Compositions in the form of a set of particles with modified release

 

The present invention relates to compositions in the form of a set of particles with modified release, which in effect gives the active ingredient pulsed or bimodal. This composition is in the form of a set of particles with modified release includes a component with the immediate-release component and with modified-release component and immediate-release includes the first set of particles containing the active ingredient, and the component with modified release includes the second set of particles containing the active ingredient, coated for controlled release, and this combination of the component with the immediate-release component and with modified release in action delivers the active ingredient pulsed or bimodal. This invention also relates to a solid oral dosage form that contains such a composition in the form of a set of particles with modified release. Profile in plasma achieved this composition in the form of a set of particles with modified release, useful in reducing tolerance p is the notes of taking the medicine. 5 C. and 31 C.p. f-crystals, 8 tab., 1 Il.

The scope of the invention

The present invention relates to compositions in the form of a set of particles with modified release. In particular, the present invention relates to compositions in the form of a set of particles with modified release, which in effect gives the active ingredient in a pulsed manner. The present invention also relates to a solid oral dosage form that contains such a composition in the form of a set of particles with controlled release.

Description of the prior art

Profile in plasma associated with the introduction of the drug, can be described as "pulse profile", in which the observed pulses of high concentrations of active ingredients, alternating with periods of low concentration. The pulse profile with two peaks, can be described as "bimodal". Similarly, we can say that the composition or dosage form, which gives this profile with the introduction demonstrates "pulsed release" of the active ingredient.

Conventional schemes frequent drug administration in which the dosage form immediate-release (HB) is injected through the periods of the each dose HB see the peak concentration of drug in plasma at intervals (areas of low concentration of the drug), manifested between successive points of introduction. Such schemes (as well as resulting from their pulse profiles in blood plasma) have specific pharmacological and therapeutic effects associated with them. For example, it is believed that the washout period provided by the fall in the concentration of active ingredient in the blood plasma between the peaks is a factor contributing to the reduction and prevention of tolerance of the patient to different types of drugs.

Many drugs controlled release designed to make the drug release with zero order kinetics. Indeed, often the specific goal of these drugs is to minimize the change from the peak to the gap in the levels of drug in plasma associated with conventional circuits frequent drug administration. However, some of therapeutic and pharmacological effects inherent in pulsed systems may be lost or reduced as a result of constant or near-constant levels in the blood plasma, achieved through systems of drug delivery to the release with zero order kinetics. So myslobodsky, typical schemes of frequent medication with HB, while the need for frequent dosing is reduced.

A typical example of a drug which may induce tolerance in patients is methylphenidate. Methylphenidate, or methyl ether-phenyl-2-piperidineacetic acid, is a stimulant that acts on the Central nervous and respiratory systems and which is used primarily to treat attention-deficit. After absorption from the gastrointestinal tract (GIT) the effects of the medication stored within 3-6 hours after oral administration of conventional tablets HB or up to about 8 hours after oral administration of drugs with a slow release. The total dose is usually in the range from 5 to 30 mg per day, in exceptional cases, increasing to 60 mg per day. When the conventional schemes of receiving methylphenidate give twice a day, usually one dose given before Breakfast and one before lunch. The last daily dose is preferably given a few hours before bedtime. Side effects associated with treatment with methylphenidate include insomnia and tolerance of the patient.

In WO 98/14168 (Alza Corp.) describes the medication is Naya dosage form includes many of the balls, containing hydrogel matrix with increasing amounts of the active ingredient in it, covered with variable amounts of material, controlling the rate of release. Appropriate combinations of doses of the active ingredient and the number and thickness of layers, the membrane may be chosen so as to obtain the profile of the increasing release, in which the concentration of active ingredient in the blood plasma is increased continuously within the specified period of time. Unlike the present invention, the task WO 98/14168 is to offer dosage form, namely, in order to avoid unequal levels in the blood (characterized by peaks and intervals) associated with conventional methods of treatment using medicines immediate-release.

In WO 97/03672 (Chiroscience Ltd.) revealed that methylphenidate exhibits a therapeutic effect when it is administered in the form of a racemic mixture or in the form of a single isomer (such as RR or d-threo-enantiomer). In addition, in WO 97/03672 (Chiroscience Ltd.) revealed the drug slow release containing d-threo-methylphenidate (DTMP). In this description indicated on the application of the composition containing the shell, through which passes the Commissioner at least 50% Withmaxduring a period of at least 8 hours. Thus, this drug does not cause the active ingredient in a pulsed manner.

Shah et al., J. Cont. Rel. (1989) 9:169-175 reveals that certain types of esters of hydroxypropylmethylcellulose, compressed into a solid dosage form with a therapeutic agent, can give bimodal release profile. However, it was noted that while the polymers from a single supplier give bimodal profile, the same polymers with almost identical characteristics of the product obtained from another source, give not bimodal release profiles.

Giunchedi et al., Int. J. Pharm (1991) 77:177-181 disclose the use of hydrophilic matrix of multicomponent drug with a pulse release of Ketoprofen. Giunchedi et al. describe what Ketoprofen is rapidly eliminated from the blood after administration of the dose (half-life from plasma (1-3 hours), and in some ways the treatment of sequential pulses of medication may be more useful than a permanent release. This describes a multicomponent drug includes four identical hydrophilic matrix tablets, placed in a gelatin capsule. Although in vivo studies show two peaks in plasma cu the blood low.

Conte et al., Drug. Dev. Ind. Pharm. (1989) 15:2583-2596 and EP 274734 (Pharmidea Srl) describe the application of three-layered tablet for delivery of ibuprofen consecutive pulses. This three-layer tablet is made of the first layer containing the active ingredient, the barrier layer (second layer) of a semi-permeable material, which is located between the first layer and the third layer containing an additional amount of the active ingredient. The barrier layer and the third layer are placed in an impenetrable shell. The first layer dissolves upon contact with the solvent liquid, while the third layer is available only after the dissolution or destruction of the barrier layer. In this tablet the first portion of the active ingredient must be released immediately. This approach also requires a semi-permeable layer between the first and the third layer in order to control the relative speed of delivery of these two parts of the active ingredient. In addition, the destruction of the semi-permeable layer leads to uncontrolled release of the second part of the active ingredient, which may be undesirable.

In the US 5158777 (E. R. Squibb & Sons Inc.) discovered the drug, including captopril in resistant to the pH of the nucleus, with the release in the intestine or the CSO release after injection. In order to form resistant to the pH of the kernel used chelating agents, such as dvuhmatchevaya salt of ethylenediaminetetraacetic acid, or surfactants, such as Polysorbate 80, or separately, or in combination with a buffer agent. These compositions have a number of captopril available for immediate release after oral administration, and an additional number of captopril, stable against pH, available for release in the colon.

US 4728512, US 4794001 and US 4904476 (American Home Products Corp.) refer to the drugs that provides three different ways of release. The product contains three groups of spheroids containing the active drug substance: the first group of spheroids is not covered and quickly dissolves when swallowed with the release of the initial dose of medicinal substance; the second group of spheroids coated, sensitive to pH, to provide the second dose; the third group of spheroids coated, independent of pH, to provide a third dose. This drug is intended to provide additional release of medicinal substances, which are subject to intense dasystemon dosage form of methylphenidate, having particles with the immediate-release and particles with a delayed release. Delayed release is achieved by using independent from pH ammoniumnitrate polymer, combined with some fillers.

Accordingly, the present invention is to provide a composition in the form of a set of particles with modified release, containing the active ingredient, which in effect causes the profile in plasma, essentially similar to the profile in plasma caused by the introduction of two or more than two dosage forms HB given consistently.

Another objective of this invention is to provide a composition in the form of a set of particles with modified release, which in effect gives the active ingredient in a pulsed manner.

Another objective of the invention is to provide a composition in the form of a set of particles with modified release, which essentially mimics the pharmacological and therapeutic effects caused by the introduction of two or more than two dosage forms HB given consistently.

Another objective of the invention is that the at reduces or eliminates the development of tolerance of the patient to the active ingredient of this composition.

Another objective of the invention is to provide a composition in the form of a set of particles with modified-release, in which the first portion of the active ingredient is released immediately upon introduction, the second part of the active ingredient is released quickly after the initial grace period, bimodal manner.

Another objective of the invention is to provide a composition in the form of a set of particles with modified release, which is capable of releasing the active ingredient bimodal or multimodal manner, in which the first portion of the active ingredient is released either immediately or after a delay period to provide a pulse of drug release, and one or more than one additional part of the active ingredient released after each of the corresponding lag-period, providing additional pulses of drug release.

Another objective of the invention is to provide a solid oral dosage forms containing the composition in the form of a set of particles with modified release of the present invention.

Another objective of the present invention includes n is Ile in the blood plasma, essentially the same as the profile in plasma caused by the introduction of two dosage forms of immediate-release given consistently, as well as a method of treatment of attention deficit, based on the introduction of such dosage forms.

Brief description of the invention

The above objectives are realized by the composition in the form of a set of particles with modified release, with the first component includes a first set of particles containing the active ingredient, and a second component comprising a second set of particles containing the active ingredient. The active ingredient contained in the first and second components may be the same or different, and the particles of the second component containing the active ingredient, coated for modified release. Alternative or additionally, the second set of particles containing the active ingredient, also contains a matrix material for modified release. Following oral delivery, the composition in action delivers the active ingredient or active ingredients pulsed manner.

In the preferred embodiment of the composition in the form of a set of particles with modifitsirovaniem.

Shell for modified release, applied to the second set of particles containing the active ingredient, causes the formation of the lag-period between the release of the active ingredient from the first set of particles containing the active ingredient, and the release of active ingredient from the second set of particles containing the active ingredient. Similarly, the presence of a matrix material for the modified release of the second aggregate particles containing the active ingredient, causes the formation of the lag-period between the release of the active ingredient from the first set of particles containing the active ingredient, and the release of active ingredient from the second set of particles containing the active ingredient. The duration of the lag period can be varied by changing the composition and/or number of shells for modified release and/or by changing the composition and/or quantity of the matrix material for the modified release. Thus, the duration of the lag period can be varied in such a way as to simulate the desired profile in plasma.

Because the profile in plasma caused by the composition in the form of sets is subject to the introduction of two or more than two dosage forms HB, given sequentially, the composition is in the form of a set of particles with controlled-release of the present invention is particularly useful for the introduction of active ingredients for which the tolerance of the patient can be a challenge. Therefore, such a composition in the form of a set of particles with modified release useful to reduce or minimize the development of tolerance of the patient to the active ingredient in the composition.

In the preferred embodiment of the present invention the active ingredient is methylphenidate, and composition in action delivers this active ingredient bimodal or pulsed manner. This composition creates the profile in plasma, which essentially mimics the profile, which is obtained by sequential injection of two doses of HB, for example, in a typical scheme of treatment with methylphenidate.

The present invention also proposed a solid oral dosage forms containing the composition according to this invention.

In the present invention is also a method of treatment of an animal, in particular human, which needs to be treated with this active ingredient, which is administered therapeu the Oia, to provide pulsed or bimodal introduction of this active ingredient.

The advantages of the present invention include a reduction in the frequency of doses required by generally accepted schemes of receiving multiple doses of HB, and retained the benefit derived from the pulse profile in the plasma. This reduced the frequency of doses is especially useful for children that eliminates the need for a dose in the middle of the school day, which may harm the patient and concern for the patient. She also has advantages in terms of compliance by the patient receiving the drug, which you can enter with reduced frequency. A reduction in the frequency of doses, which is made possible through the use of the present invention should reduce the cost of health care by reducing the time that health workers spend on the administration of medicines. In respect of methylphenidate and other controlled substances the use of drugs for administration once a day (instead of multiple doses of HB) reduces or eliminates the need to store controlled substances in the premises of schools and other institutions.

Description of drawing

Drawing illh drugs: A - 20 mg of the drug methylphenidate, have the immediate-release, which includes particles containing in the amount of 10 mg of methylphenidate (in accordance with Table 1 (2)), and the component with modified release, which includes particles containing in the amount of 10 mg of methylphenidate (in accordance with Table 2 (8); particles HB, coated to a weight gain of 30%); B - 20 mg of the drug methylphenidate, have the immediate-release, which includes particles, containing in the amount of 10 mg of methylphenidate (in accordance with Table 1 (2)), and the component with modified release, which includes particles containing in the amount of 10 mg of methylphenidate (in accordance with Table 2 (7); particles HB, coated to a weight gain of 30%); and Control-two doses of 10 mg pills of ritalin hydrochloride (Ritalin® Hydrochloride) (HB) entered at time 0 hours and 4 hours (in the amount of 20 mg of methylphenidate).

Detailed description of the invention

The term "particulate" as used here, refers to such a state of matter that is characterized by the presence of discrete particles, pellets, beads or granules, regardless of their size, shape or morphology. The term "in the plural, beads, pellets or mixtures thereof, regardless of their size, shape or morphology.

The term "modified release" as used here in relation to the composition of this invention, or shell, or shell material, or as it is used in any other context, means a release that is not immediate-release, and covers controlled release, extended release and delayed release.

The term "grace period" as it is used here, refers to the period of time between the introduction of the composition and release of the active ingredient of component representing particles.

The term "lag " period", as used here, refers to the time between delivery of the active ingredient from one component and subsequent delivery of the active ingredient from another component.

The invention will be described in detail in respect of methylphenidate as a concrete example of the active ingredient, especially suitable for the preparation of compositions in the form of a set of particles with modified release of the present invention.

The composition is in the form of a set of particles with modified release of the present is the first release of the active ingredient from the second and additional components modified there is a lag period between the release of the active ingredient of the first component and each additional component. The number of pulses in the profile arising from the action of such a composition will depend on the number of components containing the active ingredients in this composition. The composition, which contains three components, containing the active ingredient, will cause the emergence of three pulses in the profile.

In the practice of the present invention can use any active ingredient for which it is useful to combine the advantages of the pulse profile in plasma with a regimen of drugs with low frequency. In the practice of this invention are particularly useful to include active ingredients that have pharmacological and/or therapeutic effects improve as a result of the presence of the washout period between the peaks of the concentration in plasma, such as those active ingredients that are susceptible to development of tolerance in a patient. Examples of active ingredients include, but are not limited to, peptides or proteins, hormones, analgesics, agents against migraine, anticoagulants, antagonists, drugs, chelating agents, antianginal agents, chemotherapeutic AG is s connection acting on the Central nervous system such as cerebral stimulants, such as methylphenidate; active painkilling ingredients; alkaloids, such as opiates, such as morphine; cardiovascular drugs, such as nitrates; and agents for the treatment of rheumatic conditions. Also clear is that the present invention can be applied for the delivery of many drugs, which include, but are not limited to, peptides, proteins or hormones such as insulin, calcitonin, a protein that regulates gene calcitonin, natriuretic protein fibrillation, colony stimulating factor, Betaseron, erythropoietin (EPO), interferons such as-,or-interferon, somatropin, somatotropin, somatostatin, insulin-like growth factor (somatomedin), a hormone-releasing hormone luteinizing hormone (RHLH), tissue plasminogen activator (TAP), a hormone-releasing hormone (ghrh), oxytocin, estradiol, growth hormones, acetate leuprolide, factor VIII, interleukins such as interleukin-2, and the like; analgesics such as fentanyl, Sufentanil, butorphanol, buprenorphine, Levorphanol, morphine, hydromorphone, hydrocodone, Oxymorphone, mattapan, ergot alkaloids and their analogues; anticoagulants, such as heparin, hirudin, and their analogues; antiemetic agents such as scopolamine, ondansetron, domperidone, metoclopramide, and analogues; cardiovascular agents, antihypertensive agents and vasodilator agents, such as diltiazem, clonidine, nifedipine, verapamil, isosorbide-5-Mononitrate, organic nitrates, agents used in the treatment of heart disease, and their analogues; sedative agents, such as benzodiazepines, phenothiazines, and the like; chelating agents such as deferoxamine, and their analogues; antidiuretic agents such as desmopressin, vasopressin, and analogues; antianginal agents such as nitroglycerine, and analogues; antineoplastics agents, such as fluorouracil, bleomycin, and analogues; prostaglandins and their analogues; chemotherapeutic agents such as vincristine, and analogues.

The active ingredient in each component may be the same or different. For example, a composition in which the first component contains a first active ingredient, and the second component contains a second active ingredient, may be desirable for combination treatments. In fact, in one and the same component is different. Medicinal substance that is present in one of the components of the composition may be supplemented such as enhancers or sensitizing compound in another component of this composition in order to modify the bioavailability or therapeutic effect of the medicinal substance.

The term "enhancer", as used here, refers to a compound that can enhance the absorption and/or bioavailability of the active ingredient by stimulating its passage through the gastrointestinal tract of the animal, such as man. Enhancers include, but are not limited to, fatty acids with medium chain; salts, esters, ethers and derivatives, including glycerides and triglycerides; non-ionic surface-active agents, such as those that can be obtained through reaction of ethylene oxide with fatty acid, fatty alcohol, alkylphenol, or sorbitane, or ether fatty acids and glycerol; cytochrome P450 inhibitors; inhibitors of P-glycoprotein and the like, and mixtures of two or more than two of these agents.

The proportion of the active ingredient contained in each component may be the same or different, depending on the desired regimens medication. The active ingredient of my ingredients) in the second component in any quantity, sufficient to cause a therapeutic effect. Active ingredient (or active ingredients), when it comes, may be present either in the form of a single essentially optically pure enantiomer or as a racemic or other mixture of enantiomers. The active ingredient is preferably present in the composition in an amount of from 0.1 to 500 mg, preferably in an amount of from 1 to 100 mg. When the active ingredient is methylphenidate, it preferably is present in the first component in an amount of from 0.5 to 60 mg, more preferably the active ingredient is present in the first component in an amount of from 2.5 to 30 mg of Active ingredient is present in the following components in amounts within the range that is similar to that prescribed for the first component.

Time specification release to release the active ingredient from each component can be varied by modifying the composition of each component, including modifying any excipients or any shell, which may be available. In particular, the release of active ingredient can be controlled by changing the composition and/or the number of shells on the particles with modified release, the EU is the shell for the modified release of each of these components may be the same or different. Similarly, when the modified release contribute by including a matrix material for modified release, the release of active ingredient can be controlled by selecting and quantity of the matrix material for the modified release. Shell for modified release may be present in each component in any amount that is sufficient to achieve the desired delay period for each specific component. Shell for modified release may be present in each component in any amount that is sufficient to achieve the desired lag-period between components.

The lag-period or deferral period for release of the active ingredient of each component can be varied by modifying the composition of each component, including modifying any excipients and shell which can be available. For example, the first component may be a component of the immediate-release formulation in which the active ingredient is released essentially immediately after injection. Alternatively, the first component may be, for example, the component immediately after a certain grace period. The second component may be, for example, a component with immediate delayed time release, as just described, or, alternatively, a component of the slow delayed time release, or component with a prolonged-release formulation in which the active ingredient is released in a controlled fashion over an extended period of time.

As should be clear to a person skilled in the technical field, the exact nature of the curve of the concentration in the blood plasma will depend on the impact of the combination of all of the described factors. In particular, the lag-time between the delivery (and thus, the beginning of the action) of active ingredient in each component can be controlled by varying the composition and the shell (if it exists) of each component. Thus, by varying the composition of each component (including the number and nature of active(s) ingredient(s) and variation of the lag-period, you can get multiple release profiles and blood plasma. Depending on the duration of the lag-period between the release of the active ingredient of each component and the nature of the release from each component (i.e. immediate release, prolast a clearly defined peaks (for example, when the lag-period long), or the pulses may be in some degree of overlapping (for example, when the lag-period is short).

In a preferred embodiment the composition is in the form of a set of particles with modified release of the present invention has a component with the immediate-release and at least one component with modified-release component and immediate-release includes the first set of particles containing the active ingredient, and the components with modified release include the second and additional aggregate particles containing the active ingredient. The second and additional components with modified release may contain membrane for controlled release. Additionally or alternatively, the second and additional components with modified release may contain a matrix material for modified release. In effect, the introduction of such compositions in the form of a set of particles with modified release, for example having a single component with modified release, results in a characteristic pulse levels activin profile in plasma, as component with the modified release causes the second peak profile in plasma. Embodiments of the present invention containing more than one component with modified release, cause additional peaks in the profile in plasma.

Such a profile in plasma caused by the introduction of the single unit dosage form is an advantage when it is desirable to deliver two or more than two) of the pulse of the active ingredient without the need of introducing two or more than two) units of the dosage form. In addition, in the case of some diseases to have such a bimodal profile in plasma is particularly useful. For example, a typical regimen for the treatment of methylphenidate consists of the introduction of two doses of the drug immediate-release given with an interval of four hours. Discovered that this kind of regimens medication is therapeutically effective and widely used. Profile in plasma caused by such a scheme introduction, illustrated by curve "Control" in the drawing. As mentioned earlier, the development of tolerance in a patient is an undesirable effect, which is sometimes associated with treatment with methylphenidate. Consider that the amount available is nutnosti the patient due to the fact, provided that the period of leaching of the active ingredient. System of drug delivery, which ensure the delivery of the active ingredient with zero order kinetics or pseudonoise order, do not contribute to this process of washing.

Any sheath material, which is desirable way modifies the release of the active ingredient, can be used. In particular, the materials of the shell, which is suitable for use in the practice of this invention include, but are not limited to, such polymeric materials of the shell, as phthalate cellulose acetate, trimoulet cellulose acetate, phthalate of hydroxypropylmethylcellulose, polyvinyl acetate phthalate, copolymers of ammoniumnitrate, such as those available commercially under the trademark Eudragit® RS and RL, copolymers of polyacrylic acid and polyacrylate and methacrylate copolymers such as those available under the trademark Eudragit® S and L, polyvinyltrimethylsilane, succinate acetate hydroxypropylmethylcellulose, shellac; hydrogels and materials, forming a gel, such as carboxyvinyl polymers, sodium alginate, sodium-carmellose, calcium-carmellose, carboxymethylated starch, polyvinyl alcohol, garyh the degree of cross-linkage is sufficiently low, to facilitate adsorption of water and expansion of the polymer matrix; hydroxypropylcellulose, hypromellose, polyvinylpyrrolidone, cross-linked starch, microcrystalline cellulose, chitin, aminoacyl-methacrylate copolymer (Eudragit® RS-PM, Rohm & Haas), pullulan, collagen, casein, agar, gum Arabic, sodium carboxymethyl cellulose, (swellable hydrophilic polymers) poly(hydroxyethylmethacrylate) (mol. massfrom 5000 to 5000000), polyvinylpyrrolidone (mol. Massfrom 10,000 to 360000), anionic and cationic hydrogels, polyvinyl alcohol having a low residual acetate, swellable mixture of agar and carboxymethyl cellulose, copolymers of maleic anhydride and styrene, ethylene, propylene or isobutylene, pectin (mol. massfrom 30000 to 300000), polysaccharides such as agar, gum Arabic, karaya, tragakant, algini and guar, polyacrylamides, polyethylene oxides Polyox® (mol. mass100,000 to 5000000), acrylate polymers AquaKeep®, diesters polyglucin, cross-linked polyvinyl alcohol and poly-N-vinyl-2-pyrrolidone, starch glycolate, sodium (e.g. Explotab®; Edward Mandell S. Ltd.); hydrophilic polymers, such as polysaccharides, METI the oz, hydroxyethyl cellulose, nitrocellulose, carboxymethyl cellulose, cellulose ethers, polyethylene oxides (e.g. Polyox®, Union Carbide), metilcellulose, metilgidroxiatilzelllozu, cellulose acetate, cellulose butyrate, propionate, cellulose, gelatin, collagen, starch, maltodextrin, pullulan, polyvinylpyrrolidone, polyvinyl alcohol, polyvinyl acetate, esters of glycerin and fatty acids, polyacrylamide, polyacrylic acid, copolymers of methacrylic acid or methacrylic acid (for example, Eudragit®, Rohm & Haas), other derivatives of acrylic acid, esters sorbitan, natural gums, lecithins, pectin, alginates, alginate ammonium, alginates, sodium, calcium, potassium, propylene glycol alginate, agar and resins, such as gum Arabic, karaya, from carob, tragakant, Irish moss, guar, xanthan gum, scleroglucan and their mixtures and combinations. As should be clear to the specialist, to the shell, you can add excipients such as plasticizers, lubricants, solvents and the like. Suitable plasticizers include, for example, acetylated monoglycerides, butylphenylmethyl, dibutylated, diethylphthalate, dimethylphthalate, utilityservices, glycerin, propilenglicole oil, triethylcitrate, polyhydric alcohols, glycerol, acetate esters, glycerol triacetate, acetyltributyl, dibenzylidene, DirectInput, butylacrylate, diisononylphthalate, butylacrylate, dioctyladipate, epoxydecane Tallat, triisostearate, diethylhexylphthalate, di-n-octylphthalate, di-ISO-octylphthalate, di-ISO-decylphthalate, di-n-undeciphered, di-n-tridecilateral, three 2-ethylhexylacrylate, di-2-ethylhexyladipate, di-2-ethylhexylamine, di-2-ethylhexyladipate, dibutylsebacate.

When a component with modified release contains a matrix material for modified release, you can apply any suitable matrix material for the modified release or appropriate combinations of matrix materials for modified release. Such materials are known to the person skilled in the art. The term "matrix material for the modified release" as used here, includes hydrophilic polymers, hydrophobic polymers and mixtures thereof, which are capable of modifying the release of the dispersed active ingredient in vitro or in vivo. Matrix materials for modified release, fittingly, the memories, the sodium carboxymethyl cellulose, hydroxyethylcellulose, such as hypromellose and hydroxypropylcellulose, polyethylene oxide, alkylaryl, such as methylcellulose and ethylcellulose, polyethylene glycol, polyvinylpyrrolidone, cellulose acetate, butyrate cellulose acetate, phthalate cellulose acetate, trimetallic cellulose acetate, polyvinyl acetate phthalate, polyalkylacrylate, polyvinyl acetate and mixtures thereof.

The composition is in the form of a set of particles with modified release of the present invention can be incorporated into any suitable dosage form, which facilitates the release of the active ingredient pulse. In a typical case, this dosage form may be a mixture of different populations of particles containing an active ingredient comprising components with the immediate-release and modified-release, with this mixture fill the appropriate capsules, such as hard or soft gelatin capsules. Alternatively, various individual aggregate particles containing the active ingredient, you can compress (possibly with additional excipients) in the mini-pill, which can later be filled capsules which is a multilayer tablet. In this case, the first component of the composition in the form of a set of particles with modified release can be compressed into one layer, and then add the second component as the second layer of the multilayer tablet. These aggregate particles containing an active ingredient that make up the composition according to this invention, can further be included in rapidly dissolving dosage forms such as an effervescent dosage form or a fast-dissolving dosage forms.

The composition according to the present invention contains at least two sets of particles containing an active ingredient having different dissolution profiles in vitro.

Preferably, the composition according to this invention and solid oral dosage forms containing the composition, in action release the active ingredient in such a way that essentially the entire active ingredient contained in the first component is released mainly to the release of active ingredient from the second component. When the first component, for example, contains a component HB, it is preferable that the release of active ingredient from the second component was deferred until such time until it is released essentially the be deferred, as described above, by using the shell for modified release and/or a matrix material for modified release.

When it is desirable to minimize the tolerance of the patient by offering regimens medication, which helps to wash away the first dose of the active ingredient from the system of the patient, more preferably, the release of active ingredient from the second component was delayed until, until you are released essentially all the active ingredient contained in the first component, and it was further delayed until at least a portion of the active ingredient released from the first component will not be removed from the system of the patient. In the preferred embodiment of the release of active ingredient from the second component of this composition in step essentially, if not completely, delayed for a period of at least about two hours after administration of this composition.

When the active ingredient is methylphenidate, the release of active ingredient from the second component of this composition in step essentially, if not completely, delayed for a period of at least about four hours, is otnosheniya are by weight, if not stated otherwise. The term "purified water" as it is used in all the examples, refers to water that has been purified by passing it through a water filtration system.

Example 1. The composition is in the form of a set of particles with modified release containing methylphenidate.

Composition in the form of a set of particles with modified release of the present invention containing the component with the immediate-release component and with modified release and contains methylphenidate as an active ingredient, obtained as follows.

(a) Component with the immediate-release

The solution of methylphenidate-Hcl (racemic mixture 50:50) receive, in accordance with any drug given in Table 1. Then a solution of methylphenidate applied to inhomogeneous grain to approximately 16.9% of the increased weight of the solids, for example, using the apparatus for coating in the fluidized bed Glatt GPCG3 (Glatt, Protech Ltd., Leicester, UK) with the formation of particles HB component with the immediate-release

(b) Component with modified release

Particles with a slow release containing methylphenidate, is obtained by applying pokrytie coating for modified release as described in detail in Table 2. Particles with immediate-release cover shell, varying levels up to about 30% weight gain using, for example, the apparatus of the fluidized bed.

(C) Testing dissolution

Independent of the pH of the coated components from (1) to (5) of Table 2 are tested in vitro in a USP apparatus Type 1 (100 rpm) in accordance with the following Protocol: the sample is placed in 0.01 n HCl (900 ml) at pH 2.0 and 37For all aspects of sampling.

Dependent on pH of the coated components from (6) to (8) of Table 2 are tested in vitro in a USP apparatus Type 1 (100 rpm) in accordance with a modified version of the method of the Pharmacopoeia of the United States for protection in the intestine (USP 23, 1995, p. 1795): the sample is placed for 2 hours in 0.01 n HCl and then transferred to phosphate buffer pH 6.8 for the remaining moments of sampling.

Components of HB were made using three different sizes of inhomogeneous grains having dimensions of diameters of 0.5-0.6; 0.6 to 0.71 and of 0.71-0.85 mm, respectively. It was found that the particles HB formed by coating on the heterogeneous grains with diameters of 0.5-0.6; 0.6 to 0.71 and of 0.71-0.85 mm, in the aquatic environment release 100% of the active ingredient within 20 minutes.

Given the output of the above Example 1(b), shown in tables 3(a) to 3(C). These data suggest that the characteristics of the release component with modified release can be varied by changing the composition and thickness of the coating.

(g) Encapsulating the particles with immediate and delayed release

Particles with immediate and delayed release obtained in the above Examples 1(a) and (b) were encapsulated in hard gelatin capsules of size 2 up to a total dose concentration of 20 mg using, for example, encapsulating machine Bosch GKF 4000S. Concentration of total dose of 20 mg of methylphenidate was prepared from 10 mg of the component with the immediate-release and 10 mg of the component with modified release.

Table 4 shows the dissolution profiles for the two compositions in the form of a set of particles with modified release, obtained using the solution coating for immediate release, are listed in Table 1 (2), and solutions for coating for modified release, are shown in Table 2 (7) and (8). These results show that approximately 50% of actinobacteria a component with a modified release was delayed by about four hours.

The dissolution profiles shown in Table 4, show that the composition containing components coated with pH-dependent membrane, release the active component, representing methylphenidate, a pulsed manner. The first pulse occurs within 1 hour, followed by a plateau region, where the release of additional quantities of the active ingredient suppressed. In turn, followed by a plateau region, a second pulse release of the active ingredient, as shown by the increase in the concentration of drugs, ranging from four hours and later.

Example 2. The composition is in the form of a set of particles with modified release containing methylphenidate.

Containing methylphenidate composition in the form of a set of particles with modified release of the present invention, have the immediate-release component and with modified release, which has a matrix material for the modified release are in accordance with the drugs shown in Table 5 (a) and (b).

(d) Release in vivo

In biological cross-examination on l is methylphenidate-HCl, in order to compare the bioavailability of methylphenidate-HCl in these compositions in comparison with ritalin (Ritalin®, Novartis; 10 mg, administered twice with an interval of 4 hours). Pharmacokinetic evaluation was based on levels of methylphenidate in plasma, measured by sampling blood at regular intervals of time up to 48 hours after injection. Blood samples were collected for screening before and after the study.

If we turn now to the drawing, the profiles in plasma, marked "A" (modified component contains particles HB, coated according to Table 2 (8) at the level of 30%) and B (modified component contains particles HB, coated according to Table 2 (7) at the level of 30%), correspond to the concentrations of methylphenidate in plasma observed in humans volunteers after oral administration of the compositions in the form of a set of particles with modified release obtained in accordance with Example 1. In both cases, the profiles in plasma qualitatively similar to the control, which is typical of the treatment is known in the prior art methods of treatment (indicated in the drawing as "Control") and which consists of two doses of Ritalin®, consistently given with an interval of 4 chatora obtained in accordance with the above Example 1, the first peak profile in plasma caused by the component with the immediate-release, similar in regard With themaxand the width of the peak with the peak caused by the first dose of Ritalin® in the control profile. Profile a shows that the characteristic period when the conventional introduction twice a day (a good example is a control profile) is simulated by means of the composition obtained according to this invention. Profile B also shows a significant drop in concentration in the blood plasma after the initial peak. Both compositions in the form of a set of particles with modified-release effect component with modified-release is to increase the concentration in plasma after four hours after injection, which results in the second peak level. This observed effect again simulates the control.

From the drawing it is clear that these compositions in the form of a set of particles with modified release, obtained according to the present invention mimic the typical treatment twice a day (control) in terms of profiles in plasma achieved with the introduction. This release methylphenidate in vivo from compositions according to this invention was on the preliminary study of 34 children with attention deficit, injected doses of the compositions with 20 mg of methylphenidate-Hcl according to the present invention. Simulation environment in the classroom was used to compare the drugs a and B (corresponding to the drugs a and B, described above) with placebo. During the 9 hours spent pharmacodynamic evaluation that assessed attention and behavior that was determined by the scale SCAMP and functional outcome, which was defined by the number of solved math problems and the number of correct answers. Each drug has demonstrated a statistical difference from placebo in all definitions of efficiency. Individual performance indicators demonstrated that drugs a and B were similar in relation to behavior. In relation to attention and functional outcome of children taking the drug And was more focused on your current job and between 4 and 6 hours was chosen mathematical problems and more quickly than children who took the drug B.

The present invention is not limited in the amount of the specific embodiments described herein. Various modifications of this invention in addition to those described herein will be obvious to a person skilled in the art from the description of the invention and F. the modified-release having a first component that includes a first set of particles containing the active ingredient and at least one additional component, and each component includes an additional set of particles containing the active ingredient and the active ingredient contained in the first and additional components, is the same or different, and at least one additional set of particles containing the active ingredient further comprises a sheath for a modified release or alternative or additional matrix material for modified release, so that the composition after oral delivery to a subject delivers the active ingredient or active ingredients pulsed manner.

2. The composition is in the form of a set of particles with modified release under item 1, where the composition comprises a first component and one optional component.

3. The composition is in the form of a set of particles with modified release under item 2, where the first component includes a component with the immediate-release and the additional component is a component with modified vysvobozhdennym release includes particles, having a wrapper for modified release.

5. The composition is in the form of a set of particles with modified release on p. 3, where component with modified release contains a matrix material for modified release.

6. The composition according to p. 3, where component with modified release contains dependent on the pH of the polymer membrane, which releases a pulse of the active ingredient from the component with modified release after a certain grace period.

7. The composition according to p. 6, which is dependent on the pH of the polymer shell contains methacrylate copolymers.

8. The composition according to p. 6, which is dependent on the pH of the polymeric shell comprises a mixture of methacrylate and ammoniumnitrate copolymers in a ratio sufficient to achieve a pulse of the active ingredient from the component with modified release after a certain grace period.

9. The composition according to p. 8, where the ratio of methacrylate and ammoniumnitrate copolymer is 1:1.

10. The composition is in the form of a set of particles with modified release under item 1, where the first set of particles containing the active ingredient, and at least one additional sovokupnosti particles with modified release under item 1, where the first set of particles containing the active ingredient, contains two or more than two active ingredient.

12. The composition is in the form of a set of particles with modified release under item 1, where the at least one additional set of particles containing the active ingredient, contains two or more than two active ingredient.

13. The composition is in the form of a set of particles with modified release under item 1, where the active ingredient comprises, essentially, one optically pure enantiomer or a racemic or other mixture of enantiomers.

14. The composition is in the form of a set of particles with modified release under item 1, where at least one of the first and additional components further comprises enhancer.

15. The composition is in the form of a set of particles with modified release under item 1, where the amount of active ingredient contained in the first and additional components, is the same or different.

16. The composition is in the form of a set of particles with modified release under item 15, where the amount of active ingredient contained in each component is in the range from about 0.1 mg - 1,

17. The composition is in the form of a set of particles with modificarea acceptable salt, its enantiomer or mixture of enantiomers, or a mixture thereof.

18. The composition is in the form of a set of particles with modified release under item 1, where the first and additional aggregate particles containing the active ingredient, have different dissolution profiles in vitro.

19. The composition is in the form of a set of particles with modified release under item 1, where the first component is a component with the immediate-release and at least one additional component is a component with modified release.

20. The composition is in the form of a set of particles with modified release under item 19, which action releases essentially all of the active ingredient from the first set of particles containing the active ingredient, prior to release of the active ingredient of additional aggregate particles containing the active ingredient.

21. The composition is in the form of a set of particles with modified release under item 1, where the release of the active ingredient in vivo in the subject simulates the release of the same active ingredient in vivo, injected in the form of two or more than two doses forms of the active ingredient with the immediate-release.

22. The composition in the form of mnote simulates the release of the same active ingredient in vivo, input in the form of two or more than two doses forms of the active ingredient with the immediate-release.

23. The composition is in the form of a set of particles with modified release on p. 20, where the average dissolution profile in vitro in aqueous media is such that 50-100% of the active ingredient contained in the first set of particles containing the active ingredient is released within four hours after administration of this composition and 30-100% of the active ingredient contained in additional aggregate particles containing the active ingredient are released between four and eight hours after the introduction of this composition.

24. The composition is in the form of a set of particles with modified release on p. 23, where the average dissolution profile in vitro in aqueous media is such that 80-100% of the active ingredient contained in the first set of particles containing the active ingredient is released within four hours after administration of the composition, and 60-100% of the active ingredient contained in additional aggregate particles containing the active ingredient are released between four and eight hours after the introduction of this composition.

25. The composition is in the form of a set of particles with m the e characterized by the occurrence of patient tolerance to at least one active ingredient, contained in this composition.

26. The composition is in the form of a set of particles with modified release under item 1 for use in the preparation of drugs for the treatment of attention deficit.

27. The composition is in the form of a set of particles with modified release on p. 17 for use in the preparation of drugs for the treatment of attention deficit.

28. Solid oral dosage form containing the composition in the form of a set of particles with modified release under item 1.

29. Solid oral dosage form according to p. 28 containing a mixture of the first and additional sets of particles containing the active ingredient, which filled hard gelatin or soft gelatin capsules.

30. Solid oral dosage form according to p. 28, where the first and additional components separately and independently compressed into mini-tablets and they filled in hard or soft gelatin capsules.

31. Solid oral dosage form according to p. 28, where the first component is pressed into the first layer of the multilayer tablet and at least one additional component is compressed in an additional layer of a multilayer tablet.

32. Solid oral dosage form according to p. 28, where the first and Topolnitsa form on p. 32, where fast dissolving dosage form is a dosage form in the form of a rapidly dissolving tablet.

34. The method of treatment of a condition that is characterized by the occurrence of patient tolerance to the active ingredient introduced in the treatment of this condition, which is administered a therapeutically effective amount of the composition in the form of a set of particles with modified release under item 1.

35. A method for the treatment of attention deficit, which is administered a therapeutically effective amount of the composition in the form of a set of particles with modified release under item 1.

36. A method for the treatment of attention deficit, which is administered a therapeutically effective amount of the composition in the form of a set of particles with modified release on p. 17.

 

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