
having a degree of hydrolysis of about 76% to about 79%,
ALCOTEX.RTM.D F88/4 having a degree of hydrolysis of about 86% to
about 88% and commercially available from the Harlow Chemical Co.
Ltd. of Templefields, Harlow, Essex, England CM20 2BH; and
GOHSENOL.RTM. GL-03 and GOHSENOL.RTM. KA-20 commercially available
from Nippon Gohsei K.K., The Nippon Synthetic Chemical Industry
Co., Ltd., of No. 9-6, Nozaki Cho,Kita-Ku, Osaka, 530 Japan.
[0088] Suitable polysaccharides are polysaccharides of the
non-sweet, coloidally-soluble types, such as natural gums, for
example, gum arabic, starch derivates, dextrinized and hydrolyzed
starches, and the like. A suitable polysaccharide is a water
dispersible, modified starch commercially available as Capule.RTM.,
N-Lok.RTM., Hi-Cap.TM. 100 or Hi-Cap.TM. 200 commercially available
from the National Starch and Chemical Company of Bridgewater, N.J.;
Pure-Cote.TM., commercially available from the Grain Processing
Corporation of Muscatine, Iowa. In the preferred embodiment the
natural gum is a gum arabic, commercially available from TIC Gums
Inc. Belcamp, Midland. Suitable hydrocolloids are xanthan,
maltodextrin, galactomanan or tragacanth, preferably maltodextrins
such as Maltrin.TM. M100, and Maltrin.TM. M150, commercially
available from the Grain Processing Corporation of Muscatine,
Iowa.
[0089] Bioadhesive Polymers
[0090] An orally ingested drug delivery system can adhere to either
the epithelial surface or the mucus. For the delivery of bioactive
active ingredients, it is advantageous to have the system adhere to
the epithelium rather than solely to the mucous layer, although
mucoadhesion can also substantially improve bioavailability. For
some types of imaging purposes, adhesion to both the epithelium and
mucus is desirable whereas in pathological states, such as in the
case of gastric ulcers or ulcerative colitis, adhesion to cells
below the mucous layer may occur. Duchene, et al., Drug Dev. Ind.
Pharm. 14(2&3), 283-318 (1988), reviews the pharmaceutical and
medical aspects of bioadhesive systems for drug delivery.
"Bioadhesion" is defined as the ability of a material to adhere to
a biological tissue for an extended period of time. Bioadhesion is
a solution to the problem of inadequate residence time resulting
from the stomach emptying and intestinal peristalsis, and from
displacement by ciliary movement. For sufficient bioadhesion to
occur, an intimate contact is needed between the bioadhesive and
the receptor tissue, the bioadhesive must penetrate into the
crevice of the tissue surface and/or mucus, and mechanical,
electrostatic, or chemical bonds form. Bioadhesive properties of
the polymers are affected by both the nature of the polymer and by
the nature of the surrounding media. Incorporating bioadhesive
polymers in the microsphere of the present invention can be
utilized to control or increase the absorption of the nanosphere
through the mucosal lining, or to further delay transit of the
nanosphere through the gastrointestinal passages. A bioadhesive
polymer as used in the disclosure is one that binds to mucosal
epithelium under normal physiological conditions. Bioadhesion in
the gastrointestinal tract proceeds in two stages: (1) viscoelastic
deformation at the point of contact of the synthetic material into
the mucus substrate, and (2) formation of bonds between the
adhesive synthetic material and the mucus or the epithelial cells.
In general, adhesion of polymers to tissues can be achieved by (i)
physical or mechanical bonds, (ii) primary or covalent chemical
bonds, and/or (iii) secondary chemical bonds such as ionic.
Physical or mechanical bonds can result from deposition and
inclusion of the bioadhesive material in the crevices of the mucus
or the folds of the mucosa. Secondary chemical bonds, contributing
to bioadhesive properties, can comprise dispersive interactions
such as Van der Waals interactions and stronger specific
interactions, such as hydrogen bonds. Hydrophilic functional groups
primarily responsible for forming hydrogen bonds include hydroxyl
and the carboxylic groups. Suitable bioadhesive polymers for use in
the present invention include bioerodible hydrogels as described by
H. S. Sawhney, C. P. Pathak and J. A. Hubell in Macromolecules.
1993, 26:581-587, the teachings of which are incorporated herein,
polyhyaluronic acids, casein, gelatin, glutin, polyanhydrides,
polyacrylic acid, alginate, chitosan, poly(methyl methacrylates),
poly(ethyl methacrylates), poly (butyl methacrylate), poly(isobutyl
methacrylate), poly(hexl methacrylate), poly(isodecl methacrylate),
poly(lauryl methacrylate), poly(phenyl methacrylate), poly(methyl
acrylate), poly(isopropyl acrylate), poly(isobutyl acrylate), and
poly(octadecl acrylate) and poly(fumaric-co-sebacic)acid.
[0091] Polymers with enhanced bioadhesive properties can be
provided wherein anhydride monomers or oligomers are incorporated
into the polymer. The oligomer excipients can be blended or
incorporated into a wide range of hydrophilic and hydrophobic
polymers including proteins, polysaccharides and synthetic
biocompatible polymers. Anhydride oligomers can be combined with
metal oxide particles to improve bioadhesion in addition to the use
of organic additives alone. Organic dyes because of their
electronic charge and hydrophobicity/hydrophilicity can either
increase or decrease the bioadhesive properties of polymers when
incorporated into the polymers. The incorporation of oligomer
compounds into a wide range of different polymers which are not
normally bioadhesive can be used to increase the adherence of the
polymer to tissue surfaces such as mucosal membranes.
[0092] III. Targeting Mechanism
[0093] The nanospheres can be targeted specifically or
non-specifically through the selection of the pH of the material
forming the microsphere, the size of the nanosphere, and/or
incorporation or attachment of a ligand to the nanospheres. For
example, biologically active molecules, or molecules affecting the
charge, lipophilicity or hydrophilicity of the nanospheres, can be
attached to the surface of the nanospheres. Additionally, molecules
can be attached to the nanospheres which minimize tissue adhesion,
or which facilitate specific targeting of the nanosphere in vivo.
Representative targeting molecules include antibodies, ligands,
lectins, and other molecules which are specifically bound by
receptors on the surfaces of cells of a particular type.
[0094] The term "cell recognition component", as used herein,
refers to a molecule capable of recognizing a component on a
surface of a targeted cell. Cell recognition components may include
an antibody to a cell surface antigen, a ligand for a cell surface
receptor, such as cell surface receptors involved in
receptor-mediated endocytosis, peptide hormones, and the like.
[0095] In one embodiment of the present invention, the nanospheres
are modified with lectins attached to the nanosphere surface and
targeted to mucosal epithelium of the small intestine and are
absorbed into the systemic circulation and lymphatic circulation.
In an embodiment of the present invention, carbohydrates or lectins
are used to target the nanospheres of the present invention to M
cells and Peyer's Patch cells of the small intestine. In another
embodiment of the present invention lectins which bind to fucosyl
sugars are used to modify the nanospheres. Lectins are a
heterogenous group of proteins or glycoproteins that recognize
carbohydrate residues on cell surface glycoconjugates with a high
degree of specificity. Examples of lectins that can be used to
modify the nanospheres of the present invention, include but are
not limited to, lectins specific for binding to fucosyl
glycoconjugates, such as Ulex Europeas Agglutinin I (UEA); lectins
specific for binding to galactose/N-acetylgalactoseamine, such as
Phaseolus vulgaris haemagglutinin (PHA), tomato lectin
(Lycopersicon esculentum) (TL), wheat germ agglutinin (WGA);
lectins specific for binding to mannose, such as, Galanthus nivalis
agglutinin (GNA); lectins specific for mannose and/or glucose, such
as, con A/concavalan A. (See e.g., Lehr et al., 1995, in Lectins
Biomedical Perspectives, pp. 117-140, incorporated by reference
into this application). The targeting molecules can be derivatized
if desired. See e.g., Chen et al., 1995, Proceed. Internat. Symp.
Control. Rel. Bioact. Mater. 22 and Cohen WO 9503035, incorporated
by reference into this application.
[0096] In another embodiment of the invention, the nanospheres of
the present invention can be modified with viral proteins or
bacterial proteins that have an affinity for a particular residue
expressed on a cell surface or that have an affinity for a cell
surface protein or receptor. Examples of such proteins include, but
are not limited to, cholera toxin B subunit, and bacterial
adhesotopes.
[0097] In yet another embodiment of the present invention, the
nanospheres of the present invention can be modified with
monoclonal antibodies or fragments of antibodies which target the
nanospheres to a particular cell type. The nanospheres of the
present invention can be modified with ligands for specific mucosal
cell surface receptors and proteins. As used herein, the term
"ligand" refers to a ligand attached to a nanosphere which adheres
to the mucosa in the intestine or can be used to target the
nanospheres to a specific cell type in the G-I tract or following
absorption of the nanospheres onto the mucosa in the intestine.
Suitable ligands can include ligands for specific cell surface
proteins and antibodies or antibody fragments immunoreactive with
specific surface molecules. Suitable ligands can also include less
specific targeting ligands such as coatings of materials which are
bioadhesive, for example alginate and polyacrylate.
[0098] IV. Active Ingredients
[0099] The pharmaceutical active ingredient encapsulated in the
controlled release system of the present invention include, but are
not limited to, cytotoxic agents, chemotherapeutic agents,
radionuclides, gene based drugs or gene based treatment modalities,
including the use of sense, antisense nucleotide sequences,
antigens, antibodies, ribozymes, as well as chimeric
oligonucleotides constructs for gene correction. These actives may
also include DNA or RNA fragments, which code functionally active
or inactive or conditionally inactivatable proteins. Examples of
chemotherapeutic agents include inhibitors of purine synthesis
(e.g., pentostatin, 6-mercaptopurine, 6thioguanine, methotrexate)
or pyrimidine synthesis (e.g. Pala, azarbine), the conversion of
ribonucleotides to deoxyribonucleotides (e.g. hydroxyurea),
inhibitors of dTMP synthesis (5-fluorouracil), DNA damaging agents
(e.g. radiation, bleomycines, etoposide, teniposide, dactinomycine,
daunorubicin, doxorubicin, mitoxantrone, alkylating agents,
mitomycin, cisplatin, procarbazine) as well as inhibitors of
microtubule function (e.g. vinca alkaloids and colchicine).
[0100] Although all taxanes are contemplated for formulation in
compositions of the present invention an example suitable
pharmaceutical active ingredient is, Paclitaxel, (also referred to
as TAXOL.RTM.), first identified in 1971 by Wani and collaborators
(Wani MC et al., J. Am. Chem. Soc., 93: pp. 2325-2327, 1971)
following a screening program of plant extracts of the National
Cancer Institute. This complex diterpene shows cytotoxic activity
against several types of tumors and is presently used in the
treatment of some cancers such as ovarian and breast cancers.
Clinical studies suggest that Paclitaxel could eventually be used
in the treatment of over 70% of human cancers. Paclitaxel differs
from other cytotoxic drugs by its unique mechanism of action. It
interferes with cell division by manipulating the molecular
regulation of the cell cycle. Paclitaxel binds to tubulin, the
major structural component of microtubules that are present in all
eukaryotic cells. Unlike other antimitotic agents such as vinca
alkaloids and colcichine, which inhibit the polymerization of
tubulin, paclitaxel promotes this assembly of tubulin and
stabilizes the resulting microtubules. This event leads to the
interruption of cell division, and ultimately to cell death.
Various derivatives of paclitaxel may be used in accordance with
the invention, such as taxotere or other related taxanes.
Cisplatin, another of the cytotoxic chemical compounds, which may
be used in accordance with the invention, also is known as
cis-Diamminedichloroplatinum. Well known analogues of cisplatin
such as carboplatin and iproplatin (also known as
CHIP[cis-dichloro-trans-dihydroxo-bis[isopropylamine]platinum IV)
can also be used in the present invention. It will be appreciated
those of ordinary skill in the art would be familiar with other
specific cytotoxic agents that could be used in the present
invention.
[0101] Other pharmaceutical compounds that are particularly
well-suited for encapsulation according to the present invention,
include: Tamoxifen, Dacarbazine, Ifosfamide, Streptozocin,
Thiotepa, Nandrolone decanoate, Fentanyl citrate, Testosterone,
Albendazole, Esmolol, Mytomycin, Bleomycin sulfate, Dactinomycin,
Amikacin sulfate, Gentamicin, Netilmicin, Streptomycin, Tobramycin,
Doxorubicin, Epirubicin, Idarubicin, Valrubicin, Bacitracin,
Colistimethate, Oxybutinin, Antithrombin III Human, Heparin,
Lepirudin, Adenosine phosphate, Amphotericin B, Enalaprilat,
Cladribine, Cytarabine, Fludarabine phosphate, Gemcitabine,
Pentostatin, Docetaxel, Paclitaxel, Vinblastine, Vincristihe,
Vinorelbine, Batimastat, Rituximab, Trastazumab, Abciximab,
Eptifibatide, Tirofiban, Droperidol, Aurothioglucose, Capreomycin
disulfide, Acyclovir, Cidofovir, Pentafuside, Saquinavir,
Ganciclovir, Cromolyn, Aldesleukin, Denileukin, Edrophonium,
Infliximab, Doxapram, SN-38 (Irinotecan), Topotecan, Hemin,
Daunorubicin, Teniposide, Trimetrexate, Octreotride, Ganirelix
acetate, Histrelin acetate, Somatropin, Epoetin, Filgrastim,
Oprelvekin, Leuprolide, Basiliximab, Daclizumab, Glatiramer
acetate, Interferons, Muromonab-CD3, Clyclosporin A, Milrinone
lactate, Buprenorphine, Nalbuphine, Urofollitropin, Desmopressin,
Carboplatin, Cisplatin, Mitoxantrone, Estradiol,
Hydroxyprogesterone, L-Thyroxine, Etanercept, Neostigmine,
Epoprostenol, Methoxamine, Versed, Bupivacaine, Heparin, Insulin,
Antisense compounds, Ibuprofen, Fluorouracil, Mechlor,
Fluorouridine, Tiazofurin Ketoprofen, Thanive, Etoposide,
Docetaxel, Alendronate, Etidronate, Zoledronate, Ibandronate,
Risedronate, and Pamidronate. These compounds represent the
following classes of drug: Alkylating agent, Anabolic steroid,
Analgesic, Androgen, Anthelmintic, Antiadrenergic, Antibiotic,
Antibiotic, aminoglycoside, Antibiotic, antineoplastic, Antibiotic,
polypeptide, Anticholinergic, Anticoagulant, Anticonvulsant,
Antifungal, Antihypertensive, Antimetabolite, Antimitotic,
Antineoplastic, Antiplatelet, Antipsychotic, Anesthetic,
Antirheumatic, Antituberculosal, Antiviral, Antiviral (HIV), Asthma
anti-inflammatory, Biological response modifier, Cholinergic muscle
stimulant, CNS stimulant, DNA topoisomerase inhibitor, Enzyme
inhibitor, Epipodophyllotoxin, Folate antagonist, Gastric
antisecretory, Gene therapy agents, Gonadotropin-releasing, Growth
hormone, Hematopoietic, Hormone, Immunologic agent,
Immunosuppressant, Inotropic agent, Local anesthetic, Narcotic
agonist/antagonist, Ovulation stimulant, Pituitary hormone,
Platinum complex, Sex hormone, Thyroid hormone, TNF inhibitor
(arthritis), Urinary cholinergic, Vasodilator, and Vasopressor.
Other suitable active agents are described in U.S. Pat. No.
6,656,955 hereby incorporated by reference into this application.
The present invention is very well suited for the incorporation of
functional excipients, such as gum benzoin or essential oils that
improve absorption of poorly-absorbed drugs, in some cases by
inhibiting drug efflux proteins. As discussed in more detail
elsewhere herein, there are a number of sites within, and at the
surface of the particles, where actives, excipients, and functional
excipients can be localized within the context of this
invention.
[0102] V. Processing Method
[0103] Va. Nanospheres
[0104] The encapsulated active agent in the nanospheres of the
present invention can be prepared by the steps of (1) heating
hydrophobic materials to a temperature above the melting point to
form a melt, (2) dissolving or dispersing the active agent in the
melt, (3) emulsifying the melt in the aqueous phase; and (4)
cooling the dispersion to ambient temperature to form a fine
suspension.
[0105] The active ingredients can be incorporated into hydrophobic
solid nanospheres, the pH sensitive microsphere, or in both the
nano and micro spheres.
[0106] Vb. Microspheres
[0107] The controlled release system of the present invention can
be prepared by the steps of (a) incorporating the selected active
agents into the hydrophobic interior of the nanospheres, (b)
forming an aqueous mixture comprising one or more active agents,
the nanospheres, and a pH sensitive material, and (c) spray drying
the mixture of the present invention to form a dry powder
composition. Accordingly, the nanospheres can be encapsulated into
the microsphere structure. One or more of the active agents, which
can be the same or different than the active agents incorporated in
the nanosphere, can be incorporated into the microsphere
structure.
[0108] A process for producing the multi component controlled
release system includes the following steps:
[0109] (i) heating a hydrophobic material to a temperature above
the melting point to form a melt;
[0110] (ii) dissolving or dispersing the selected first active
agent into the melt;
[0111] (iii) dissolving or dispersing a second active agent, and
the pH sensitive materials, in the aqueous phase and heating it to
above the melting temperature of the hydrophobic material;
[0112] (iv) mixing the hot melt with the aqueous phase to form a
dispersion;
[0113] (v) high shear homogenization of the dispersion at a
temperature above the melting temperature until a homogeneous fine
dispersion is obtained having a sphere size of from about 1 microns
to about 2 microns;
[0114] (vi) cooling the dispersion to ambient temperature; and
[0115] (vii) spray drying the emulsified mixed suspension to form a
dry powder composition.
[0116] Homogenization can be accomplished in any suitable fashion
with a variety of mixers known in the art such as simple paddle or
ribbon mixers although other mixers, such as ribbon or plow
blenders, drum agglomerators, and high shear mixers may be used.
Suitable equipment for this process include a model Rannie 100 lab
homogenizer available from APV Gaulin Inc. Everett, Mass., a rotor
stator high shear mixer available from Silverson Machines, of East
Long Meadow, Mass., or Scott Processing Equipment Corp. of Sparta,
N.J., and other high sear mixers.
[0117] The suspension is spray dried to remove the excess water.
Spray drying is well known in the art and been used commercially in
many applications, including foods where the core material is a
flavoring oil and cosmetics where the core material is a fragrance
oil. Cf. Balassa, "Microencapsulation in the Food Industry", CRC
Critical Review Journal in Food Technology, July 1971, pp 245-265;
Barreto, "Spray Dried Perfumes for Specialties, Soap and Chemical
Specialties", December 1966; Maleeny, Spray Dried Perfumes, Soap
and San Chem, January 1958, pp. 135 et seq.; Flinn and Nack,
"Advances in Microencapsulation Techniques", Batelle Technical
Review, Vo. 16, No. 2, pp. 2-8 (1967); U.S. Pat. Nos. 5,525,367;
and 5,417,153 which are incorporated herein as references.
[0118] The use of pH activated microspheres which provide varying
rates of diffusion are contemplated. For example, the active
ingredients encapsulated in the pH activated microspheres may
diffuse at any of the rates of the following:
[0119] at steady-state or zero-order release rate in which there is
a substantially continuous release per unit of time;
[0120] a first-order release rate in which the rate of release
declines towards zero with time; and
[0121] a delayed release in which the initial rate is slow, but
then increases with time.
[0122] Nanospheres formed of a hydrophobic material provide a
controlled release system in order to release the active agent over
an extended period of time by molecular diffusion. Active agents in
the hydrophobic matrix of the nanospheres can be released by
transient diffusion. The theoretical early and late time
approximation of the release rate of the active ingredients
dissolved in the hydrophobic matrix of the nanospheres can be
calculated from the following equations:
[0123] Early time approximation
(m.sub.t/m.sub.sec)<0.4 1 M t M .infin. = 4 ( D p t .PI. r 2 ) 1
/ 2 - D p t r 2 ( 1 ) M t / M .infin. t = 2 ( D p .PI. r 2 t ) 1 /
2 - D p r 2 ( 2 )
[0124] Late time approximation
(m.sub.t/m.sub..infin.)>0.6 2 M t M .infin. = 1 - 4 ( 2.405 ) 2
exp ( - ( 2.405 ) 2 D p t r 2 ) ( 3 ) M t / M .infin. t = 1 - 4 D p
r 2 exp ( - ( 2.405 ) 2 D p t r 2 ) ( 4 )
[0125] wherein:
[0126] r is the radius of the cylinder,
[0127] m.sub..infin. is the amount of active agent released from
the controlled release system after infinite time;
[0128] m.sub.t is the amount of active agent released from the
controlled release system after time t; and
[0129] D.sub.p is the diffusion coefficient of the active agent in
the matrix.
[0130] The release rate for releasing the active agents from the
hydrophobic nanospheres is typically slower than the release rate
for releasing active agent from the pH sensitive matrix. The active
agents can be selected to be incorporated into either the
hydrophobic nanospheres or the pH sensitive matrix depending on the
desired time for release of the active agents. For example, a
predetermined first active agent can be incorporated in the pH or
salt sensitive matrix to be released first and a predetermined
second active agent can be incorporated in the hydrophobic
nanospheres for release over an extended period of time during or
after the first agent has been released. For example, the pH
sensitive matrix formed in accordance with the present invention
can release the first active agent at a predetermined pH to provide
a "burst" with continued release of the first active agent and
nanospheres formed in accordance with the present invention can
release the active agent depending on the release rate from an
initial time such as a day or within few days, up to a period of
few weeks.
[0131] In the preferred embodiment, the active agent is present at
a level from about 0.01% to about 60%, preferably from about 1% to
about 50% by weight of the microsphere. In the preferred
embodiment, the nanospheres are generally present in the pH
sensitive matrix at a level from about 1% to about 80%, preferably
from about 1% to about 60% by weight of the matrix material with
the balance being the active agents, and the pH sensitive
materials. In the preferred embodiment, the pH sensitive matrix is
generally present at a level from about 1% to about 80%, preferably
from about 1% to about 60% by weight of the matrix material with
the balance being the active agents, and the hydrophobic
materials.
[0132] The subject methods may be used to treat a wide variety of
hosts, including mammalian hosts, such as domestic animals, e.g.
pets and livestock, rare or exotic animals, and humans. Cellular
proliferative diseases amenable to treatment with the subject
formulations are diseases characterized by the abnormal
proliferation of cells. Diseases characterized by the abnormal
proliferation of cells include neoplasia, psoriasis, hyperplasia
and the like.
[0133] Neoplastic diseases amenable to treatment according to the
subject methods include neoplastic dieases characterized by the
development of solid tumors or lesions, including solid malignant
tumors of the lung, breast, colon, rectum, ovaries, stomach,
pancreas, uterus, testicles, brain, liver, head and neck.
[0134] Particular neoplastic cellular proliferative diseases that
may be treated with the subject methods include carcinomas,
sarcomas and melanomas, such as basal cell carcinoma, squamous cell
carcinoma, melanoma, soft tissue sarcoma, solar keratoses, Kaposi's
sarcoma, cutaneous malignant lymphoma, Bowen's disease, Wilm's
tumor, hepatomas, colorectal cancer, brain tumors, mycosis
fungoides, Hodgkins lymphoma, polycythemia ver, lymphomas, oat cell
sarcoma, superficial and invasive bladder tumors, ovarian cancer,
etc.
[0135] The compounds can be administered orally, rectally,
parenterally, or by injection, alone or in combination with other
therapeutic agents including antibiotics, steroids, etc., to a
mammal in need of treatment. Oral dosage forms include tablets,
capsules, dragees, and similar shaped, compressed pharmaceutical
forms. Isotonic saline solutions containing 20-100
milligrams/milliliter can be used for parenteral administration
which includes intramuscular, intrathecal, intravenous and
intra-arterial routes of administration. Rectal administration can
be effected through the use of suppositories formulated from
conventional carriers such as cocoa butter.
[0136] Dosage regimens must be titrated to the particular
indication, the age, weight, and general physical condition of the
patient, and the response desired but generally doses will be from
about 1 to about 1000 milligrams/day as needed in single or
multiple daily administration.
[0137] The compositions preferably are formulated in unit dosage
form, meaning physically discrete units suitable as a unitary
dosage, or a predetermined fraction of a unitary dose to be
administered in a single or multiple dosage regimen to human
subjects and other mammals, each unit containing a predetermined
quantity of active material calculated to produce the desired
therapeutic effect in association with a suitable pharmaceutical
excipient.
[0138] Pharmaceutical compositions thus comprise one or more
compounds of the present invention associated with at least one
pharmaceutically acceptable carrier, diluent or excipient. In
preparing such compositions, the active ingredients are usually
mixed with or diluted by an excipient or enclosed within such a
carrier which can be in the form of a capsule or sachet. When the
excipient serves as a diluent, it may be a solid, semi-solid, or
liquid material which acts as a vehicle, carrier, or medium for the
active ingredient. Thus the compositions can be in the form of
tablets, pills, powders, elixirs, suspensions, emulsions,
solutions, syrups, soft and hard gelatin capsules, suppositories,
sterile injectable solutions and sterile packaged powders. Examples
of suitable excipients include lactose, dextrose, sucrose,
sorbitol, mannitol, starch, gum acacia, calcium silicate,
microcrystalline cellulose, polyvinylpyrrolidinone, cellulose,
water, syrup, and methyl cellulose, the formulations can
additionally include lubricating agents such as talc, magnesium
stearate and mineral oil, wetting agents, emulsifying and
suspending agents, preserving agents such as methyl- and
propylhydroxybenzoates, sweetening agents or flavoring agents.
[0139] The carrier system of the present invention can be
incorporated in pharmaceutical and health care products.
[0140] The invention can be further illustrated by the following
examples thereof, although it will be understood that these
examples are included merely for purposes of illustration and are
not intended to limit the scope of the invention unless otherwise
specifically indicated. All percentages, ratios, and parts herein,
in the Specification, Examples, and claims, are by weight and are
approximations unless otherwise stated.
Preparation of a pH Sensitive Drug Delivery Systems
EXAMPLE 1
[0141] The following procedure is used for the preparation of multi
component controlled release system with the chemotherapeutic drug
paclitaxel (taxol), a high molecular weight, lipophilic deterpenoid
isolated from the western yew, as the active agent encapsulated in
the solid hydrophobic nanosphere matrix. The nanosphere hydrophobic
matrix is candelilla wax, commercially available from Strahl &
Pitsch Inc. of West Babylon, N.Y. The microsphere pH sensitive
matrix is a pH dependent anionic polymer stable at pH 7.4 and
solubilizing at pH 6 and lower.
[0142] 40 grams of candelilla wax is placed in an oven at
80.degree. C. and allowed to melt. 500 grams of deionized water are
placed into Igallon vessel, fitted with an all-purpose silicon
rubber heater (Cole-Palmer Instrument Company). 50 grams of the pH
sensitive polymer were added to the water and the aqueous solution
is heated to 90.degree. C. while mixing it with a propeller mixer.
The candelilla wax is removed from the oven. 10 grams of paclitaxel
are dispersed into the melt by hand with a glass rod. The drug/wax
mixture is poured into the aqueous solution and the dispersion is
homogenized at 25,000 psi using a Rannie 100 lab homogenizer
available from APV Gaulin Inc. The dispersion is cooled to ambient
temperature by passing it through a tube-in-tube heat exchanger
(Model 00413, Exergy Inc. Hanson Mass.) to form a suspension. The
resulting suspension is spray dried with a Bowen Lab Model Drier
(at Spray-Tek of Middlesex, N.J.) utilizing 250 c.f.m of air with
an inlet temperature of 380.degree. F., and outlet temperature of
225.degree. F. and a wheel speed of 45,000 r.p.m to produce a free
flowing, dry powder, consisting of 10% paclitaxel.
EXAMPLE 2
[0143] The following procedure is used for the preparation of multi
component controlled release system with the chemotherapeutic drug
doxorubicin (hydroxydaunomycin hydrochloride) (commercially
available from Sigma) as the drug encapsulated in the solid
hydrophobic nanosphere matrix. Doxorubicin (hydroxydaunomycin
hydrochloride) is commercially available as the hydrochloride salt.
It is an antineoplastic antibiotic but it is too cytotoxic to be
used as an anti-infective agent. The exact mechanism of its
anticancer activity is not well understood but some evidence
suggests that the drug forms a complex with DNA which inhibits both
DNA synthesis and DNA-dependent RNA synthesis by the resulting
template disordering. Cells that are the most sensitive to
doxorubicin are from rapidly proliferating tissues such as those of
normal bone marrow, gastrointestinal mucosa, and hair follicles
(Budavari, et al., 1989). Doxorubicin is administered intravenously
and commonly used in the treatment of solid tumors including
bladder carcinoma, breast carcinoma, ovarian carcinoma, gastric
carcinoma, malignant lymphomas, and acute lymphoblastic and
myeloblastic leukemias. Doxorubicin is rapidly metabolized in a
first pass effect through the liver by an aldo-keto reductase
enzyme which forms doxorubicinol, the metabolite with the major
antineoplastic activity. A common adult dose of doxorubicin would
be a 60 to 75 mg/m.sup.2 (skin area), intravenous injection once
every 21 days, but other schedules require smaller injections
(20-30 mg/m.sup.2) either once weekly or for 3 to 4 successive days
every few weeks (Trissel, L. A., Handbook on Injectable Drugs,
(8.sup.th ed.), American Society of Hospital Pharmacists, Inc.,
1994). The nanosphere hydrophobic matrix is candelilla wax,
commercially available from Strahl & Pitsch Inc. of West
Babylon, N.Y. The microsphere pH sensitive matrix is a pH dependent
anionic polymer stable at pH 7.4 and solubilizing at pH 6 and
lower.
[0144] 40 grams of candelilla wax is placed in an oven at
80.degree. C. and allowed to melt. 500 grams of deionized water are
placed into 1 gallon vessel, fitted with an all-purpose silicon
rubber heater (Cole-Palmer Instrument Company). 50 grams of the pH
sensitive polymer were added to the water and the aqueous solution
is heated to 90.degree. C. while mixing it with a propeller mixer.
The candelilla wax is removed from the oven. 10 grams of
doxorubicin are dispersed into the melt by hand with a glass rod.
The drug/wax mixture is poured into the aqueous solution and the
dispersion is homogenized at 25,000 psi using a Rannie 100 lab
homogenizer available from APV Gaulin Inc. The dispersion is cooled
to ambient temperature by passing it through a tube-in-tube heat
exchanger (Model 00413, Exergy Inc. Hanson Mass.) to form a
suspension. The resulting suspension is spray dried with a Bowen
Lab Model Drier (at Spray-Tek of Middlesex, N.J.) utilizing 250
c.f.m of air with an inlet temperature of 380.degree. F., and
outlet temperature of 225.degree. F. and a wheel speed of 45,000
r.p.m to produce a free flowing, dry powder, consisting of 10%
doxorubicin.
EXAMPLE 3
[0145] The following procedure is used for the preparation of multi
component controlled release system with the chemotherapeutic drug
fluorodeoxyuridine (FUDR) (commercoially available Sigma) as the
active agent encapsulated in the hydrophobic nanosphere matrix. The
nanosphere hydrophobic matrix is beeswax wax, commercially
available from Strahl & Pitsch Inc. of West Babylon, New-York.
The microsphere pH sensitive matrix is a pH dependent anionic
polymer stable at pH 7.4 and solubilizing at pH 6 and lower. 40
grams of beeswax wax is placed in an oven at 80.degree. C. and
allowed to melt. 500 grams of deionized water are placed into 1
gallon vessel, fitted with an all-purpose silicon rubber heater
(Cole-Palmer Instrument Company). 50 grams of the pH sensitive
polymer were added to the water and the aqueous solution is heated
to 90.degree. C. while mixing it with a propeller mixer. The
beeswax is removed from the oven, 10 grams of fluorodeoxyuridine
are mixed into the melt by hand with a glass rod. The drug/wax
mixture is poured into the aqueous solution and the dispersion is
homogenized at 25,000 psi using a Rannie 100 lab homogenizer
available from APV Gaulin Inc. The dispersion is cooled to ambient
temperature by passing it through a tube-in-tube heat exchanger
(Model 00413, Exergy Inc. Hanson Mass.) to form a suspension. The
resulting suspension is spray dried with a Bowen Lab Model Drier
(at Spray-Tek of Middlesex, N.J.) utilizing 250 c.f.m of air with
an inlet temperature of 380.degree. F., and outlet temperature of
225.degree. F. and a wheel speed of 45,000 r.p.m to produce a free
flowing, dry powder, consisting of 10% fluorodeoxyuridine.
[0146] It is to be understood that the above-described embodiments
are illustrative of only a few of the many possible specific
embodiments which can represent applications of the principles of
the invention. Numerous and varied other arrangements can be
readily devised in accordance with these principles by those
skilled in the art without departing from the spirit and scope of
the invention.
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