WO1992020325A1 - Engineering the local inflammatory response as a means of controlled release drug delivery - Google Patents
Engineering the local inflammatory response as a means of controlled release drug delivery Download PDFInfo
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- WO1992020325A1 WO1992020325A1 PCT/US1992/004059 US9204059W WO9220325A1 WO 1992020325 A1 WO1992020325 A1 WO 1992020325A1 US 9204059 W US9204059 W US 9204059W WO 9220325 A1 WO9220325 A1 WO 9220325A1
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- excipient
- cellular regulator
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
- A61K9/0024—Solid, semi-solid or solidifying implants, which are implanted or injected in body tissue
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- A61K38/18—Growth factors; Growth regulators
- A61K38/1841—Transforming growth factor [TGF]
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- A61K38/19—Cytokines; Lymphokines; Interferons
- A61K38/191—Tumor necrosis factors [TNF], e.g. lymphotoxin [LT], i.e. TNF-beta
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- A61K38/19—Cytokines; Lymphokines; Interferons
- A61K38/20—Interleukins [IL]
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- A61K38/19—Cytokines; Lymphokines; Interferons
- A61K38/21—Interferons [IFN]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- A61K38/22—Hormones
- A61K38/27—Growth hormone [GH] (Somatotropin)
Definitions
- This invention relates generally to drug delivery systems and particularly to a product, consisting of a drug and cellular regulator, which, when introduced subcutaneously into a human or animal, affects the local tissue response, thereby affecting the release and absorption rate of the drug into general circulation.
- Methods include long acting oral dosage forms, bolus injections, transdermal patches and sub-cutaneous implants.
- the polymeric systems consist either of matrices of non-biodegradable polymers or matrices of biodegradable polymers.
- Such polymer-based systems are combined with the drug to create either a matrix erosion system, in which the drug is evenly distributed in a polymer matrix and is released as the polymer breaks down in biological fluid after introduction into the subject, or a matrix diffusion system in which the drug is released by diffusion through the polymer matrix, or a matrix diffusion/erosion system in which the drug is released by diffusion through the polymer matrix, as well as by erosion as the surface of the polymer breaks down.
- Microspheres in aqueous or oil suspension have also been used in which the drug is coated with a bioerodible polymer and injected subcutaneously. The microspheres erode and release the drug according to the size and number of microspheres.
- systems utilizing hydrogels and polymeric reservoirs have been devised.
- the nonpolymeric systems include compressing mixtures of the drug and an excipient into a pellet. Such nonpolymeric systems can also be made of a totally fused pellet or a partially fused pellet.
- a drug and an excipient are melted and recrystallized to form a crystalline matrix; in a partially fused pellet, a mixture of a drug and an excipient having a lower melting temperature than the drug is heated and cooled such that only the excipient melts and recrystallizes.
- Cholesterol matrix systems have also been developed.
- the systems suffer from various inherent problems including: foregoing general permeability to macromolecules; swelling of macromolecules, resulting in their being trapped in the erosion or diffusion systems; highly water soluble macromolecules exhibiting volatile dissolution kinetics in implants; proteins aggregating under certain pH conditions, turning into gel-like substances and thereby impeding release; large molecular weight molecules having problems being taken up by transport cells; surface erosion resulting in indefinite duration that may present a prolonged period of sub-effective drug release, and the requirement of removing the implant at the end of the effective release period.
- the invention provides a product, including a biologically active substance, at least one cellular regulator, and optionally an excipient, and a method whereby such product is introduced subcutaneously into a human or animal.
- the cellular regulator is capable of controlling, by either stimulating or inhibiting, one or more of the processes that are associated with the local inflammatory response resulting from the subcutaneous implant, such as production of macrophages, proliferation of fibrous tissue encapsulating the implant, infiltration of the fibrous capsule by new blood vessels and lymphatics, and transport of lipophilic or hydrophilic molecules into or out of the encapsulated implant.
- the cellular regulator aids in generating a "paraglandular" compartment surrounding the subcutaneous implant, which is capable of active and interactive processing, including the release of the biologically active substance from the "paraglandular" compartment.
- This invention thus exploits the naturally occurring local inflammatory response by artificially manipulating the presence, concentration, and order of appearance, of one or more cellular regulators, so as to affect the kinetics of release of the biologically active substance from the encapsulated implant.
- the biologically active substance preferably is a drug.
- the cellular regulator preferably is a cytokine.
- the optional excipient may be part of any one of a variety of drug delivery systems, including polymeric systems, non-polymeric systems, microspheres, hydrogels, polymeric reservoirs or cholesterol matrices, which serve as the embodiment for the implant.
- Fig. 1 is a cross-sectional view of a "paraglandular" compartment after implanted drug pellet was removed, as viewed by scanning electron microscopy (SEM);
- Fig. 2 is a cross-sectional view of the compartment lumen surrounding an implanted pellet, as viewed by SEM;
- Fig. 3 is a cross-sectional view of the compartment wall showing blood vessels and relative tissue densities, as viewed by SEM;
- Fig. 4 is a cross-sectional view of two blood vessels of capillary size in the middle region of the capsule wall, as viewed by SEM;
- Fig. 5 is another view of the sample depicted in Fig. 4 with intact erythrocytes inside blood vessels, as viewed by SEM;
- Fig. 6 is a thin section of a fibroblast with collagen fibrils of normal periodicity, as viewed by transmission electron microscopy (TEM);
- Fig. 7 is a thin section of fibrous wall, excised at 6 months, showing a few lipid-engorged foam cells among loose collagen fibrils, as viewed by TEM;
- Fig. 8 is a thin section of fibrous wall, excised at 13 months, showing significantly denser populations of lipid-engorged foam cells and denser collagen fibrils than are present in Fig. 7 at 6 months, as viewed by TEM.
- This invention pertains to a drug delivery system, including a drug and a cellular regulator, which, when introduced subcutaneously into a subject, affects the local tissue response, and thereby results in controlled release of the drug.
- This invention is designed to exploit the local inflammatory response by artificially manipulating both the presence and concentrations of various cellular regulators to favorably influence the controlled release of drug from an implanted delivery system.
- the invention is designed to affect drug release and absorption from the foreign body implant. This invention thus represents a new approach to drug delivery systems.
- the invention involves the implantation of a biologically active substance which is to be delivered to a human or an animal in a therapeutically effective amount, and at least one cellular regulator which is present in sufficient amount to affect the local inflammatory response which will result from implantation.
- a biologically active substance which is to be delivered to a human or an animal in a therapeutically effective amount, and at least one cellular regulator which is present in sufficient amount to affect the local inflammatory response which will result from implantation.
- the biologically active substance may be any substance having biological activity, including protein, polypeptide, polynucleotide, nucleoprotein, polysaccharide, glycoprotein, lipoprotein, and synthetic and biologically engineered analogues of such molecules.
- the biologically active substance is a drug.
- a drug is a substance used on or administered to humans or animals as an aid in diagnosis, treatment or prevention of disease or other abnormal conditions, for relief of pain or suffering, or to control, affect, maintain or improve a physiological or pathological condition.
- Classes of drugs which are intended to be included within this invention include anti-AIDS substances, anti-cancer substances, antibiotics, anti-viral substances, enzyme inhibitors, neurotoxins, opioids, hypnotics, tranquilizers, anti-convulsants, muscle relaxants and anti-Parkinson substances, anti-spasmodics and muscle contractants, anti-hypertensives, analgesics, anti-pyretics and anti-inflammatory agents- local anesthetics, prostaglandins, anti-depressants, anti-psychotic substances, anti-emetics, imaging agents, specific targeting agents, neurotransmitters and proteins.
- Anti-AIDS substances are substances used to treat or prevent Autoimmune Deficiency Syndrome (AIDS) .
- examples of such substances include CD4, 3'-azido-3'-deoxythymidine (AZT), 9-(2-hydroxyethoxymethyl)-guanine acyclovir (acyclovir), phosphonoformic acid, 1-adamantanamine, peptide T, and 2',3' dideoxycytidine.
- Anti-cancer substances are substances used to treat or prevent cancer. Examples of such substances include methotrexate, cisplatin, prednisone, hydroxyprogesterone caproate, medroxyprogesterone acetate, megestrol acetate, diethylstilbestrol, ethinyl estradiol, tamoxifen, testosterone propionate, fluoxymesterone, vinblastine (VLB), vincristine, vindesine, etoposide, teniposide, dactinomycin (actinomycin D), daunorubicin (daunomycin; rubidomycin) , doxorubicin, bieomycin, plicamycin (mithramycin), mitomycin (mitomycin C) , -asparaginase, hydroxyurea, procarbazine (N-methylhydrazine, MIH) , mitotane, aminoglutethimide, mechlorethamine,
- Antibiotics are art recognized and are substances which inhibit the growth of or kill microorganisms. Antibiotics can be produced synthetically or by microorganisms. Examples of antibiotics include pennicillin, tetracycline, minocycline, doxycycline, vanomycin, bacitracin, kanamycin, neomycin, erythromicin and cephalosporins.
- cephalosporins examples include cephalothin (keflin, seffin), cephapirin (cefadyl), cefazolin (ancef, kefzol), cephalexin (keflex) , cephradine (anspor, velosef), cefadroxil (duricef, ultracef), cefamandole (mandol), cefoxitin (mefoxin), cefaclor (ceclor), cefuroxime (zinacef), cefonicid (monocid) , ceforanide (precef) , cefotaxime (claforan), moxalactam (moxam), ceftizoxime (cefizox), ceftriaxone (rocephin), and cefoperazone (cefobid) .
- Anti-viral agents are substances capable of destroying or suppressing the replication of viruses.
- anti-viral agents include ⁇ -methyl- ⁇ .-adamantane methylamine (ri mantadine), l- ⁇ -D-ribofuranosyl-l,2,4-triazole-3 carboxamide (ribavirin) , 9-[2-hydroxy-ethoxy]methylguanine (Acyclovir), adamantanamine, 5-iodo-2'-deoxyuridine (Idoxuridine) and adenine arabinoside (Vidarabine) .
- Enzyme inhibitors are substances which inhibit an enzymatic reaction.
- enzyme inhibitors include edrophonium chloride,
- Neurotoxins are substances which have a toxic effect on the nervous system, e.g. nerve cells.
- Neurotoxins include adrenergic neurotoxins, cholinergic neurotoxins, dopaminergic neurotoxins, and other neurotoxins.
- adrenergic neurotoxins include N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine hydrochloride.
- cholinergic neurotoxins include acetylethylcholine mustard hydrochloride acetyl AF-64.
- dopaminergic neurotoxins include 6-hydroxydopamine HBr, l-methyl-4-(2-methylphenyl)-1,2,3,6- tetrahydro-pyridine hydrochloride, l-methyl-4-phenyl-2,3- dihydropyridinium perchlorate, N-methyl-4-phenyl-l,2,5,6- tetrahydropyridine HCl, l-methyl-4-phenylpyridinium iodide.
- neurotoxins include L- ⁇ -methyl- ⁇ , ⁇ -diaminopropionic acid hydrochloride, ( ⁇ )- ⁇ -methyl- ⁇ , ⁇ -diaminopropionic acid hydrochloride, L- ⁇ -oxalyl- , ⁇ -diaminopropionic acid, and quinolinic acid.
- Opioids are substances having opiate like effects that are not derived from opium.
- Opioids include opioid agonists and opioid antagonists.
- Opioid agonists include codeine sulfate, fentanyl citrate, hydrocodone bitartrate, loperamide HCl, morphine sulfate, noscapine, norcodeine, normorphine, thebaine.
- Opioid antagonists include nor—binaltorphimine HCl, buprenorphine, ⁇ -chlornaltrexamine 2HC1, ⁇ -funaltrexamione HCl, nalbuphine HCl, nalorphine HCl, naloxone HCl, naloxonazine, naltrexone HCl, and naltrindole HCl(NTI).
- Hypnotics are substances which produce a hypnotic effect.
- Hypnotics include pentobarbital sodium, phenobarbital, secobarbital, thiopental and mixtures, thereof, heterocyclic hypnotics, dioxopiperidines, glutarimides, diethyl isovaleramide, ⁇ -bromoisovaleryl urea, urethanes and disulfanes.
- Tranquilizers are substances which provide a tranquilizing effect.
- tranquilizers include chloropromazine, promazine, fluphenzaine, reserpine, deserpidine, and meprobamate.
- Anti-convulsants are substances which have an effect of preventing, reducing, or eliminating convulsions.
- examples of such agents include primidone, phenytoin, valproate, Chk and ethosuximide.
- Muscle relaxants and anti-Parkinson agents are agents which relax muscles or reduce or eliminate symptoms associated with Parkinson's disease.
- Examples of such agents include mephenesin, methocarbomal, cyclobenzaprine hydrochloride, trihexylphenidyl hydrochloride, levodopa/carbidopa, and biperiden.
- Anti-spasmodics and muscle contractants are substances capable of preventing or relieving muscle spasms or contractions.
- examples of such agents include atropine, scopolamine, oxyphenonium, and papaverine.
- Anti-hypertensives are substances capable of counteracting high blood pressure. Examples of such substances include ⁇ -methyldapa and the pivaloyloxyethyl ester of ⁇ -methyldapa.
- Analgesics are substances capable of preventing, reducing, or relieving pain.
- Examples of analgesics include morphine sulfate, codeine sulfate, meperidine, and nalorphine.
- Anti-pyretics are substances capable of relieving or reducing fever and anti-inflammatory agents are substances capable of counteracting or suppressing inflammation.
- anti-inflammatory agents include aspirin (salicylic acid), indomethacin, sodium indomethacin trihydrate, salicylamide, naproxen, colchicine, fenoprofen, sulindac, diflunisal, diclofenac, indoprofen and sodium salicylamide.
- Local anesthetics are substances which have an anesthetic effect in a localized region.
- anesthetics include procaine, lidocain, tetracaine and dibucaine.
- Prostaglandins are art recognized and are a class of naturally occurring chemically related, long-chain hydroxy fatty acids that have a variety of biological effects. Examples of such agents include E2 and El.
- Anti-depressants are substances capable of preventing or relieving depression.
- Examples of anti-depressants include imipramine, amitriptyline, nortriptyline, protriptyline, desipramine, amoxapine, doxepin, maprotiline- tranylcypromine, phenelzine, and isocarboxazide.
- Anti-psychotic substances are substances which modify psychotic behavior. Examples of such agents include phenothiazines, butyrophenones and thioxanthenes.
- Anti-emetics are substances which prevent or alleviate nausea or vomiting.
- An example of such a substance includes dramamine.
- Imaging agents are agents capable of imaging a desired site, e.g. tumor, jln vivo.
- imaging agents include substances having a label which is detectable in vivo, e.g. antibodies attached to fluorescent labels.
- the term antibody includes whole antibodies or fragments thereof.
- Specific targeting agents include agents capable of delivering a therapeutic agent to a desired site, e.g. tumor, and providing a therapeutic effect.
- targeting agents include agents which can carry toxins or other agents which provide beneficial effects.
- the targeting agent can be an antibody linked to a toxin, e.g. ricin A or an antibody linked to a drug.
- Neurotransmitters are substances which are released from a neuron on excitation and travel to either inhibit or excite a target cell.
- Examples of neurotransmitters include dopamine, serotonin, ⁇ -aminobutyric acid, norepinephrine, histamine, acetylcholine, and epinephrine.
- protein is art-recognized and for purposes of this invention also encompasses peptides.
- the proteins or peptides may be any bioactive protein or peptide, naturally occurring or synthetic.
- proteins include antibodies, enzymes, steroids, growth hormone and growth hormone-releasing hormone, gonadotropin-releasing hormone, and its agonist and antagonist analogues, somatostatin and its analogues, gonadotropins such as luteinizing hormone and follicle-stimulating hormone, peptide-T, thyrocalcitonin, parathyroid hormone, glucagon, vasopressin, oxytocin, angiotensin I and II, bradykinin, kallidin, adrenocbrticotropic hormone, thyroid stimulating hormone, insulin, glucagon and the numerous analogues and congeners of the foregoing molecules.
- salts or non-salt form both forms are intended to be encompassed.
- other art recognized biologically accepted salts can be used in place of the listed salt-form.
- acceptable salts include hydrochloride, hydrobromide, sulfate, laurelate, palmatate, phosphate, nitrate, borate, acetate, maleate, tartrate, oleate, salisilate, salts of metals, means or organic cations, e.g. quarternary ammonium.
- a derivative is a drug which is structurally similar to the foregoing list of drugs and is capable of achieving the same or substantially the same function or activity.
- An equivalent is an agent capable of achieving the same or substantially the same intended function or activity.
- the biologically active substance is present in sufficient amount to achieve a therapeutic effect for at least three months of delivery. In certain preferred embodiments the biologically active substance is present in sufficient amount to achieve a therapeutic effect for at least three months of systemic delivery.
- a therapeutically effective dose is that amount necessary to prevent, treat, or reduce the symptoms associated with the particular condition or disease being treated.
- the cellular regulator is any substance that affects the local tissue response, including but not limited to a cytokine or an oncogene product homologous to a cytokine, or any compound which may inhibit or otherwise affect such regulators, such as a steroidal or non-steroidal anti-inflammatory.
- a cytokine or an oncogene product homologous to a cytokine or any compound which may inhibit or otherwise affect such regulators, such as a steroidal or non-steroidal anti-inflammatory.
- Cytokines are involved in controlling the proliferation and differentation of mammalian cells and cellular interactions in the immune and inflammatory responses.
- the cellular regulator is present in sufficient amount to accelerate, decelerate, increase, or decrease the local inflammatory response to the implant.
- the cellular regulator is present in sufficient amount to increase or decrease the release of biologically active substance relative to an implant with no cellular regulator. This effect may result for example from the cellular regulator stimulating or retarding macrophage production, proliferation of fibrous tissue encapsulating the implant, infiltration of the fibrous capsule by new blood vessels and lymphatics, transport of lipophilic molecules across the encapsulated implant, transport of hydrophilic molecules across the encapsulated implant, or preventing or suppressing chemotaxis.
- the cellular regulator is .in addition to the biologically active substance.
- the cellular regulator is present in sufficient concentration to affect the local tissue response, but is not present in sufficient concentration to achieve a therapeutic effect for the particular condition or disease being treated.
- the cellular regulator preferably is an interleukin, interleukin inhibitor or interleukin receptor, including interleukin 1 through interleukin 10; an interferon, including alpha, beta and gamma; a hematopoietic factor, including erythropoietin, granulocyte colony stimulating factor, macrophage colony stimulating factor and granulocyte-macrophage colony stimulating factor; a tumor necrosis factor, including alpha and beta; a transforming growth factor (beta), including beta-1, beta-2, beta-3, inhibin, and activin; a chemotactic factor, including neutrophil-activating protein, monocyte chemoattractant protein, macrophage-inflammatory protein, SIS (small inducible secreted), platelet factor, platelet basic protein, and melanoma growth stimulating activity; a growth factor, including epidermal growth factor, transforming growth factor (alpha), fibroblast growth factor, platelet-derived growth factor, platelet-derived endo
- the invention embodies a system in which one or more than one cellular regulators are introduced.
- Various combinations of cellular regulators, as well as various times of introduction of different cellular regulators, can be devised to either stimulate or inhibit various aspects of the local inflammatory response, so as to finely tune the rate of release of the biologically active substance and maximize the therapeutic efficacy of the particular biologically active substance involved in the patient's treatment.
- the invention embodies delivering the biologically active substance and the cellular regulator into the subject by injection or implantation.
- a phased effect on the local inflammatory response can be achieved by varying the timing and order of the injections.
- the biologically active substance and the cellular regulator may be present in the same physical unit or in separate physical units. More than one cellular regulator may also be used, either in the same physical unit or in separate physical units. Varying the timing and order of implantations of the physical units can be used to achieve a phased effect on the local inflammatory response.
- the biologically active substance and cellular regulator may be introduced alone or in combination with an excipient.
- the excipient may be part of a polymeric system consisting of matrices of biodegradable or non-biodegradable polymers; a nonpolymeric system consisting of compressed mixtures, totally fused pellets or partially fused pellets; microspheres; hydrogels; polymeric reservoirs; or cholesterol matrices.
- a polymeric system consists of matrices of polymers combined with a biologically active substance.
- Such systems include (i) matrix erosion systems, in which the biologically active substance is evenly distributed in a polymer matrix and is released as the polymer breaks down in biological fluid after introduction into the subject, (ii) matrix diffusion systems in which the biologically active substance is released by diffusion through the polymer matrix, and (iii) matrix diffusion/erosion systems in which the biologically active substance is released by diffusion through the polymer matrix, as well as by erosion as the surface of the polymer breaks down.
- Biodegradable polymers that have been used in such systems include hydroxycarboxylic acids, especially lactic acid and glycolic acid. Cholesterol and ethylene vinyl acetate copolymers have also been used.
- Nonpolymeric systems can be fabricated by compressing mixtures of the biologically active substance and a nonactive biocompatible binder into a pellet. The rate of release and the uniformity of release depend both on the relative amounts of the drug and binder and on the homogeneity of the .fixture prior to compression.
- Nonpolymeric systems also include totally fused pellets in which the biologically active substance is melted together with a nonpolymeric carrier and then recrystallized by cooling, to form the fused pellet.
- a partially fused pellet can be fabricated by mixing a biologically active substance and a nonpolymeric carrier having a lower melting temperature than the biologically active substance, and heating and then cooling the mixture, such that only the carrier melts and recrystallizes, capturing the unmelted drug.
- Such totally and partially fused pellets are characterized by nondiffusional, erosion-based, drug release. See, for example, co-pending applications Serial No. 07/565,273, “Multiple Drug Delivery System,” filed August 9, 1990 and Serial No. 07/163,328, "Partially Fused Peptide Pellet,” filed March 2, 1988.
- Microspheres are systems in aqueous or oil suspensions, in which the drug is coated with a bioerodible polymer and injected subcutaneously. The microspheres erode and release the drug according to the size and number of microspheres.
- a hydrogel is designed to release a biologically active substance contained therein, when the composition is placed in an aqueous environment. See, for example, U.S. Patent No.
- 4,526,938 issued to Churchill et al., which describes a composition comprising a polypeptide and a copolymer, in which the hydrophobic component is biodegradable and the hydrophilic component may or may not be biodegradable, and in which the composition is capable of absorbing water to form a hydrogel when placed in water or an aqueous physiological type environment, from which the polypeptide is then released over an extended period of time.
- a polymeric reservoir is a tubular device possessing interconnected porous walls.
- the interconnected porous reservoir walls provide a continuous path for the migrating biologically active substance which then diffuses from the reservoir at a rate governed by the tortuosity of the diffusion path.
- the polymeric reservoir is fabricated from a polylactone, including polycaprolactone or its copolymers, or polyvalerolactone and its copolymers, containing an additive, such as a polyether which is selectively removed by treatment with an appropriate solvent to form the interconnected pores therein.
- a cholesterol matrix delivery system comprises a cholesterol matrix permeable to passage by diffusion of the biologically active agent contained therein. See, for example, U.S. Patent No. 4,452,775 issued to Kent, in which the matrix consists of cholesterol powder and cholesterol prills optionally in combination with a binding agent and a lubricating agent, and in which the biologically active substance is dispersed throughout the matrix.
- a cellular regulator as described in this invention, is designed to overcome the various drawbacks that each of these previously described systems exhibit on their own.
- the stimulation or inhibition of the local inflammatory response upon introduction of a cellular regulator into these systems will result in an enhanced "paraglandular" compartment and a means for controlled release of the drug.
- the cellular regulator may be present as a core within a pellet, or the cellular regulator may be coated onto the surface of a pellet so as to have an initial stimulatory effect on the local inflammatory response, or the cellular regulator may be impregnated throughout a pellet to provide a continuous effect on the local inflammatory response, or the cellular regulator may be layered in a pellet to provide a time-variant effect on the local inflammatory response.
- Figure 1 is an SEM of a cross-sectional view of a "paraglandular" compartment 10, excised after 7 months of implantation of a drug pellet in a subject, with the implanted drug pellet removed.
- the wall 12, lumen 14, and bed 16 of the compartment 10 are apparent.
- Capillary openings 18 are present at the bed 16.
- Connective tissue 20 is loose at the periphery of the compartment 10, and much denser towards the bed 16.
- Figure 2 is an SEM of a cross-sectional view of the compartment lumen 14, excised after 7 months, surrounding an implanted drug pellet 22.
- Figure 3 is an SEM of the compartment wall 12, excised after 13.5 months, showing blood vessels 24 and relative connective tissue densities. Looser connective tissue 20 is present at the outer compartment wall 12.
- Figure 4 is an SEM of two blood vessels 24 of capillary size, excised after 13 months, in the middle region of the capsule wall 12.
- Connective tissue 20 surrounds the blood vessels 24.
- Figure 5 is an SEM of another view of the sample depicted in Fig. 4, showing intact erythrocytes 26 inside blood vessels 24.
- Connective tissue 20 surrounds the blood vessels 24.
- Figure 6 is a TEM of a thin section of a fibroblast 28, excised after 3 months, with collagen fibrils 30 of normal periodicity in the fibrous portion of the compartment.
- Figure 7 is a TEM of a thin section of fibrous wall 32, excised after 6 months, showing a few lipid engorged foam cells 34, i.e. , lipid-laden macrophages, among loose collagen fibrils 30.
- Figure 8 is a TEM of a thin section of fibrous wall 32, excised after 13 months, showing significantly denser populations of lipid engorged foam cells 34 and denser collagen fibrils 30 than are present in Fig. 7 after 6 months of drug pellet implantation.
- a comparison of Figures 7 and 8 supports the theory that the concentration of foam cells increases with time post-implantation of the drug pellet. The above pictures are consistent with the foam cells either entering the blood and lymphatic vessels, or extruding the lipid at the vessel surface.
- Mass spectrometric data supports the theory that the foam cells absorb the NET as it is released from the pellet surface.
- NET levels in the capsule tissue at 3 to 10.5 months post-implantation were, respectively, 0.05% and 8.4%. Such an increase correlates qualitatively with the increase in foam cell population in the capsule wall for the same period.
- the local inflammatory response plays an essential role in the active processing of drug delivery systems.
- This invention utilizes the theory that the implant, in inducing a local inflammatory response, results in the recruitment of macrophages and the concomitant release of various cytokines.
- the implant becomes coated with macrophages, and absorption of the drug from the implant becomes, inter alia, a function of foam cell transport to the local vasculature and lymphatics.
- Some of the cytokines stimulate fibroblast production and the establishment of angiogenesis for the capsule.
- the resultant serum concentrations of released drug are a function of this active processing of the drug implant.
- the rate and extent of this active processing by manipulating the various elements that contribute to this processing, one can regulate the rate and extent of drug release from the implant.
- an angiogenesis factor would be combined in matrix with a bio-erodible polymer, such as poly-dl lactide or glycolide, as a sheath around a core drug implant.
- a bio-erodible polymer such as poly-dl lactide or glycolide
- the sheath would be formed so as to gradually erode, releasing the angiogenesis factor, and thus preparing the tissue environment for delivery of the core drug.
- hGH human or bovine species
- macrophage is directly or indirectly the source of the hostile factors mentioned above, it is also directly or indirectly the source of the growth factors which are associated with sufficient neovascular development (angiogenesis) necessary to optimize the absorption of the- active protein.
- GH is t nonlipophilic, it suffers additional difficulties relative to absorption in the lipid environment.
- matrices of protein and lipophilic compounds such as steroids can be acheived by selecting combinations of excipients and active ingredients that allow the melting and recrystallization of the excipient only. This does not preclude the material which undergoes a phase change from also being an active ingredient.
- the granular powder of number one is introduced into an intimate mixture of 5 milligrams of cholesterol palmitate and 0.7 milligrams of epidermal growth factor, transforming growth factor beta or more specific angiogenic cytokine.
- the rod is allowed to cool and recrystallize at room temperature.
- the resulting pellet is implanted into the subcutaneous tissue of a cow by means of a Harman Injector; U.S. Patent No. 4,820,267.
- the corticoid is soluble within the cholesterol palmitate matrix and thus diffuses from the rod carrying the GH with the result of both suppressing the local inflammatory response (thus macrophage) and providing a lipid buffer for the protein.
- angiogenic factor representing about 8% of the non-GH/corticoid component of he matrix, thus stimulating neovascularization at the local implant site.
Abstract
Description
Claims
Priority Applications (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP4511176A JPH06507634A (en) | 1991-05-14 | 1992-05-13 | Design of local inflammatory responses as a controlled release drug delivery vehicle |
NO934114A NO934114L (en) | 1991-05-14 | 1993-11-15 | Control of local inflammatory response by means of controlled delivery |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US69976391A | 1991-05-14 | 1991-05-14 | |
US699,763 | 1991-05-14 |
Publications (1)
Publication Number | Publication Date |
---|---|
WO1992020325A1 true WO1992020325A1 (en) | 1992-11-26 |
Family
ID=24810811
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/US1992/004059 WO1992020325A1 (en) | 1991-05-14 | 1992-05-13 | Engineering the local inflammatory response as a means of controlled release drug delivery |
Country Status (7)
Country | Link |
---|---|
EP (1) | EP0584220A1 (en) |
JP (1) | JPH06507634A (en) |
AU (1) | AU1979392A (en) |
CA (1) | CA2103045A1 (en) |
HU (1) | HUT67238A (en) |
NO (1) | NO934114L (en) |
WO (1) | WO1992020325A1 (en) |
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1994023706A1 (en) * | 1993-04-20 | 1994-10-27 | Endocon, Inc. | Foam cell drug delivery |
WO1994028871A1 (en) * | 1993-06-07 | 1994-12-22 | Endocon, Inc. | Implant stimulated cellular immunity |
Citations (13)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP0092918A2 (en) * | 1982-04-22 | 1983-11-02 | Imperial Chemical Industries Plc | Continuous release formulations |
US4452775A (en) * | 1982-12-03 | 1984-06-05 | Syntex (U.S.A.) Inc. | Cholesterol matrix delivery system for sustained release of macromolecules |
EP0139286A2 (en) * | 1983-10-14 | 1985-05-02 | Sumitomo Pharmaceuticals Company, Limited | Prolonged sustained-release preparations |
US4591496A (en) * | 1984-01-16 | 1986-05-27 | Massachusetts Institute Of Technology | Process for making systems for the controlled release of macromolecules |
EP0223708A2 (en) * | 1985-11-18 | 1987-05-27 | Research Triangle Institute | Porous bioabsorbable polyesters |
WO1988002632A1 (en) * | 1986-10-16 | 1988-04-21 | President And Fellows Of Harvard College | Combinations of tumor necrosis factors and anti-inflammatory agents and methods for treating malignant and non-malignant diseases |
US4748024A (en) * | 1987-04-06 | 1988-05-31 | Endocon, Inc. | Flash flow fused medicinal implants |
US4818542A (en) * | 1983-11-14 | 1989-04-04 | The University Of Kentucky Research Foundation | Porous microspheres for drug delivery and methods for making same |
WO1989009620A1 (en) * | 1988-04-14 | 1989-10-19 | Peter Leskovar | Drug for treating cancer, aids and viral diseases |
WO1990010437A1 (en) * | 1989-03-09 | 1990-09-20 | Endocon, Inc. | Partially fused peptide pellet |
WO1992002211A1 (en) * | 1990-08-09 | 1992-02-20 | Endocon, Inc. | Multiple drug delivery system |
WO1992002240A2 (en) * | 1990-07-27 | 1992-02-20 | Repligen Corporation | Novel methods and compositions for treatment of angiogenic diseases |
EP0224885B1 (en) * | 1985-11-28 | 1992-05-20 | Wakunaga Seiyaku Kabushiki Kaisha | Antitumor composition. |
-
1992
- 1992-05-13 WO PCT/US1992/004059 patent/WO1992020325A1/en not_active Application Discontinuation
- 1992-05-13 EP EP19920912037 patent/EP0584220A1/en not_active Withdrawn
- 1992-05-13 CA CA 2103045 patent/CA2103045A1/en not_active Abandoned
- 1992-05-13 HU HU9303214A patent/HUT67238A/en unknown
- 1992-05-13 JP JP4511176A patent/JPH06507634A/en active Pending
- 1992-05-13 AU AU19793/92A patent/AU1979392A/en not_active Abandoned
-
1993
- 1993-11-15 NO NO934114A patent/NO934114L/en unknown
Patent Citations (13)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP0092918A2 (en) * | 1982-04-22 | 1983-11-02 | Imperial Chemical Industries Plc | Continuous release formulations |
US4452775A (en) * | 1982-12-03 | 1984-06-05 | Syntex (U.S.A.) Inc. | Cholesterol matrix delivery system for sustained release of macromolecules |
EP0139286A2 (en) * | 1983-10-14 | 1985-05-02 | Sumitomo Pharmaceuticals Company, Limited | Prolonged sustained-release preparations |
US4818542A (en) * | 1983-11-14 | 1989-04-04 | The University Of Kentucky Research Foundation | Porous microspheres for drug delivery and methods for making same |
US4591496A (en) * | 1984-01-16 | 1986-05-27 | Massachusetts Institute Of Technology | Process for making systems for the controlled release of macromolecules |
EP0223708A2 (en) * | 1985-11-18 | 1987-05-27 | Research Triangle Institute | Porous bioabsorbable polyesters |
EP0224885B1 (en) * | 1985-11-28 | 1992-05-20 | Wakunaga Seiyaku Kabushiki Kaisha | Antitumor composition. |
WO1988002632A1 (en) * | 1986-10-16 | 1988-04-21 | President And Fellows Of Harvard College | Combinations of tumor necrosis factors and anti-inflammatory agents and methods for treating malignant and non-malignant diseases |
US4748024A (en) * | 1987-04-06 | 1988-05-31 | Endocon, Inc. | Flash flow fused medicinal implants |
WO1989009620A1 (en) * | 1988-04-14 | 1989-10-19 | Peter Leskovar | Drug for treating cancer, aids and viral diseases |
WO1990010437A1 (en) * | 1989-03-09 | 1990-09-20 | Endocon, Inc. | Partially fused peptide pellet |
WO1992002240A2 (en) * | 1990-07-27 | 1992-02-20 | Repligen Corporation | Novel methods and compositions for treatment of angiogenic diseases |
WO1992002211A1 (en) * | 1990-08-09 | 1992-02-20 | Endocon, Inc. | Multiple drug delivery system |
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1994023706A1 (en) * | 1993-04-20 | 1994-10-27 | Endocon, Inc. | Foam cell drug delivery |
WO1994028871A1 (en) * | 1993-06-07 | 1994-12-22 | Endocon, Inc. | Implant stimulated cellular immunity |
Also Published As
Publication number | Publication date |
---|---|
NO934114L (en) | 1994-01-14 |
NO934114D0 (en) | 1993-11-15 |
AU1979392A (en) | 1992-12-30 |
EP0584220A1 (en) | 1994-03-02 |
HUT67238A (en) | 1995-03-28 |
JPH06507634A (en) | 1994-09-01 |
CA2103045A1 (en) | 1992-11-15 |
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