KR101197540B1 - Long-term delivery formulations and methods of use thereof - Google Patents

Abstract

The present invention provides methods, kits and compositions for prolonged release of a drug at therapeutically constant effective levels for neurological disorders in which there are problems with the treatment regimen. In particular, the present invention relates to a method of treating a psychiatric disorder.

Long-term drug release, copolymer

Description

LONG-TERM DELIVERY FORMULATIONS AND METHODS OF USE THEREOF

FIELD OF THE INVENTION The present invention relates to formulations for long term delivery, methods for their preparation and their use, comprising biodegradable substrates and active agents. The present invention also relates to formulations for long term delivery of risperidone and 9-OH-risperidone compositions for the treatment of psychosis.

Psychosis is a pathological condition of the brain that causes abnormal cognition, emotions or moods, and is characterized by malformed, identifiable symptoms, especially in terms of work performance, interaction and human affinity. The symptom severity, duration of illness, and functional impairment of the disease may vary. Millions of people of all ages worldwide have suffered from psychiatric disorders for a long time, resulting in economic burdens of considerable human hardship and loss of productivity. In some cases, the psychiatric disorder may be acute, lasting weeks to months. In other instances, the disease may be chronic, lasting years or even decades.

Due to the progress in research in the fields of neuroscience and molecular biology, the use of drugs to treat psychosis is rapidly increasing. In addition, developments in the field have led to the development of new drugs and delivery mechanisms that are more effective in treating psychosis and other brain pathologies and involve little side effects.

Non-compliance of drugs is a common problem in various diseases. Non-compliance causes certain medical and social problems when the subject drug is a neuropathic drug (antipsychotic) such as chlorpromazine or haloperidol (Rogers, A. et al. 1998, "The meaning and management of neuroleptic medication: A study of patients with a diagnosis of schizophrenia ", Social Science and Medicine 47 (9): 1313-1323). There are many reasons why patients with mental disorders do not accept prescribed medication. One quarter to two thirds of patients point to side effects as the first reason for drug discontinuation (del Campo, EJ et al. 1983, "Rehospitalized schizophrenics: what they report about illness, treatment and compliance", J of Psychosocial Nurs. And Mental Health Serv. 21 (6): 29-33). Others point to a lack of support for the patient's family (Robinson et al., 2002). In another study, the severity of psychopathology was found to be directly linked to noncompliance in experimental and outpatient experimental conditions (Fenton, WS et al., 1997, "Determinants of medication compliance in schizophrenia: empirical and clinical findings ", Schizophrenia Bull. 23 (4): 637-651). The most obvious propensity to suggest relapse and hospitalization in schizophrenic patients is non-compliance with treatment regimens with antipsychotic agents (Csernansky JG, Schuchart EK: Relapse and rehospitalization rates in patients with schizophrenia effects of second generation antipsychotics.CNS Drugs 2002 , 16: 473-484; Doering S, Muller E, Kopcke W, Pietzcker A, Gaebel W, Linden M, Muller P, Muller-Spahrn F, Tegeler J, Schussler G: Predictors of relapse and rehospitalization in schizophrenia and schizoaffective disorder. Schizophr. Bull 1998, 24: 87-98). Other studies have reported increased nonconformities (up to 55%). In the UK, where the rate of neuroleptic compliance was 50%, it was concluded that non-compliance had more influence on non-intake rates of prescription drugs (Rogers et al., L998, supra, p. 1315).

Economic and social health care burden due to lack of mental health was estimated at 2.3 billion per year (Menzin et al., 2003), and treatments that subsidize long-term medication or exclude patients from the decision-making process have shown substantial clinical outcomes. Was improved.

DISCLOSURE OF INVENTION

In one embodiment, the invention delivers a drug in pseudo zero-order kinetics in vivo, administering to the patient a first formulation of the drug in complex form with a biodegradable polymer and in vivo. Administering to the patient a second formulation of the drug, which is delivered substantially faster than the first formulation, and in complex form with the biodegradable polymer, wherein the treatment of the drug with administration of the first and second formulations It provides a method of treating a neurological disorder in a patient in need of such treatment, in which a circulating level is formed and thus a method of treating a neurological disorder.

In another embodiment, the invention delivers a drug in pseudo zero order kinetics in vivo, administering to the patient a first formulation of the drug in complex form with a biodegradable polymer and substantially less than the first formulation in vivo. Fast delivery of the drug, administering to the patient a second formulation of the drug in the form of a complex with the biodegradable polymer, wherein the administration of the first and second formulations by reimplanting It provides a method, in which the level of the chemical circulation is continuously formed.

In another embodiment, the present invention provides a first formulation of a drug in complex form with a biodegradable polymer and delivers the drug in pseudo zero order kinetics in vivo, and a complex form with a biodegradable polymer, with a higher release rate than the first formulation. Kits for continuous delivery of a drug are provided, including a second formulation of a fast drug.

In one embodiment, the present invention provides a poly (d, l-lactide / glycolide) (PLGA) copolymer having a ratio of lactide: glycolide of about 100: 0 to 50:50 of about 95-98% (w / w) And an antipsychotic agent (about 2 to about 5% w / w), wherein the antipsychotic agent is risperidone or 9-OH- risperidone.

DETAILED DESCRIPTION OF THE INVENTION

The present invention provides, for example, a formulation for long-term continuous delivery and a method of using the same.

In one embodiment, the present invention delivers the drug in pseudo zero order kinetics in vivo, administering to the patient a first formulation of the drug in complex form with a biodegradable polymer and substantially less than the first formulation in vivo. Rapid delivery of the drug, the method comprising administering to the patient a second formulation of the drug in the form of a complex with a biodegradable polymer, thereby administering the first and second formulations to form a therapeutic circulating level of the drug, Therefore, the present invention provides a method of treating a neurological disorder in a patient in need of treatment, which is a method of treating a neurological disorder.

In another embodiment, the present invention provides a method of treating a neurological disorder in a patient in need of treatment using a kit comprising a formulation, as described further below.

In one embodiment, the method is such that the release rate of the drug is faster than the first dosage form, in one example faster than the second dosage form, or in other cases slower than the second dosage form, or in other examples, is higher than the first dosage form. The method may further comprise administering one or more additional formulations comprising the drug in complex form with the slow, biodegradable polymer. In one example, the one additional formulation has a drug release peak before the release peak of either the first formulation or, in another example, the second formulation. In another formulation, said one additional formulation exhibits a release peak coincident with the release peak of the first formulation or another example, or a release peak of a drug formed following the release peak of the first formulation.

In one embodiment, this method, kit, and composition of the present invention is in the form of a complex with a biodegradable polymer that produces by-products that are metabolized or, in other instances, non-toxic or otherwise pathologically non-toxic, as further described below. Including or using a first formulation.

In one example, the degradation products of PLGA, lactic acid and glycolic acid are non-toxic, water-soluble products of normal metabolism that are released or further metabolized to carbon dioxide and water in the Krebs cycle.

In one example, the term “in complex” or “complex” refers to the dispersion of drug molecules in a biodegradable polymer matrix. In one example, the drug is located in an interstitial space in the polymer matrix, which can be implemented via rapid solvent extraction, in another example, after which the polymer concentration is increased, thereby increasing the viscosity of the polymer rapidly. In other instances, the diffusivity of the entrapped drug thus decreases.

In one example, the term "fast solvent extraction" means that the polymer concentration increases and subsequently the viscosity increases, so that the solvent is removed at a rate that the polymer chain is not kinetically aligned to the recrystallization point.

In one embodiment, the drug may be encapsulated within the biodegradable polymer matrix and, thus, any factor that may affect its initial loading, in other instances subsequent release, or in other cases, both of them. Can be utilized according to the method of the invention and in the kits and compositions of the invention. In other instances, such factors may include, in particular, the initial concentration of the solvent, its molecular size and polarity, the temperature and pressure at which the solvent is removed, the molecular weight number (MWn) of the biodegradable polymer substrate, and its polydispersity. index), the size and polarity of the drug, the proportion and distribution of monomers in the copolymer chain, or a combination thereof. In addition, the D / L ratio of each monomer in the biodegradable polymer will affect the release rate. In one example, the term D / L ratio refers to a monomer molecule that takes the direction in which the cross-polarized ense is rotated (D-right, L-left) when observing a single optically active monomer such as lactic acid. Is rain. Since most mammals have D-specific enzymes, this ratio will affect the digestibility of biodegradable biopolymers and thus their molecular weight and hence viscosity, thus affecting the release rate of all captured drugs. .

In one embodiment, the term “circulation level” refers to the concentration of drug in blood serum measured by serum separation and determination of drug concentration.

In one embodiment, the term “therapeutic” means forming a prophylactic response as desired as a result of the method of the invention or as a result of the administration of the kit or composition of the invention. In one example, the desired response may be relief (complete or in another partial) relief of symptoms associated with a particular disease or disorder, such as schizophrenia, depression, psychotic anxiety or a combination thereof. In another embodiment, using the methods, kits, or compositions of the present invention, where inappropriate side effects occur (eg, treatment results in immunodeficiency in patients), the present invention provides for the administration of appropriate palliatives during treatment regimens.

In the example disclosed in Example 12, neurological disordered schizophrenia can be treated with risperidone as a drug, for example, by complexing the drug with a biodegradable polymer exhibiting the release profile disclosed in FIG. 7A. In another example, a formulation comprising a drug in the form of a complex with five different polymers may be used simultaneously, with the three complexes administered in order to link the release delay in sustained release implants (FIGS. 7D and 7E). "Starter set", which refers to. In the above aspect of the invention, the starter set comprises the first complex of immediate release profile and the other two fast release complexes of slightly slower release profile, the first complex of two Is administered simultaneously with the rapid release complex. In one embodiment, the starter set is administered with, or just before, a “maintenance set” comprising at least one, alternatively two, alternatively three, or alternatively four complexes, and treatment of risperidone Provide a consistent level of circulation. The maintenance set is provided at the time when release is complete, i.e. at 100% release of the drug from the starter set complex. In another example, the maintenance set may comprise a fifth complex, for example, the fifth complex is an implant comprising a drug and a biodegradable substrate, with a higher absolute content of drug than other complexes. In one example, the release peak of the fifth complex occurs concurrently with a decrease in drug release in the other complexes that make up the “maintenance set”. According to this aspect of the invention, the release profile of each complex is optimally combined to provide the desired constant risperidone circulation level (FIG. 7E).

In one example, the maintenance set may be re-administered to the patient indefinitely to provide long term treatment.

In another example, the methods of the present invention include repeated use, such as the use of the method according to the present invention involves the administration of one or more formulations as repeated individual treatments for a period of time. In one embodiment, the methods of the present invention include periodic use, eg, one or more formulations of the present invention may be administered at a fixed time period. In one example, the method may comprise an interim evaluation of the treatment, and the formulation may be altered to any improvement signal function of the pathological patient, including symptomatic relief or other pathological relief, as will be appreciated by those skilled in the art. . As another example, the treatment may be modified depending on the lack of response to the particular formulation administered.

In another example, the formulation of drug and polymer implants is made without solvents or emulsifiers but instead by solvent casting from acetone and subsequent compression molding. In one embodiment, acetone is chosen as the solvent for casting, or in another embodiment drug and biodegradable polymers use other FDA class III solvents (minimum low toxicity required to remove residual solvent) that are water soluble at concentrations above 100 mg / ml. do. In another example, the resulting implant is acceptable for bioavailability, as demonstrated in rodents, which can be assessed over time, such as after implantation in mice and rats, over time, such as 3 weeks to 3 months after transplantation. Can be.

In one example, the solvent template is performed with a solvent selected from the solvents listed in Table 1 (FDA Class III Solvent (FDA Guideline Q3C)).

Table 1 FDA Class III Solvent (FDA Guideline Q3C))

Acetic acid Cumen Heptane 2-methyl-1-propanol Acetone Dimethyl sulfoxide Isobutyl Acetate Pentane Anisol ethanol Isopropyl acetate 1-pentanol 1-butanol Ethyl acetate Methyl acetate 1-propanol 2-butanol Ethyl ether 3-methyl-1-butanol 2-propanol Butyl acetate Ethyl formate Methylethyl ketone Propyl acetate tert-butylmethyl ether Formic acid Methylisobutyl ketone

In another embodiment, the methods, kits, and compositions of the present invention provide a drug release profile due to the interaction of each drug with the corresponding polymer. In another example, other factors that may affect the release pattern from the polymer system include diffusion rate, drug / polymer affinity, pH, source / sink concentration, average molecular weight (MW _W ), average polymer Water (MW _n ), its ratio (polydispersity index (PDI)) and biopolymer plasticizing ability of physiological fluids.

In one embodiment, the first formulation and the second formulation in the methods, kits and compositions of the present invention are administered within 1-48 hours of each other. In another embodiment, the first formulation is administered simultaneously with the second formulation. In one embodiment, the first formulation is administered prior to administration of the second formulation. In another embodiment, the first formulation is administered after administration of the second formulation.

In one embodiment, the methods, kits and compositions of the present invention use biodegradable polymers, and examples of biodegradable separators are poly (d, l-lactide-glycolide) copolymers (PLGA). In one example, the biodegradable PLGA polymer may be described in (Kitchell JP, Wise DL (1985) Poly (lactic / glycolic acid) biodegradable drug-polymer matrix systems.Methods Enzymol 112: 436-448).

In one embodiment, the biodegradable polymer is polylactide, polyglycolide, polycaprolactone, copolymers thereof, trimers thereof or any combination thereof. In one embodiment, the copolymer thereof is atactic, or in another embodiment syndiotactic. In one example, the biodegradable thermoplastic polyesters are polylactide, polyglycolide, copolymers thereof, trimers thereof or combinations thereof.

In one example, the biodegradable thermoplastic polyester is 50/50 poly (DL-lactide-co-glycolide). In another example, the biodegradable thermoplastic polyester is 75/25 poly (DL-lactide-co-glycolide). In another example, the biodegradable thermoplastic polyester is 85/15 poly (DL-lactide-co-glycolide). In another example, the biodegradable thermoplastic polyester is 60/40 poly (DL-lactide-co-glycolide). In another example, the biodegradable thermoplastic polyester is 90/10 poly (DL-lactide-co-glycolide). In another embodiment, the biodegradable thermoplastic polyester includes any combination of poly (DL-lactide-co-glycolide), which is complexed with the drug to form the desired release profile. In one example, the biodegradable thermoplastic polyester can be present in any suitable amount, provided that the biodegradable thermoplastic polyester is at least substantially insoluble in aqueous media or body fluids.

In another example, the biodegradable thermoplastic polyester is preferably from about 50% to about 98% by weight, such as from about 50% to about 60% by weight, in another embodiment from about 60% to about 75% by weight in the flowable composition. , In another example from 75% to about 90%, in other embodiments from about 90% to about 95%, or in other embodiments from about 95% to about 98% by weight.

In one embodiment, the average molecular weight of the biodegradable thermoplastic polymer is from about 10,000 to about 200,000, in other embodiments from about 15,000 to about 25,000, in other embodiments from about 25,000 to about 45,000, in other embodiments from about 45,000 to about 75,000, in other embodiments from about 75,000 to about 100,000, In another example from about 100,000 to about 150,000, or in another example from about 150,000 to about 200,000.

In one embodiment, the lactic monomer constituting the PLGA is 50-100% of the PLGA polymer, in another 50-60%, in another 60-70%, in another 70-80%, in another 80-90%, or in another 90 Concentration is -100%, or other examples include 100% PLA.

In one embodiment, the term “about” refers to a deviation of 1-20%, in another example of 1-10%, in other embodiments of 1-5%, in other embodiments of 5-10%, or in other embodiments of 10-20%.

In one embodiment, in the drug-polymer complex in certain formulations, the drug content is 2-75% by weight, in other embodiments 2-5% by weight, in other embodiments 5-10% by weight, in other embodiments 10-25% by weight, in other embodiments 25-35 % By weight, 35-50% by weight in another example, or 50-75% by weight in another example.

In one example, the complex may be formed through covalent bonds with water soluble polymers such as polyethylene glycol, copolymers of polyethylene glycol and polypropylene glycol, carboxymethyl cellulose, dextran, polyvinyl alcohol, polyvinylpyrrolidone or polyproline have. For example, modifications can increase the solubility of the compound in aqueous solution, eliminate aggregation, enhance the physical and chemical stability of the compound, and reduce the immunogenicity or reactivity of the compound or combinations thereof. You can.

In another embodiment, the methods, kits, and compositions of the present invention provide for the treatment of any disease or disorder in which it is desirable to deliver one or more drugs for an extended period of time.

Any symptom, disease or disorder by therapy with a particular compound or combination of compounds is understood to be considered as part of the present invention, which therapy consists of a particular compound or combination of compounds and forms a therapeutic circulating level. Providing a first dosage form, wherein the providing of the first dosage form is accompanied by treatment of the second dosage form concurrently with or after the second dosage form to form a therapeutic circulation level and is obtained with the second dosage form. The established circulation level is achieved at the same time as the circulation level by the first formulation is lowered, and the circulation level is formed for a long time.

The first formulation of the methods, kits and compositions according to the invention may be in the range of, for example, a "steady state" (zeroth order) release profile, or a nearly steady state, or for example a + 5-10% deviation from a steady state. The drug is delivered in pseudo-0th order kinetics and a therapeutically effective amount of drug is delivered over a period of time. In another example, a variation in the range of + 5%, another + 10%, another + 20%, or another + 30% is observed at the target serum level. In one embodiment, the time period is 3-10 months after administration. In one embodiment, the time period is 14 days to 6 months after administration.

In one embodiment, the release profile of the formulations used in the methods, kits and compositions according to the invention is as shown in FIG. 7A, in another example 7B, in another example 7C, in another example 7C, in another 7D or in another example 7E, Or in another example, similar to the profile.

In one example, the formulation may be administered as a controlled release patch. In another embodiment, the subject therapeutic drug is delivered in a transdermal patch mode. The patch is, for example, a flat concave device with a permeable membrane on one side, and may also include a membrane in which the adhesive and medicament for placing the patch on the patient's skin are in contact with the skin that can be released from the patch reservoir and permeable into the skin. . On the outer side of the patch, for example, an impermeable layer of a substrate is formed, and the membrane portion and the outer side are connected around the patch, and a drug and carrier reservoir is formed between the two layers. The patch technique allows the active ingredient to be in continuous contact with the epidermis. For a substantial total time in this condition, the drug molecule may be diffused into the bloodstream by, for example, a concentration gradient, or in another example, a transdermal drug delivery system may be performed by a patch technique. Typical drug delivery systems include patches with active ingredients such as drugs incorporated therein, and the patches also include adhesives for skin attachment to position the active ingredient very close to the skin. Exemplary patching techniques are available from Ciba-Geigy Corporation and AIza Corporation. Such transdermal delivery devices can be readily adapted to the use of amphetamine compounds. In one embodiment, the maintenance set of drug is administered once every three months in the form of a patch.

In one embodiment, the formulation is in the form of an implant. In another embodiment, the release of the drug and in other instances the diffusion of the drug is substantially different for the various drugs. In one example, the design for one compound does not directly vary otherwise.

In one embodiment, an antipsychotic agent, or in another embodiment 9-OH- risperidone, is used in the treatment of neurological disorders, such as bipolar disorder, as part of the methods, kits, and compositions of the present invention.

In one embodiment, the methods, kits, and compositions of the present invention may be used for tyrotropin-releasing hormone, or L-dopa delivery, for treating Parkinson's disease. In another embodiment, the methods, kits, and compositions of the present invention can be used for naltrexone delivery for treating drug addiction.

It is understood that the formulations used in the methods, kits and compositions of the present invention may include a combination of drugs that may be part of a disorder treatment regimen in one example.

In one embodiment, the present invention provides a method of treating neurological disorders wherein the concentration of the drug is from about 2 to about 50 weight percent of the first or second formulation. In another example, the drug is at a concentration of about 2 to about 5 weight percent of the first or second agent. In one embodiment, the drug is at a concentration of about 5 to about 10 weight percent of the first or second formulation. In another example, the drug is at a concentration of about 10 to about 15 weight percent of the first or second formulation. In one embodiment, the drug is at a concentration of about 15 to about 20 weight percent of the first or second formulation. In another example, the drug is in a concentration of about 20 to about 30 weight percent of the first or second formulation. In one embodiment, the drug is in a concentration of about 30 to about 40 weight percent of the first or second formulation. In another example, the drug is in a concentration of about 40 to about 50 weight percent of the first or second formulation.

In one embodiment, the present invention provides a method of treating a neurological disorder, wherein the drug used is risperidone, 9-OH- risperidone, haloperidol, olanzapine, clozapine, aripiprazole, quetiapine, ziprasidone or mixtures thereof.

In one example, the first and second formulations have at least one generic drug.

In another example, the first formulation comprises risperidone and 9-OH- risperidone and the second formulation comprises 9-OH- risperidone, or in another example, the first formulation comprises risperidone and haloperidol and the second formulation is haloperidol. Or in another example, the first formulation comprises quetiapine and 9-OH- risperidone and the second formulation comprises 9-OH- risperidone.

In one embodiment, the first formulation comprises a therapeutic drug for chronic disease. In another example, the second formulation comprises a therapeutic drug in an acute period of chronic disease. For example, one can treat a recurrent disease, such as multiple sclerosis, in which each formulation includes Copaxon, and the first formulation additionally contains beta-interferon or another immunomodulatory compound. It may include.

In another example, the second formulation has a faster release rate than the first formulation. In one example, the term “faster release rate” means a relative increase in concentration in serum circulation levels of the subject drug as a function of time. In one example,% drug release as a function of time is shown graphically in FIG. 4B.

In another example, the second formulation can be administered by depot injection. In another example, the second formulation is administered as microspheres containing drugs encapsulated in a biodegradable polymer matrix.

In one embodiment, the first formulation of the methods, kits and compositions according to the invention has a substantially slow release rate of the drug to provide long term sustained release. Substantially slow means, for example, 1/10 times the average release rate of a normal formulation.

In one embodiment, the present invention provides a method for treating a neurological disorder, wherein the first formulation is an implant and is administered subcutaneously, and the second formulation comprises an oral drug form, parenteral form or intravenous form.

In one embodiment, the expression “parenteral administration” herein refers to a dosage form, generally by injection, other than intestinal and topical administration, examples of which are intravenous, intramuscular, intraarterial, intrathecal, intraarticular, orbital Intra, intracardiac, dermal, intraperitoneal, intranasal, subcutaneous, subcutaneous, intraarticular, intratumoral, subcapsular, subarachnoid, intraspinal and intrasternal injections and infusions.

In another embodiment, the present invention provides the subject with periodic administration of the first and second formulations. The order of administration of the first, second, or any additional formulation containing the drug is within the scope of the present invention and one of ordinary skill in the art would be able to alter the order of administration to provide the desired level of circulation of the drug. I will understand.

In one embodiment, the first and second formulations are administered to the subject when the serum circulating level of the drug is below the therapeutic threshold of the drug. In another example, the first and second formulations are administered to a subject when the serum circulation level of the drug is 1 ng / ml or less.

In another embodiment, the present invention provides a method for treating a neurological disorder, wherein the first and second formulations are administered to a subject for about 160-200 days after the first administration. In one embodiment, the first and second formulations are administered to the subject for about 160-180 days after the first administration of the formulation. In another example, the first and second formulations are administered to the subject for about 180-200 days after the first administration of the formulation.

In another example, the present invention provides a method of addressing the need for more sustained treatment or, in one embodiment, a method of treating neurological disorders relating to a long term drug delivery method using an implantable system for treating schizophrenia. Implantation systems have the ability to optimize the therapeutic properties of a medicament in another example, and in one example provide a safer, more effective or more reliable treatment. In another embodiment, the present invention generally provides a method for treating neurological disorders in which a medicament is required in small amounts and the side effects can be minimized. In one example, the physician can remove the implant system through an adverse event, providing reversibility. In another example, the present invention provides a method for treating a neurological disorder, in which forced removal at the last delivery time is eliminated using a biodegradable system, reducing the genetic morbidity in patients in half.

In one embodiment, the present invention provides a method of treating a neurological disease or disorder that requires a long duration of treatment. In one embodiment, the drug is used to treat HIV and other viral diseases, mycobacterial infections, cancer, multiple sclerosis, diabetes, kidney disease or any other disease for which the methods, kits or compositions of the present invention have proven useful.

In another embodiment, the invention relates to a nervous system, such as AIDS-related dementia, schizophrenia, bipolar disorder, borderline personality disorder (BPD), Alzheimer's disease (AD), psychotic depression or other psychiatric disorders that cause confusion or psychosis Provide a method for treating a disorder.

In one embodiment, the drugs used according to the methods, kits or compositions of the present invention are applicable to such therapeutic regimens as disclosed herein. In one embodiment, the drug is a peptide, protein, nucleic acid or compound.

In one embodiment, the term “drug” refers to a molecule that alleviates a patient's symptoms, disease or disorder when administered to a patient. In one embodiment, the drug is a synthetic molecule, or in another example the drug is a natural compound isolated from origin found in nature.

In one embodiment, the drug is an antihypertensive, an antidepressant, an anxiety agent, an anticlotting agent, an anticonvulsant, a blood glucose-lowering agent, an anti-inflammatory agent ( decongestants, antihistamines, antitussive, anti-infiamniatories, antipsychotic agents, cognitive enhancers, cholesterol lowering agents, antiobesity agents , Autoimmune disorder agent, anti-impotence agent, antibacterial, antifungal, hypnotic, anti-Parkinsonism in agent, antibiotic, antiviral, anti Anti-neoplastic, barbituate, sedative, nutritional agent, beta blocker, emetic, anti-emetic, Diuretic, anticoagulant, Cardiotonic, androgens, corticoids, anabolic agents, growth hormone secretagogues, anti-infective agents, coronary vasodilators, Carbonic anhydrase inhibitors, antiprotozoal, gastrointestinal agents, serotonin antagonists, anesthetics, hypoglycemic agents, dopaminergic agents, Alzheimer's agents, anti-ulcer agents, platelet inhibitors and glycogen phosphorylase inhibitors may be included.

According to this aspect of the invention, and in one embodiment, examples of drugs used according to the invention are in particular prazosin, nifedipine, trimazosin, amlodipine and doxazosin mesylate antihypertensives, including (doxazosin mesylate); Anti-anxiety hydroxyzine; Blood sugar lowering agents such as glipizide; Anti-erectile dysfunctions such as sildenafil citrate; Anti-tumor agents such as chlorambucil, lomustine or echinomycin; Betamethasone, prednisolone, piroxicam, aspirin, fiurbiprofen and (+)-N- {4- [3- (4-fluorophenoxy) phenoxy ] -2-cyclopenten-1-yl} -N-hydroxyurea ((+)-N- {4- [3- (4-fluorophenoxy) phenoxy] -2-cyclopenten-I-yl} -N-hyroxyurea Anti-inflammatory agents such as); Antiviral agents such as acyclovir, nelfinavir or virazole; Vitamins / nutrients such as retinol and vitamin E; Vomiting agents such as apomorphine; Diuretics such as chlorthalidone and spironolactone; Anticoagulants, such as dicumarol; Cardiac agents such as digoxin and digitoxin; Androgens such as 17-methyltestosterone and testosterone; Mineral corticoids such as desoxycorticosterone; Steroidal sleeping pills / anesthetics such as alfaxalone; Assimilation materials such as fluoxymesterone or methanstenolone; Fluoxetine, pyroxidine, venlafaxine, sertraline, paroxetine, sulfideride, [3,6-dimethyl-2- (2,4,6) -Trimethyl-phenoxy) -pyridin-4-yl]-(retylpropyl) -amine or 3,5-dimethyl-4- (3'-pentoxy) -2- (2 ', 4', 6'-trimethyl Antidepressants such as phenoxy) pyridine; Antibiotics such as ampicillin and penicillin G; Anti-infective agents such as benzalkonium chloride or chlorhexidine; Coronary vasodilators such as nitroglycerin or mioflazine; Sleeping pills, such as etomidate; Carbon dehydratase inhibitors such as acetazolamide or chlorzolamide; Antifungal agents such as econazole, terconazole, fluconazole, voriconazole or griseofulvin; Antiprotozoal agents such as metronidazole; Imidazole-type anti-tumor agents such as tubulazole; Anthelmintic agents such as thiabendazole or oxfendazole; Antihistamines such as asestizol, levocabastine, cetirizine or cinnarizine; Anti-inflammatory agents such as pseudoephedrine; Antipsychotic agents such as fluspirilene, penfluridole, risperidone or ziprasidone; Gastrointestinal agents such as loperamide or cisapride; Serotonin antagonists such as ketanserin or mianserin; Anesthetics such as lidocaine; Hypoglycemic agents such as acetohexamide; Antiemetic agents such as dimenhydrinate, antibacterial agents such as cotrimoxazole; Dopaminergic materials such as L-DOPA; Alzheimer's therapeutics such as THA or donepezil; Anti-ulcer agents / H2 antagonists such as famotidine; Sedatives / sleeping pills, such as chlordiazepoxide or triazolam; Dilators such as alprostadil; Platelet inhibitors such as prostacyclin; ACE inhibitors / antihypertensives such as enalaprilic acid or lisinopril; Tetracycline antibiotics such as oxytetracycline or minocycline; Macrolide antibiotics such as azithromycin, clarithromycin, erythromycin, or spiranmycin and [R- (R * S *)]-5-chloro -N- [2-hydroxy-3 {methoxymethylamino} -3-oxo-1- (phenylmethyl) -propyl] -1H-indole-2-carboxamide or 5-chloro-1-hindol-2 Glycogen kinase inhibitors such as -carboxylic acid [(1S) -benzyl (2R) -hydroxy-3-((3R, 4S) dihydroxy-pyrrolidin-1-yl-)-oxypropyl] amide Include.

Further examples of drugs used according to the present invention include glucose-lowering chlorpropamide, antifungal fluconazole, anti-cholesterol atorvastatin calcium, antipsychotic thiothiene hydrochloride ( thiothixene hydrochloride, anxiolytic hydroxyzine hydrochloride or doxepin hydrochloride, antihypertensive amlodipine besylate, anti-inflammatory piroxicam, celicoxib ) And valdieoxib, and the antibiotics carbenicillin indanyl sodium, bacampicillin hydrochloride, troleandomycin and doxycycline hyclate. .

In another embodiment, the drug of the invention is a platinum group compound (e.g., spiroplatin, cisplatin and carboplatin), methotrexate, fluorouracil, adriamycin (adriamycin), mitomycin, misamcin, ansamitocin, bleomycin, cytosine arabinoside, arabinosyl adenine, mercaptopolylysine, bin Vincristine, busulfan, chlorambucil, melphalan (e.g., PAM, L-PAM, or phenylalanine mustard), mercaptopurine, mitotane, procar Proearbazine hydrochloride, dactinomycin (actinomycin D), daunorubicin hydrochloride, doxorubicin hydrochloride, paclitax (paclitaxel) and other taxane compounds, rapamycin, manumycin A, TNP-470, plicamycin (mithramycin), aminoglutethimide, esturamustine phosphate sodium (estramustine phosphate sodium), flutamide, leuprolide acetate, megestrol acetate, tamoxifen citrate, testolactone, trilostane, amsa Amsacrine (m-AMSA), asparaginase (L-asparaginase), Erwina asparaginase, interferon alpha-2a, interferon alpha-2b, teniposide, VM-26), vinblastine sulfate (VLB), vincristine sulfate, bleomyein sulfate, hydroxyurea, procarbazine, and dakar Other anti-tumor agents such as dacarbazine; Somatic cell division inhibitors such as etoposide, colchicine and vinca alkaloid; Radiotherapy agents such as radioactive iodine and phosphorus products; Hormones such as progestins, estrogens and antiestrogens; Anti-helmintic, antimalarial and antitubulolytic agents; Biologics such as immune serum, antitoxins, and antitomic; Rabies prevention agents; Bacterial vaccines; Virus vaccines; Respiratory products such as xanthine derivatives, theophylline and aminophylline; Thyroid and antithyroid agents such as iodine products; Cardiovascular products, including chelating agents, mercury diuretics, and cardiac glycosides; Glucagon; Blood products such as parenteral iron, hemin, hematoporphyrin and derivatives thereof; Muramyldipeptide, muralmyltripeptide, microbial cell wall components, lymphokine (e.g. bacterial endotoxins such as lipopolysaccharides, macrophage activating factor), subpopulations of bacteria (e.g. Biological response modifiers such as mycobacterial, corynebacteria), synthetic dipeptides N-acetyl-muramil-L-alanyl-D-isoglutamine; Ketoconazole, nystatin, griseofulvin, flucytosine (5-fc), myconazole, amphotericin B, lysine, cyclosporin and beta- Antifungal agents such as lactam antibiotics (eg sulfazecin); Growth hormone, melanocyte stimulating hormone, estradiol, beclomethasone dipropionate, betamethasone, betamethasone and betamethasone sodium phosphate, betamethasone disodium phosphate, betamethasone phosphate vetamethasone sodium phosphate, cortisone acetate, dexamethasone, dexamethasone acetate, dexamethasone sodium phosphate, flunisolide, hydrocortisone, hydrocortisone, hydrocortisone, hydrocortisone Hydrocortisone cypionate, hydrocortisone sodium phosphate, hydrocortisone sodium succinate, methylprednisolone, methylprednisolone acetate, methylprop Dinisolone sodium succinate, paramethasone acetate, prednisolone, prednisolone acetate, prednisolone sodium phosphate, prednisolone tebutate, prednisone, triamcinolone triamcinolone triamcinolone triamcinolone tricinocinolone hormones such as acetonide, triamcinolone diacetate, triamcinolone hexacetonide, fludroeortisone acetate, oxytocin, vasopressin and derivatives thereof; Cyanocobalamin neinoic acid, retinoids and derivatives such as vitamins such as retinol palmitate and alpha-cotoferol; Peptides such as manganese superoxide dismutase; Enzymes such as alkaline phosphatase; Anti-allergic agents, such as amelexanox; Anticoagulants such as phenprocoumon and heparin; Circulatory drugs such as propranolol; Metabolic potentiator such as glutathione; Para-aminosalicylic acid, isoniazid, capreomycin sulfate cycloserine, ethambutol hydrochloride ethionamide, pyrazinamide, rifampin And anti-tuberculosis agents such as streptomyin sulfate; Antiviral agents such as amantadine azidothymidine (AZT, DDI, Fosearnet, or Zidovudine), ribavirin, and vidarabine monohydrate (adenine arabinoside, ara-A); Diltiazem, nifedipine, verapamil, erythritol tetranitrate, isosorbide dinitrate, nitroglycerin (glyceryl trinitrate) and pentaerytate Antianginal agents such as pentaerythritol tetranitrate; Anticoagulants such as phenprocoumon and heparin; Dapsone, chloramphenicol, neomycin, cefaclor, cefadroxil, cephalexin, cephalexin, cephradine erythromycin, clindaniycin, lincomycin , Amoxicillin, ampicillin, becpicillin, carbenicillin, carbenicillin, dicloxacillin, cyclacillin, picloxacillin, hetacillin Antibiotics such as penicillin, methicillin, nafcillin, naxacillin, oxacillin, penicillin G, and penicillin V, ticarcillin rifampin and tetracycline; Difluunisal, ibuprofen, indomethacin, meclofenamate, mefenamic acid, naproxen, oxyphenbutazone, phenylbutazone Anti-inflammatory agents such as phenylbutazone, pyroxicam, sulindac, tolmetin, aspirin and salicylate; Antiprotozoal agents such as chloroquine, hydroxychloroquine, metronidazole, quinine and meglumine antimonate; Antirheumatic agents such as penicillamine; Narcotic, such as paregoric; Opiates such as codeine, heroin, methadone, morphine and opium; Cardiac glycosides such as deslanoside, digitoxin, digoxin, digitalin and digitalalis; Atracurium mesylate, galamine triethiodide, hexafluorenium bromide, metocurine iodide, pancuronium bromide, Neuromuscular blockers such as succinylcholine chloride (suxamethonium chloride), tubocurarine chloride and vecuronium bromide; Amobarbital, amobarbital sodium, aprobarbital, butabarbital sodium, chloral hydrate, ethchlorvynol, ethinamate, flurazepam hydrochloride, glue Tetamide (glutethimide), metotrimeprazine hydrochloride, metyprilon, midazolam hydrochloride, paraldehyde, pentobarbital, pentobarbital Sedatives such as sodium, phenobarbital sodium, secobarbital sodium, talbutal, temazepam and triazolam; Bupivacaine hydrochloride, chloroprocaine hydrochloride, ethidocaine hydrochloride, lidocaine hydrochloride, mepivacaine hydrochloride, procaine Local anesthetics such as procaine hydrochloride and tetracaine hydrochloride; Such as droperidol, etomidate, dropperidol and fentanyl citrate, ketamine hydrochloride, metohexital sodium and thiopental sodium General anesthetics; And radioactive particles or ions such as strontium, rhenium iodide, and yttrium.

In one embodiment, the methods, kits, and compositions of the present invention provide for the use of a combination of drugs, provided that one drug is common in formulations administered to a subject at one time, the combinations described above in each formulation may be different.

In one embodiment, the methods of the present invention can be operated through the use of a kit comprising a formulation as described.

In one embodiment, the present invention delivers a drug with pseudo zero order kinetics in vivo and has a first dosage form of the drug complexed with a biodegradable polymer, and a biodegradable polymer having a faster release rate than the first dosage form in vivo. And a second formulation of a drug in complex form with a kit for continuous delivery of one or more drugs.

In another embodiment, the present invention provides a kit for continuous delivery of a drug that, when administered with the first and second formulations of the kit, provides continuous delivery for about one week to about 14 months. In one embodiment, the combination of the first and second formulations in the kit provides for continuous delivery from about one week to about one month after administration. In another example, the combination of the first and second formulations in the kit provides for continuous delivery from about 1 month to about 1 month after administration. In one embodiment, the combination of the first and second formulations in the kit provides continuous delivery for about 3 months to about 6 months after administration. In another example, the combination of the first and second formulations in the kit provides continuous delivery for about 6 months to about 9 months after administration. In another example, the combination of the first and second formulations in the kit provides continuous delivery for about 9 months to about 12 months after administration. In another example, the combination of the first and second formulations in the kit provides continuous delivery for about 12 months to about 14 months after administration.

In one embodiment, kits and compositions as disclosed herein are used in accordance with the methods of the present invention, in other instances the use includes other kits as part of systemic therapy or in combination with other compositions, in other examples And use of only a simple portion of the designated kit, or the use of the specific formulation contained therein.

The kits of the present invention can be used in all the ways described above, and in other instances, all compositions or formulations disclosed herein can be used.

In one embodiment, the present invention provides about 95-98% (w / w) poly (d, l-lactide / glycolide) (PLGA) copolymer and about 2 to about 5% (w / w) antipsychotic Wherein the lactide: glycolide ratio of the poly (d, l-lactide / glycolide) copolymer is from about 100: 0 to about 50:50, and the antipsychotic agent is risperidone or 9-OH- It is characterized in that risperidone, it provides a composition for treating mental disorders.

Formulations of the present invention may be provided, for example, orally, parenterally, topically or subcutaneously. In another example, the formulations take the form that is appropriate for each route of administration. For example, the formulation is administered in the form of tablets or capsules or in other instances by injection, infusion, inhalation, eye lotion, ointment, rectal suppository or controlled release patch.

In one embodiment, the therapeutic circulation level of the drug is 0.1-10 ng / ml. In another embodiment, the therapeutic circulation level of the drug is 0.1-0.5 ng / ml. In one embodiment, the therapeutic circulation level of the drug is 0.5-1.0 ng / ml. In another embodiment, the therapeutic circulation level of the drug is 1.0-1.5 ng / ml. In one embodiment, the therapeutic circulation level of the drug is 1.5-2.5 ng / ml. In another embodiment, the therapeutic circulation level of the drug is 2.5-5 ng / ml. In one embodiment, the therapeutic circulation level of the drug is 5-10 ng / ml.

In one embodiment, the present invention provides that the aforementioned levels of circulation are formed in about 1-31 days with administration of the second formulation. In another example, administration of the second formulation forms the above-described circulation levels for about 1-7 days. In one embodiment, administration of the second formulation forms the above-described circulation levels for about 7-14 days. In another example, administration of the second formulation forms the above mentioned circulation levels for about 14-21 days. In one example, administration of the second formulation forms the above-described circulation levels for about 22-31 days.

In one embodiment, administration of the first formulation in the present invention forms a circulating level for about 21-180 days. In another example, administration of the first formulation forms a circulating level for about 21-31 days. In one example, administration of the first formulation forms a circulating level for about 31-60 days. In another example, administration of the first formulation forms a circulating level for about 60-90 days. In one embodiment, administration of the first formulation forms a circulating level for about 90-120 days. In another example, administration of the first formulation forms a circulating level for about 120-150 days. In another example, administration of the first formulation forms a circulating level for about 150-180 days.

In one embodiment, the present invention provides a circulating level of at least one desired drug, which is maintained for about 1-420 days. In one embodiment, the present invention provides a circulating level of at least one desired drug, which is maintained for about 14-420 days. In one embodiment, the present invention maintains a circulating level of drug for about 75-420 days. In another example, the circulation level is maintained for about 75-180 days. In one example, the circulation level is maintained for about 180-270 days. In another example, the circulation level is maintained for about 270-365 days. In one example, the circulation level is maintained for about 365-420 days.

In another example, the present invention provides the use of an implant inserted subcutaneously. In one example, the implantation process can be easily tolerated using local anesthetics prior to subcutaneous placement. In another example, the use of a rigid implant prevents the need for means to guide the implant under the skin and reduces the risk of intramuscular placement.

In another example, the formulation may take the form of a patch or injection into an intravenously, intracavitarily, intranodely, or any other suitable site for transplantation at any desired tissue site, It may take the form of a port scan. In another example, the route of administration and the interval of administration can each be adjusted to an individual individual. In one example, the time interval may include administration once every six months of the formulation. In other instances, the treatment regimen according to the methods of the present invention and other forms of treatment that do not involve the administration of drugs, such as the interaction of the psychiatrist and / or therapist with the patient in the use of the kits / compositions of the present invention will be involved. Can be.

In one embodiment, the present invention provides a method of treating a disease or disorder wherein at least one of the formulations is in the form of an implant, such as a disc or other food rod. In another example, the polymer and drug are mixed in a 60/40 weight ratio and solvent cast from acetone. The film produced can be extruded into an implant in the form of a disc having an average thickness of 1.22 + 0.0 mm, weight 493 + 2 mg, density 1.28 + 0.0 g / cc and a diameter of 20 mm, as illustrated below. In one example, the rod implants are made as disclosed in Example 10 below, and have other diameters of about 1 to 2 mm, lengths of about 10 to about 40 mm, or a combination thereof as another example. The appearance of the implant can be changed to any form that provides the desired release profile, as will be apparent to one of ordinary skill in the art, and, as will be apparent to those skilled in the art, in one embodiment, to adjust a suitable drug load, or to be implanted in another example. It has dimensions that can be modified to meet the environment or any other considerations that will affect the method of the present invention.

In one embodiment, the present invention delivers a drug with pseudo zero-order kinetics in vivo and has a faster release rate than the first formulation in vivo and a biodegradable polymer in combination with a biodegradable polymer. Provided is a kit for sustained delivery of a drug, comprising a second formulation of the drug in complex form.

In another embodiment, the present invention provides a kit for continuous delivery of a drug that provides continuous delivery for about 1 week to about 14 months after the combined administration of the first and second formulations of the kit. In one embodiment, continuous delivery is provided for about 1 week to about 1 month after the combined administration of the first and second formulations of the kit. In another example, continuous delivery is provided for about 1 to about 3 months after the combined administration of the first and second formulations of the kit. In one embodiment, continuous delivery is provided for about 3 to about 6 months after the combined administration of the first and second formulations of the kit. In another example, continuous delivery is provided for about 6 to about 9 months after the combined administration of the first and second formulations of the kit. In one embodiment, continuous delivery is provided for about 9 to about 12 months after the combined administration of the first and second formulations of the kit. In another example, continuous delivery is provided for about 12 to about 14 months after the combined administration of the first and second formulations of the kit.

In one embodiment, the kits and compositions of the following formulations are used in the manner described above, in whole, in part, or in combination with other kits or with other compositions as part of systemic therapy.

In one embodiment, the present invention provides that the formulation is a rod-like implant, as in the example described above, wherein the rod implant has a diameter of about 1 to about 2 mm, a length of about 10 to about 40 mm, or a combination thereof. Characterized in that, there is provided a kit for sustained delivery of a drug.

In one embodiment, the present invention provides a flowable composition suitable for use as a controlled release implant of risperidone or 9-OH- risperidone. In another example, the flowable composition comprises a biodegradable thermoplastic polyester that is at least initially substantially insoluble in an aqueous medium or body fluid. In one embodiment, the flowable composition is formulated as a subcutaneous injectable delivery system. The injectable composition preferably has a volume of about 0.20 ml to about 0.40 ml, or about 0.30 ml to 0.50 ml. The injectable composition is preferably formulated for administration about once a month, or in another example about once every three months, or in another example once every four months to about once every six months. Preferably, the flowable composition is a liquid or gel composition suitable for injection into a patient.

In one embodiment, the present invention provides a composition for treating psychotic disorders in the form of microparticles, for example in the form of microparticles prepared as described in Example 11 below. In another example, the microparticles of the present invention have an average width (D _3,2 ) of about 150 μm + 50 μm, or in another example about 0.75 + 25 nm. In another example, formulations used in the methods of the present invention or incorporated into the kits or compositions of the present invention may comprise nanoparticles comprising a drug complexed with a biodegradable substrate, as described herein. .

The compositions of the present invention can be applied to humans by any suitable route of administration, including oral and sublingual, by oral, nasal, such as spray, rectal, vaginal, parenteral, intrarac and external, topical, powder, ointment or drops. It can be administered to other animals.

In one example, the composition can be delivered to a controlled release system. For example, the substance can be administered using intravenous infusion, an osmotic pump for implantation, transdermal patches, liposomes or other dosage forms. In one example, a pump can be used (see Langer, supra; Sefton, CRC Crit. Ref. Biomed. Eng. 14: 201 (1987); Buchwald et al., Surgery 88: 507 (1980); Saudek et al., N. Engl. J. Med. 321: 574 (1989). In other examples, polymeric materials can be used. In another example, a controlled release system may be placed in close proximity to a therapeutic target, ie the brain, so that only a fraction of the systemic dose may be needed (eg, Goodson, in Medical Applications of Controlled Release, supra, vol. 2, pp. 115). -138 (1984)). Other controlled release systems are discussed in Langer's comment (Science 249: 1527-1533 (1990).

In another embodiment, the composition is in a form suitable for oral, intravenous, intraarterial, intramuscular, subcutaneous, parenteral, muscle permeable, dermal permeable or topical administration. In one embodiment, the composition is a controlled release composition. In another example, the composition is a secondary composition. In one embodiment, the composition is a liquid dosage form. In another example, the composition is a solid dosage form.

In one embodiment, the compositions of the present invention may be in the form of pellets, tablets, capsules, solutions, suspensions, dispersions, emulsions, elixirs, gels, ointments, creams, patches or suppositories.

The pharmaceutical preparations of the invention can be prepared by known dissolution, mixing, granulation, extrusion, coextrusion or tablet manufacturing processes. For oral administration, the active ingredient or physiologically acceptable derivatives thereof, such as salts, esters, N-oxides, etc., are mixed with conventional additives corresponding to the purpose, such as vehicles, stabilizers or inert gases, which are conventional To a form suitable for administration such as tablets, coated tablets, hard gelatin capsules, soft gelatin capsules, aqueous, alcoholic or oily solutions. Examples of suitable inert vehicles include potato starch, alginic acid or stearic acid or magnesium stearate, in combination form such as corn starch, corn starch, gelatin, corn starch in combination with a binder such as lactose, sucrose or acacia There is a general tablet base, in combination with a lubricant.

The composition may also contain minor amounts of auxiliary substances such as wetting agents, emulsifiers, pH buffers to enhance the efficacy of the active ingredient.

The active ingredient may be formulated into the composition as a pharmaceutically acceptable neutralized salt form. Pharmaceutically acceptable salts include acid addition salts (formed with free amino acid groups of polypeptides or antibody molecules), and acid addition salts include inorganic acids such as hydrochloric acid or phosphoric acid, and organic acids such as acetic acid, oxalic acid, tartaric acid and mandelic acid. Formed together. In addition, salts formed from free carboxyl groups may be derived from inorganic bases and organic bases such as isopropylamine, trimethylamine, 2-ethylamino ethanol, histidine, procaine, such as sodium, potassium, ammonium, calcium or parc hydroxide, for example. Can be.

Compositions of the invention are, for example, formulated for oral delivery, and the active compound may be combined with excipients, and includes digestible tablets, oral tablets, troches, capsules, elixirs, suspensions, syrups, wipers It may be used in the form of a wafer (wafer) or the like. In addition, tablets, troches, pills, capsules, and the like may include: binders such as gum tragacanth, acacia, corn starch or gelatin; Excipients such as dicalcium phosphate; Disintegrants such as corn starch, potato starch, alginic acid; Lubricants such as magnesium stearate; And sweeteners such as sucrose, lactose or saccharin which can be added or flavoring agents such as peppermint, wintergreen oil or cherry flavoring. When the dosage unit form is a capsule, it may contain a liquid carrier as well as a substance of the aforementioned type. Various other materials may be present as coatings or may be present to modify the physical dosage unit form. For example, tablets, pills or capsules can be treated with shellac, sugar or both. The syrups of Elysir may contain the active compound, sucrose as a sweetening agent, methyl and propylparabine as preservatives, and a celery or orange flavor as pigments and flavorings. The active compounds can also be incorporated into sustained release, pulsatile release, controlled release or postponed release preparations and formulations.

Such compositions are, for example, liquid or lyophilized or otherwise dried formulations, diluents of various buffer contents (e.g. Tris-HCl, acetate, phosphate), pH and ionic strength, albumin or gelatin to prevent surface adsorption. Additives, detergents (e.g. Tween 20, Tween 80, Pluronic P68, bile salts), solubilizers (e.g. glycerol, polyethylene glycerol), antioxidants (e.g. ascorbic acid, sodium metabisulfite), preservatives (e.g. thimero) Covalent bonds of polymers, complexes with metal ions to proteins such as flesh, benzyl alcohol, paravins), bulking substances or tonicity modifiers (e.g. lactose, mannitol), polyethylene glycol, Or incorporation of the substance into particulate preparations of polymer compounds such as polylactic acid, polyglytolic acid, hydrogel, or liposomes, microemulsions, micelles, unilam vesicles (unilam) material incorporation into ellar vesicles, multiple thin film vesicles, erythrocyte ghosts or spirooplasts. Such compositions will affect the physical state, solubility, stability, rate of in vivo release and rate of in vivo clearance. Controlled release compositions or sustained release compositions include formulations in lipophilic depots (eg, fatty acids, waxes, oils). Also included in the present invention are particulate compositions coated with a polymer (eg poloxamer or poloxamine).

In another embodiment, the compositions of the present invention comprise one or more pharmaceutically acceptable carrier materials.

In one embodiment, the carrier used in the composition is biocompatible, in other instances biodegradable. In another example, the formulation may provide that one active ingredient is released at a relatively constant level. However, in other instances, faster release rates may be suitable immediately after administration. In another example, the release of the active compound can be branched by the occurrence of an event. The events that trigger the release of the active compound may be the same in one example or different in another. The event that triggers the release of the active ingredient may be, for example, moisture exposure, other lower pH exposures, or alternatively exposure to a temperature threshold. Formulations of such compositions are well within the general skill level of the art using known techniques. Examples of useful carriers in this regard include microparticles such as poly (lactide-co-glycolide), polyacrylates, latex, starch, cellulose, dextran and the like. Another example of a smokeable release carrier is a supramolecular biovector, comprising an outer layer consisting of a hydrophilic non-liquid core (eg, crosslinked polysaccharides or oligosaccharides) and optionally an amphiphilic compound such as a phospholipid. . The amount of active compound contained in a sustained release formulation is determined, for example, by the site of administration, the rate of release and the expected duration, and the nature of the condition to be treated, inhibited or inhibited.

In one embodiment, the methods, kits or compositions of the invention can be used to improve the therapeutic efficacy of a cancer therapy or HIV, herpes simplex, herpes zoster, mycobacterium infection, cancer, mental disorders, multiple sclerosis, diabetes, kidney disease, Chronic pain, hepatitis, or any other applicable disease or disorder, such as, for example, long-term treatment regimens with repeated administration of one or more drugs, can enhance the treatment of chronic diseases that are beneficial.

1 is a graph showing haloperidol release over a total of 443 days in PLGA disks implanted in monkeys.

2A is a graph showing a total of 379 days haloperidol release in a single PLGA disk system implanted in a rabbit.

2B is a graph showing a total of 379 days haloperidol release in a combination PLGA disk system implanted in rabbits.

FIG. 3 is a graph showing the cumulative release rate of in vitro risperidone in an implant, expressed as total risperidone weight released.

4A is a graph showing the cumulative release rate of 20, 40 or 60% (w / w) risperidone dispersed in a 85:15 PLGA in a 50 mg implant.

4B is a graph showing the cumulative release rate of 20, 40 or 60% (w / w) of risperidone dispersed in a PLGA of 85:15 in each implant as a percentage of drug content.

FIG. 5 is a graph showing in vitro cumulative release in disc or rod implants. FIG. The difference in the release profiles was not statistically significant.

FIG. 6 is a graph showing a continuous delivery model of biodegradable implants that were allowed to vary in target serum levels during implantation every six months.

FIG. 7A is a graph showing estimates of serum release from a single polymer.

FIG. 7B is a graph showing serum release estimates by replanting a single polymer substrate every six months.

7C is a graph showing serum release estimates by replanting a maintenance set with a single polymer substrate and peak release over three months every six months.

7D is a graph showing the expected release rate in the starter polymer set, with the first four months of treatment shortened.

FIG. 7E is a graph showing the expected rate of release in combination therapy comprising a single polymer system and a maintenance set with three months of peak release every 6 months and a starter polymer set that shortens the first 4 months of treatment.

8A is a graph showing the release rate of 40% haloperidol in implants made with 75:25 PLGA.

8B is a graph showing the release rate of 40% haloperidol in implants made with 85:15 PLGA.

8C is a graph showing the cumulative release rates of two theoretical polymer systems for 154 days.

FIG. 9 is a graph showing the exercise activity tested before implant removal (total distance traveled for 20 minutes) and exercise activity 48 hours after transplant removal.

FIG. 10 is a western blot of D2 receptor protein in the striatal membrane of rats treated with haloperidol-PLA or PLA alone for 3 months.

11A is a graph showing the cumulative release rate of risperidone dispersed in a PLGA biodegradable substrate.

FIG. 11B is a graph showing the cumulative release rate of 9-OH-risperidone dispersed in a PLGA biodegradable substrate.

12 is a graph showing the cumulative release rate of 20% (w / w) 9-OH- risperidone dispersed in an 85:15 PLA: PGA block copolymer biodegradable substrate.

FIG. 13 is a graph showing the cumulative release rate of 20% (w / w) risperidone dispersed in an 85:15 PLA: PGA block copolymer biodegradable substrate.

14A is a graph showing the effect of implants on rats or mice in an in vivo behavioral test using a prepulse inhibition of startle (PPI).

14B is a graph showing the effect of implants on rats or mice in an in vivo behavioral test using PPI following amphetamine administration.

14C is a graph showing the effect of risperidone implants on rats or mice in an in vivo behavioral test with PPI before and after amphetamine administration.

14D is a graph showing cumulative release rate of risperidone in 85:15 (PLA: PGA) PLGA implants as a function of time.

14E is a graph showing the effect of risperidone implants on rats or mice in an in vivo behavioral test using PPI.

14F is a graph showing the effect of risperidone implants on rats or mice in an in vivo behavioral test using PPI after vehicle injection.

14G is a graph showing the effect of risperidone implants on rats or mice in an in vivo behavioral test using PPI after amphetamine administration.

15A is a graph showing cumulative release rate of quetiapine in 85:15 (PLA: PGA) PLGA implant as a function of time.

FIG. 15B is a graph showing the effect of quetiapine release before and after apomorphine injection on PPI compared to the control.

15C is a graph showing the effect of quetiapine injection before and after apomorphine injection in PPI compared to the control and mock apomorphine injection groups.

FIG. 16A is a graph showing cumulative release rate of clozapine in 85:15 (PLA: PGA) PLGA implant as a function of time.

16B is a graph showing the effect of clozapine implants before and after apomorphine placebo injection on PPI compared to control and mock apomorphine injection groups.

16C is a graph showing the effect of clozapine implants before and after apomorphine injection on PPI compared to control and mock apomorphine injection groups.

FIG. 17A is a graph showing cumulative release of haloperidol in an 85:15 (PLA: PGA) PLGA implant as a function of time.

17B is a graph showing haloperidol release effect on PLGA implants on PPI.

18A is a graph showing the effect of initial drug loading on cumulative release of risperidone in vitro in 85:15 (PLA: PGA) PLGA implants.

18B is a graph showing the effect of initial drug loading on cumulative release of functional risperidone in vitro in 85:15 (PLA: PGA) PLGA implants.

The following examples are intended to more fully illustrate preferred examples of the present invention. However, these examples are not to be construed as limiting the broad scope of the invention.

Example 1 Haloperidol Release of PLGA Implants in Monkeys

Monkey In vivo Release of Haloperidol:

Experiments were conducted to evaluate the one-year continuous delivery of haloperidol in primates. As a control for antipsychotic drug exposure in postmortem human schizophrenia, the long-term exposure effect of haloperidone on the cortical structure of primates was evaluated. The experiment proceeded with 14 months of haloperidol release in monkeys.

object:

All protocols were approved by the Institutional Animal Care and Use Committee of the University of Pittsburgh. Two monkeys (Macaca The implant was inserted into the fasciculais, Rangos Research Facility. One had a non-drug control implant and the other had a 40% by weight haloperidol added implant. Haloperidol (Sigma, St. Louis, Mo.) was administered at about 1 mg / kg / day for 12 months, so that the serum concentration was 2-10 ng / ml. Each implant has a polylactic acid (PLA) to polyglycolic acid (PGA) ratio of 75:25, 85:15, 90:10 (high intrinsic and low intrinsic viscosity), 95: 5 and 100: 0 (Medisorb ^® Aldermes, Cincinnati, OH) was made from each poly (d, l-lactic-glycolic acid) copolymer (PLGA) polymer.

Implant Manufacturing:

The polymer and haloperidol were mixed at a 60/40 weight ratio and solvent molded from acetone (Fisher Scientific, Pittsburgh, Pa.). The produced film was extruded into a disc shape of 20 mm length, average thickness 1.22 + 0.0 mm, weight 493 + 2 mg and density 1.28 + 0.0 g / cc.

Pharmacokinetic Determination:

Blood was drawn twice a month. After centrifuging the sample, the UV detector Haloperidol concentrations were analyzed by high-pressure liquid chromatography (HPLC) equipped (FIG. One). No drug was detected in the analysis of control animals.

result:

As graphed in FIG. 1, haloperidol release was measured for a total of 443 days. Mean serum concentrations for the first 224 days were 10.5 + 1.5 ng / ml. The concentration of haloperidol in the serum for 176 days was then maintained at a lower concentration until the end of the release. The average concentration during this period is 4.0 + 0.4 ng / ml. During the last 45 days, release was reduced by 1/10 fold to an average of 1.2 + 0.3 ng / ml.

Example 2 Release of Haloperidol from Two Polymeric PLGA Systems in Rabbit Implants

Release of haloperidol from rabbits:

To aid in localization to the implant site at necropsy, the rabbits were implanted. Two different implant systems were tested. To confirm the existing facts in monkeys, one contains a mixture of five different polymers (see Example 1). The other consists of a long lasting single polymer system for reducing the initial spike while maintaining the release for one year. These studies demonstrated 13 months of haloperidol release in rabbits.

object:

Rabbits (N = I2, Covance, Denver, PA) weigh between 4.0 and 5.7 kg. Haloperidol for an average dose of 418 + 7 mg / kg, containing 5 animals, 100% poly (lactic acid) (PLA) and providing a daily content of 1.13 + 0.02 mg / kg / day for 365 days An implant with a load of 40% (w / w) was supplied. The other five rabbits were implanted with a combination polymer system comprising 75:25, 85:15, 90:10 high intrinsic viscosity, 90:10 low intrinsic viscosity, and 100: 0 PLGA. The mean dose in these groups is 473 + 4 mg / kg, which is expected to be given 365 days with an average of 1.29 + 0.03 mg / kg / day per day. As a control, two rabbits were given a drug-free implant. One of the controls was given a 100% PLA implant to mimic single polymer conditions, and the other was 75:25 , 85:15, 90:10 high intrinsic viscosity, 90:10 low intrinsic to mimic a combination polymer system. An implant consisting of viscosity and 100: 0 PLGA was provided.

Implant Manufacturing:

Rabbit implants were prepared by the method described in Example 1 for monkeys, their average weight was 536 + 2 mg and density was 1.24 + 0.00 g / cc.

Pharmacokinetic Decisions:

Blood was drawn twice a month. Haloperidol in serum was determined by HPLC and UV detection after solid phase extraction (Oasis MDC columns, Waters, Milfor MA) (FIG. 2).

Histopathology:

Five rabbits were killed after 9 months to obtain intermediate pathological analysis. The remaining seven rabbits were killed after another four months of testing. The implant was found in situ when all animals were killed except for the control group. HPLC / UV and NMR spectroscopy confirmed the presence of haloperidol in the implant and the PLGA degradation product. Histological analysis confirmed that all organ systems of the control and treated rabbits were within normal levels.

result:

As shown in the graph of FIG. 2A, the release of haloperidol from a single polymer system in rabbits for a total of 379 days had an average serum concentration of 2.5 + 0.4 ng / ml for the first 224 days. Mean concentrations between 57 and 274 days were 3.8 + 0.4 ng / ml.

As shown in the graph of FIG. 2B, the release of haloperidol from the combination polymer system in rabbits for a total of 379 days had an average serum concentration of 2.5 + 0.4 ng / ml for the first 224 days. Mean concentrations between 57 and 274 days were 3.8 + 0.4 ng / ml.

In the multiple polymer system design, serum levels during the first seven months were higher than serum levels for the subsequent seven months (FIG. 2B). Implants made from polymers that degrade more rapidly, such as 75:25 PLGA, seem to have a larger initial release. Thus, the weight of 75:25 PLGA implant can be reduced in subsequent experiments to lower the initial release capacity.

Example 3: Release of Risperidone from PLGA Implants

Risperidone Stability:

Risperidone (10 mg) was dissolved in 100 [mu] l of acetonitrile and dissolved in 1000 ml of PBS at pH 7.0 to make 10,000 ng / ml of the final solution. The risperidone solution was then stored in a photosafe yellow bottle at 37 ° C. and stirred at 40 rpm. Three ml weekly samples of 1 ml were taken and tested for drug content by UV spectroscopy (Amersham Biosciences, Buckinghamshire, UK). As a result, the concentration of the drug showed an overall decrease of 0.05 ng / day, that is, 0.12% for 285 days, but remained stable.

In vitro risperidone release from individual polymers:

The risperidone release profiles of the three polymers were analyzed. Implants were prepared as described in Example 1 above, with 20% and 50:50 (PLA: PGA) high intrinsic viscosity (IV), 65:35 low intrinsic viscosity, and risperidone (w / w) (RBI Flanders, NJ) 75:25 High intrinsic viscosity contains 80% polymer, composed of PLGA. Three implants were placed in each photoprotected amber bottle (500 ml) with PBS, placed at 37 ° C. and stirred at 40 rpm. 1 ml aliquots were taken from each bottle three times a week, 1 ml of buffer was added back to the bottle to maintain the same volume, and the drug content was analyzed by UV spectroscopy (Amersham Biosciences, Buckinghamshire, UK).

result:

As shown in the graph of FIG. 3, 50:50 high intrinsic viscosity, 65:35 The cumulative release of risperidone of an implant containing either low intrinsic viscosity and 75:25 high intrinsic viscosity PLGA and 20% drug loading is expressed as the total weight of released risperidone and follows a typical saturation curve. Drug release is a function of the concentration of the PGA fraction in the polymer matrix, with lower fraction concentrations of PGA slowing the release of risperidone.

Example 4 Determination of Maximum Load of Risperidone in Implants

Determination of drug maximum load of risperidone

To determine the maximum concentration of risperidone available in the implant, drug concentration effects on the risperidone release profile were tested. The maximum drug load per implant system is used to minimize the implant system size, making it more acceptable.

Way:

Implants were made using a single polymer (85:15 PLGA high intrinsic viscosity) combined with risperidone at a rate of 20, 40 or 60% drug (w / w). The degradation time of the polymer is 4 months. The weight of each implant is 50 + 10 mg, with drug contents of 10, 20 and 30 mg respectively. Representative release profiles, expressed in mg total risperidone of each 50 mg implant over 40 days, are graphically depicted in FIG. 4A. Representative release profiles, expressed as percentage of risperidone in each 50 mg implant over 40 days, are shown graphically in FIG. 4B.

Example 5 Haloperidol Release in PLGA Implants As a Function of Implant Form

background:

Large wounds due to disc shaped implants can in some cases reduce their applicability to human subjects. Therefore, the implant structure was modified into a rod-shaped implant which can be inserted into a 4 mm hole. Hard PLGA implants do not require tools to guide the implant under the skin to ensure subcutaneous insertion rather than intramuscular insertion. Preliminary experiments were conducted to examine the effect of implant morphology on haloperidol release.

Way:

Haloperidol (40% w / w) was combined with 50:50 PLGA (60% w / w) by solvent casting. It was then extruded into a disc or slowly extruded using a high pressure piston extruder (DACA Instruments, Goleta, Calif.).

result:

These two types of release profiles are shown in FIG. 5. The graph of FIG. 5 shows in vitro cumulative release from disk and rod implants. Each point is the average of three observations of a disc or rod implant. Each implant was dissolved at 37 ° C., 40 rpm and dark conditions in 500 ml of PBS at pH 7.0. The weight of the rod and disc shaped implants was checked. No obvious difference was observed between the release profiles of the two implant types evaluated under these conditions.

Example 6: Control of Release Profile to Maintain a Constant Level of Drug in Serum

Gaussian Release profile:

The release profile of a single polymer system in rabbits suggests that biodegradable implants can deliver antipsychotic agents for extended treatment periods (FIG. 2A). This design prevents the initial high serum concentrations and the Gaussian release pattern shows a three month delay in achieving the target serum concentrations. However, the symmetrical nature of the release profile leaves room for the possibility of duplicate transplants every six months to continue drug delivery throughout the treatment period (FIG. 6), thus reducing the poor drug release of one implant set. Offset by gradual onset.

6 shows a continuous delivery model of biodegradable implants. The release profile of 100% poly (lactic acid) (PLA) implants in rabbits is temporarily superimposed between the 6 month cycle (grey trend line) and the model reinjection interval. The estimated concentrations in serum were summed at each time point and represented by total release plot (X). The test trendline is a total emission data model. Reinjecting every six months, the system fluctuates in the vicinity of the desired serum concentration range.

Example 7: Long-Term Release Drug Therapy Adjustment for Human Patients

Scaling for Humans

In practice, there are differences in metabolism of many drugs, including haloperidol, and rabbits and monkeys require 15 to 30 times higher doses than humans for the same concentration in plasma (Bacopoulos et al., 1980; Jibiki et al. , 1993; Klintenberg et al, 2002). Humans require about 1 mg / kg / month of haloperidol when provided as a depot preparation, and an implant system containing 600 mg provides one year of treatment for 50 kg of patients. Thus, the implant is 1.5 mg with a 40% drug load for one year of drug treatment. High potency drugs such as risperidone are used here to allow this approach. The release profile of risperidone indicates that in vivo systems can achieve long term delivery of more than 6 months when incorporated into the PLGA delivery system.

Example 8 Long-Term Release of Risperidone

Physicochemical Properties of Risperidone in Long-Term Delivery Systems:

Stability of risperidone

The stability of risperidone was assessed after solvent casting in acetone and slow extrusion, confirming that the compound can withstand the general processing of the implant. Then, a self-life study was conducted, which examined the content of risperidone, with various implants stored at various times of up to one year at 4 ° C. Risperidone was stable for 10 months in a physiological aqueous environment (37 ° C., phosphate buffered 0.9% saline, pH7.0) upon UV spectroscopy. Risperidone maintained its characteristic HPLC-MS peak residence time and weight even after solvent moulding and extrusion. In addition, risperidone is analyzed by quantitative HPLC equipped with a UV detector, which degrades to less than 1% when stored for one year, and similarly, risperidone has a physiological aqueous environment (37 ° C., phosphate buffered 0.9% saline, pH7.0). Decomposes to less than 1% when stored within 1 year.

Stability of PLGA Copolymer:

Stability of the ten PLGA polymers in production storage was simplified by intrinsic viscosity and glass transition temperature (Tg) measurements. After 1 year of storage in a 4 ° C. dry environment after solvent casting and extrusion, the intrinsic viscosity of the PLGA polymer changed to less than 5% and Tg varied below 2 ° C.

Way:

material

Risperidone is synthesized by the GMP method. Commercially available pharmaceutical grades of risperidone and acetone (USP / EP) were used.

The following PLGA is used:

number PLGA type
PLA: PGA (IV) Tg (℃) Decomposition interval in months One 50:50 (L) 50-55 1-2 2 50:50 (H) 50-55 1-2 3 65: 35 (L) 45-50 3-4 4 65:35 (H) 45-50 3-4 5 75:25 (L) 48-53 4-5 6 75:25 (H) 48-53 4-5 7 85:15 (L) 50-55 5-6 8 85:15 (H) 50-55 5-6 9 100: 0 (L) 50-55 12-16 10 100: 0 (H) 50-55 12-16

Physiology In solution Risperidone  Over time stability:

Three sets of risperidone solutions were prepared as follows: risperidone (10 mg) was dissolved in 100 [mu] l of acetonitrile and then in 1000 ml of PBS at pH 7.0 to give 10,000 ng / ml of the final solution. The risperidone solution was then stored in 37 ° C. in a light-safe yellow bottle. Three aliquots (100 μl) of each sample were HPLC analyzed at monthly intervals. Thereafter, the concentration of risperidone was graphed over time, and the slope of the resulting curve indicates the stability of the compound.

Stability of Risperidone and PLGA Polymers During Transplantation:

A risperidone implant consisting of 5% drug and 95% polymer (w / w) by solvent extrusion from acetone and then slow extrusion at a diameter of 5 mm / sec piston at 60 ° C. in a rod of 3.6 mm diameter and 20 + 10 mm length. Made. The prepared material was analyzed for risperidone content by in vitro quantitative analysis by HPLC. The measurements are expressed as the ratio of the initial weight of risperidone in the implant material.

Polymer:

The stability of PLGA was analyzed after the preparation process. Control implants were prepared in the absence of drug by solvent casting in acetone followed by slow extrusion. Manufactured material Ubbelhode suspended in a constant temperature (25 ℃) ^-. And an intrinsic viscosity variations in the acetone by using a level viscometer (suspended-level viscometer), 20-100 ℃ and 10 a differential scanning calorimeter (diferential in Tg change was analyzed using scanning calorimetry. Both intrinsic viscosity and Tg were measured before and after implant preparation.

In vivo release profile determination of risperidone, as a function of biodegradable copolymer physico-chemical properties:

Discharge pattern of individual polymers:

A single polymer system containing 100% PLA and 50% drug loading forms a Gaussian release profile, peak concentration at 6 months and in the treatment range (1 ng / L or more) at 2-8 months post implantation. Belong to (Fig. 7a). The symmetrical nature of the release profile indicates that duplicate implants can be used every six months to maintain drug delivery during the treatment period. Such a system provides for continuous therapeutic drug delivery because, with each retransplantation, a constant reduction in one set of implants is then offset by the gradual initiation of the set. Typical release of risperidone is shown in FIG. 11A, which shows cumulative release of risperidone dispersed in a PLGA biodegradable substrate. A similar profile is observed for 9-OH- risperidone in FIG. 11B, and similarly, FIG. 12 shows 20% (w / w) of 9-OH dispersed in a PLA: PGA block copolymer biodegradable substrate at 85:15. Indicates cumulative release of risperidone. FIG. 13 is a cumulative release graph of 20% (w / w) risperidone dispersed in a 85:15 PLA: PGA block copolymer biodegradable substrate.

In order to prevent relatively long initial retention times and high amplitude vibrations around a suitable therapeutic concentration range, additional polymer implants or rapid release formulations can be combined, and their implants can be replaced during the treatment period so that the level of therapeutic drug is treated. Form pseudo zero release sustained over time (FIGS. 7B-7E).

Example 9: Haloperidol Release in PLGA Implants

Implant manufacturing

Implants were prepared by solvent casting and extrusion. 75% polylactide and 25% polyglycolide (75:25 PLGA) polymer and 85% polylactide and 15% polyglycolide (85:15 PLGA) polymer were placed in the combined release system for 5 months. Each copolymer has a respective degradation period, which is determined by the lactide to glycolide ratio and the molecular weight of the molecular product produced. For in vivo experiments in rats, 100% polylactide (PLA) was used as additional polymer. The intrinsic viscosity in chloroform of all polymers (Alkermes Inc., Cincinnati, OH) was 0.66-0.80 DL / g and the molecular weight distribution was 120-140 kD. Each polymer and haloperidol (Sigma, St. Louis, Mo.) were dissolved in acetone and then solvent cast at 60 ° C. for 72 hours. The solvent cast material was extruded at a final density of 1.1 + 0.05 g / cc at 80 ° C., 25,000 psi.

In vitro analysis:

Each implant was placed in 1 L of PBS at pH 7.0 and placed in a stirrer at 37 ° C. Haloperidol concentrations were measured by GCMS (National Medical Services, Willow Grove, PA). Each assay included an implant negative control made only of polymer and a 100 ng / ml haloperidol standard to assess the stability of haloperidol over time in solution.

animal:

Implants were tested in rats (Harlan, Indianapolis, IN) (n = 9) and mice (Jackson Labs, Bar Harbor, ME) (n = 16). All experimental animals were bred in AAALAC accredited animal laboratories at the University of Pennsylvania. All protocols were approved by the Animal Care Committee (IACUC). Animals were maintained weekly and nightly at 12:12 and performed all tests and experiments during the day.

Transplantation / Removal Surgery:

Mice and rats were anesthetized with ketamine / xylazine (100/10 mg / kg, i.p.). The dorsal skin of the experimental animal was incised 1 cm with a surgical scalpel. The subdermal space was visualized with hemostatic agents and a single implant was positioned with forceps between the dermis and muscle. The surgical staple wound was then sealed. Four weeks after implantation, the implant location was confirmed by palpation, and the same anesthesia and incision were performed to remove the implant. The promoted implant was easily removed with forceps.

Behavioral test:

Sixteen C57bl / 6 mice were implanted with 75:25 PLGA alone (n = 8) or implants made with 20% haloperidol (n = 8) at 75:25 to assess the effect of the implant on behavior. Three weeks after transplantation, the total distance traveled for 20 minutes was confirmed. The implants were then removed and recovered for 48 hours and then retested 20 minutes after apomorphine inoculation (0.5 mg / kg i.p.) (Sigma, St Louis, MO).

Western blot:

Six Sprague Dawley (SD) rats were implanted with PLA and 30-40% haloperidol. Three rats were implanted with only PLA. Implants were maintained in all experimental animals for 3 months before removal. After 72 hours of implant removal, rats were killed and the brain recovered quickly, then divided into quarters (cortex, hippocampus, striatum, cerebellum) and frozen in liquid nitrogen. Western blots were performed for quantitative analysis of D2 receptor proteins on progenitors. Cortical proteins recovered from a single animal were used with all blots as internal controls at three concentrations (2.5, 5 and 10 μg) to confirm the label intensity in the straight line of the quantitative software. Only blots where the intensity of the sample falls within the linear range of the internal standard were analyzed. Western blot was performed with polyclonal antibody WR-3526, which is directed against amino acids 272-282 of the D2 receptor protein (Research and Diagnostic Antibodies, Berkeley, Ca). Striata sites were homogenized in homogenization buffer (20 mM HEPES, 2 mM EDTA, 1 mM PMSF, 2 μM aprotinin and 2 mM DTE) and then sonicated for 30 seconds. Samples were centrifuged at 100,000 g for 1 hour at 4 ° C. The pellet was resuspended and dissolved in homogenization buffer containing 0.1% Triton X-100. The protein was extracted by shaking occasionally for 45 minutes on ice. After extraction, the protein was centrifuged at 30,000 g for 30 minutes at 4 ° C. Protein samples were added to 25% 4 × NuPAGE sample buffer with 10% reducing agent (Invitrogen) and heat shocked at 70 ° C. for 10 minutes. Samples were separated at 200 volts for 50 minutes on a 10% premade mini-gel. Protein was transferred to PVDF under 30 volts for 1 hour. Blots were blotted with 5% milk in TBS (20 mM Tris, pH = 7.5, 0.5 M NaCl) and washed for 15 minutes. The blot was then reacted overnight with anti-D2-receptor antibody, washed with TBS, and then for 1 hour with goat anti rabbit Horceradish peroxidase conjugate (BioRad, 1: 4800). The blot was then reacted with the chemiluminescent substrate (Pierce) for 1 minute, wrapped in plastic and then exposed to radiophotographic film.

dose:

The intensity of each band was quantified with a densitometry model 7100 and quantitative analysis software (Bio Rad, Hercules, Calif.) And expressed as the ratio corresponding to rat1 to calculate the intensity ratio (rat1 = ratio 1). In order to perform quantitative comparisons according to the conditions, all samples were run simultaneously in a single blot.

In vitro:

The haloperidol concentrations for the two polymers as well as the merged values are shown in FIG. 8 AC. 8 graphically shows each implant in PBS at pH 7 on a stirrer at 37 ° C. Sample buffers were taken at one or two week intervals to check haloperidol concentrations with GCMS. Cumulative release is expressed as percentage of total drug load in buffer measured over time. Cumulative haloperidol concentrations in 75:25 and 85:15 PLGA polymers. Each graph shows the results obtained from three implants (circles, squares and triangles) with a 4 ^th degree polynomial average line for three values.

Implants made with 75:25 PLGA containing 40% haloperidol showed a first phase release pattern with slow release from 0 to 28 days (about 0.29% / day / implant). The second stage, with faster release, appeared between 28 and 84 days (about 1.28% / day / implant). On day 66, 50% of the total haloperidol load of implants made with 75:25 PLGA was released (FIG. 8A). Implants made with 85:15 PLGA containing 40% haloperidol showed a release pattern similar to the slow release step from about 0 to 56 days (about 0.26% / day / implant). The second stage, with faster release, appeared between 56 and 140 days (about 0.95% / day / implant). Implants made with 85:15 PLGA released 50% of haloperidol load on day 88 (FIG. 8B). In the release pattern of the theoretical hybrid system consisting of 75:25 and 85:15 PLGA, 40% haloperidol, the initial stage averaged 0.34% / day from 0 to 28 days, with faster releases averaged from 28 to 140 days. 0.82% / day. The release of half of the total haloperidol load of the 75:25 and 85:15 PLGA combined systems was on day 78 (FIG. 8C). The values of the positive control solution (100 ng / ml) remained stable for 154 days (0 days = 106, 154 days = 100, mean + standard deviation, experimental interval = 106 + 11 ng / ml).

In vivo motor activity

The locomotor activity in the mice implanted with haloperidol or blank polymer is shown in FIG. 9. All animals were tested for 3 weeks after implantation of 75:25 PLGA alone or implants made with 75:25 PLGA and 20% haloperidol. Baseline locomotor activity was measured for 20 minutes. The average distance traveled for animals implanted with control implants was 12223 + 433 cm, and the average distance traveled for animals implanted with haloperidol containing implants was 7664 + 450 cm. Therefore, the migration distance of mice transplanted with haloperidol implants was significantly shorter than that of the control group (p <0.01). The implant was then removed and all animals recovered for 48 hours. One experimental animal implanted with a control implant died under anesthesia during removal. 48 hours after implant removal, 0.5 mg / kg ip of apomorphine, which has been shown to increase motor activity in mice (Ninan and Kulkarni 1999), was given to experimental animals and a 20 minute post-test exercise was performed. After apomorphine provision, the average migration distance of control animals was 4721 + 476 cm, whereas the average migration distance of experimental animals with haloperidol containing implants is 8531 + 2536 cm. Therefore, after implant removal and exposure to apomorphine, the migration distance of mice with haloperidol implants was longer than that of control mice (p <0.01).

Western blot:

Western blots of ancestral membranes obtained in all rats identified a band of about 50 kD (FIG. 10) molecular weight corresponding to the estimated molecular weight of the full-length D2 receptor protein (Expert Protein Analysis System, Swiss Institute of Bioinformatics, http: // www .expasy.ch /) (Bunzow et al 1988). The average density of the bands was quantified compared to the bands in lane 1 (haloferidol treated rats). Three blots showed that the relative density for the 50 kD band in rats implanted with haloperidol implants was 0.90 + 0.07 (mean + standard deviation), and the relative density of control rats was 0.64 + 0.02 (p <0.001, two tail t- test).

Example 10 Long-Term Treatment of Risperidone Implants for Schizophrenia

Implant Manufacturing:

Risperidone Disc Implants

Implants were prepared by solvent casting and / or compression molding. Combination systems released for 12-14 months include two polymers 75% polylactide and 25% polyglycolide (75:25 PLGA), and 85% polylactide and 15% polyglycolide (85:15 PLGA). Exist. Each copolymer has a respective degradation period, which is determined by the lactide to glycolide ratio and the molecular weight of the molecule produced. All of the polymers (Alkermes Inc., Cincinnati, OH) have an intrinsic viscosity of 0.66 + 0.80 DL / g in chloroform and a molecular weight distribution of 120,000-140,000. Each polymer and risperidone (Sigma, St. Louis, MO) can be dissolved in acetone and solvent casted at 60 ° C. for 72 hours. Solvent template materials were made into discs of diameter 20 mm, thickness 1.2 + 0.00 mm and final density 1.2 + 0.1 g / cc.

Risperidone Rod Implant

Rod implants can be produced by extrusion molding. PLGA of 50% polylactide and 50% polyglycolide (50:50 PLGA) is a two month release system. All of the polymers (Alkermes Inc., Cincinnati, OH) have an intrinsic viscosity of 0.66 + 0.1 DL / g in chloroform and have a molecular weight distribution of 120,000-140,000. The polymer and risperidone (Sigma, St. Louis, MO) were dissolved in acetone at a 95: 5 weight ratio and finalized at 60 ° C. at a piston speed psi of 5 mm / sec using a high pressure piston extruder (DACA Instruments, Goleta, CA). Implants with a density of 1.1 + 0.1 g / cc were extruded. 3.5 + 0.5 mm in diameter and 20 + 10 mm in length. The release profile can be modified by varying the ratio of monomers (lactide: glycolide), the initial loading of the drug, and the manufacturing process.

Experimental Controls and Monitoring:

A) The first control subject is exposed to risperidone for 6 months through a multi-polymer system.

B) The second control subject is fed the first multi-polymer system and then retransplanted a "maintenance" implant at 6 months to provide 12 months of continuous drug therapy until autopsy.

C) Feed the first multi-polymer system to provide normal delivery for 6 months to the third control subject, but do not replant the maintenance implant. These control subjects are tested 12 months after transplantation to assess toxicity after discontinuation of drug treatment.

D) To confirm the results of mechanical damage of the implant during the delivery interval, a broken implant is fed to the fourth control subject.

E) To confirm the toxic effect of the drug independent of the delivery system under test, the fifth control subject is fed a positive control and administered oral risperidone daily or risperidone injection.

F) To analyze the effect of polymer material independent of risperidone, the last control subject is fed a blank implant without drug as a negative control.

Stick implant placement

Implants with different release profiles were inserted subcutaneously in patients in need. The implant may be placed in a 4 mm incision in the shoulder. If the implant is hard, no implant-guide is necessary.

Measures the effectiveness of treatment for schizophrenia:

Improved Brief Psychiatric Rating Scale (BPRS) scores in patients under treatment (Dinakar, HS et al., [2002] Efficacy of Olanzapine and Risperidone for Treatment-Refractory Schizophrenia Among Long-Stay State Hospital Patients, Psychiatric Services, Vol. 53 , No. 6, pp 755-757), no significant side effects such as weight gain were observed. It also improves negative symptoms (alogia, affective flattening, avolition, insensitivity, social withdrawal and attentional impairment) and intellectual performance. (Honey, GD, et al., [1999] Differences in Frontal Cortical Activation by a Working Memory task after Substitution of Risperidone for Typical Antipsychotic Drugs in Patients with Schizophrenia.PNAS, vol. 96, No. 23, pp. 13432- 13437).

Serum levels of risperidone:

Every three months, 2 ml of blood was collected from the subject or from a patient in need of transplant / replantation. Serum was separated by centrifugation of blood. Risperidone concentrations were determined by solid phase extraction (MCX, Waters) and HPLC / UN detection.

Example 11 Microparticles for Oral Delivery of 9-OH-risperidone for Short-Term Treatment of Bipolar Disorder (1-3 Weeks)

Microparticle Manufacturing:

Prepared from poly (glycolic acid) and poly (d, l-lactic acid) copolymers with a lactide to glycolide ratio of 75:25 and containing 9-hydroxy- risperidone in an 98: 2 weight ratio as active ingredient. Microparticles were prepared. PLGA copolymer and 9-hydroxy- risperidone were dissolved in acetone and EVA as a dispersed phase. Continuous phases were prepared with PVA, water, ethyl acetate and benzyl alcohol. Emulsions were prepared by pumping 20:80 ratio of dispersed and continuous phases with a static mixer (Kenics ^® KM Series Static Chemineer, Dayton, OH). The size of the final microspheres can be controlled by phase ratio, flow rate, temperature and continuous phase composition. The prepared emulsion was passed through a quench liquid. After incubation, the prepared microspheres were filtered, washed repeatedly with a series of appropriate solvents, and dried.

Microsphere Dosage:

Microspheres were incorporated into capsules and administered orally to patients in need. Excipients may be incorporated into the microspheres and used as ingestible capsules, or they may contain binders, excipients, lubricants and possibly liquid carriers.

Treatment efficacy:

In patients with long-term treatment, at least seven were observed above the baseline and mean Global Assessment of Functioning (GAF) levels of CGI (Clinical Global Impression). Treatment was very acceptable and no symptoms worsened while taking 9-OH-risperidone (Ghaemi, S.N. [1997] Acute Treatment of Bipolar Disorder with Adjunctive Risperidone in Outpatients Can J Psychiatry, Vol 42, pp. 196-199).

Example 12: Sustained Release Treatment of Mental Disorders Using Second-Generation Antipsychotics

Starter Formulations:

To compensate for the relatively long-term inducer associated with achieving therapeutic blood-serum levels in hard implants, it contains an antipsychotic agent to promptly raise blood serum levels in patients with psychotic disorders above the therapeutic level. Formulations in injectable form. Injectable formulations are taken orally with fast-release PLGA microparticles containing antipsychotic drugs, reaching the therapeutic level in one day, with peak delivery lasting two weeks.

Implants:

Single Polymer Implants:

Implants prepared as described above are prepared from a single copolymer containing antipsychotic agents. The release profile is designed to last 6-8 months until therapeutic levels form and complete degradation within 3 weeks of transplantation, and peak release is achieved for 5-7 months after transplantation. In order to compensate for high amplitude fluctuations in optimal serum levels of antipsychotic agents that can be formed from a single implant, a second maintenance set, a single copolymer composition can be added, with peak delivery of the composition being 10-14 weeks. Complete degradation occurs within 4-5 months after transplantation. Examples of cumulative release profiles of various antipsychotic agents in PLGA implants are shown graphically in FIGS. 14D, 15A, 16A, and 17A.

Multi-Copolymer Composite Implants:

Using co-extrusion, high load core PLGA (85:15 PLA) with an extended release profile to be maintained at the therapeutic level for a long time of replanting once every nine months or alternatively reducing the implant size. (PGA, high intrinsic viscosity) copolymers, external low-load fast-release PLGA (50:50 15 PLA: PGA, low intrinsic viscosity) and composite implant cores, which can eliminate retention sets and increase degradation time Merge as.

Blood serum monitoring for antipsychotic concentrations:

Every 3 months, 2 ml of blood was drawn from the subject or a patient in need of transplant / replantation. The blood was then centrifuged to separate serum. After solid phase extraction (MCX, Waters) and HPLC / UV detection, the concentration of antipsychotic agent was determined in comparison to known standards.

Treatment efficacy monitoring:

Efficacy monitoring depends on the mental disorder being treated. In general, an improvement in intellectual work, stable mood or mood swings in patients, or in particular an improvement in work ability, is observed and maintains intimacy with others and with society. There were no significant side effects and the number of hospital stays decreased. The effect of the antipsychotic drug released from the implant is shown in FIGS. 14-17.

While various examples of the invention have been described above, it should be understood that these are merely examples and are not limiting. Thus, the breadth and scope of the present invention should not be limited to any of the above illustrated, but should be limited to the appended claims and their equivalents.

Example 13: Optimization of Drug Loading:

background

A study was conducted to examine the effect of drug concentration on risperidone release profile. The purpose of the study was to determine the maximum concentration of risperidone that can be used in the implant. The maximum concentration was used for the implant to make the implant as small as possible and more easily tolerated. Using a single polymer (85:15 PLGA high intrinsic viscosity), an implant was prepared comprising 20% by weight, 40% by weight, or 60% by weight of risperidone (FIG. 18A). The degradation period of this polymer is 4 months. Each implant weighs about 50 mg and contains 10, 20 and 30 mg of drug, respectively, at 20%, 40% or 60% drug loading conditions. This study was repeated and other percentages were also tested.

result

18A-B show cumulative release of risperidone in implants with a drug load of 20%, 40% or 60% by weight and containing 85:15 PLGA. Each point is the average of three experiments and displays a trend line to represent the overall emission pattern. a) Release in mg of total risperidone in each 50 mg implant. b) Release, expressed as percentage of drug content in each implant type.

Claims (45)

delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete 40 to 90% (w / w) poly (lactide / glycolide) (PLGA) copolymer having a molar ratio of lactide: glycolide of 90:10 to 50:50; And 10 to 60% (w / w) antipsychotic agent, The antipsychotic agent is risperidone or 9-OH- risperidone, Implant composition for the treatment of mental disorders, characterized in that the solid implant composition. 36. The implant composition of claim 35 wherein the concentration of the PLGA copolymer is 90% (w / w). 36. The implant composition of claim 35 wherein the concentration of the PLGA copolymer is 80% (w / w). 36. The implant composition of claim 35, wherein the antipsychotic agent is 9-OH- risperidone. 39. The implant composition of claim 38 wherein the molar ratio of lactic monomer to glycolic monomer of PLGA is 85:15. 39. The implant composition of claim 38 wherein the molar ratio of lactic monomer to glycolic monomer of PLGA is 75:25. 39. The implant composition of claim 38 wherein the molar ratio of lactic monomer to glycolic monomer of PLGA is 65:35. 39. The implant composition of claim 38 wherein the molar ratio of lactic monomer to glycolic monomer of PLGA is 50:50. delete 36. The implant composition of claim 35 wherein the implant is disk or rod-shaped. 45. The implant composition of claim 44, wherein the rod-shaped implant has a diameter of 1 to 4 mm, a length of 10 to 40 mm, or a combination thereof.

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