Preparative form of hydrocodone controlled release

 

Described solid oral dosage form of hydrocodone controlled release (options). Dosage form includes effective for analgesia amount of hydrocodone or its pharmaceutically acceptable salt comprising from 0.5 to 1250 mg, and the agent for controlled release, sufficient to bring the dosage form in a condition suitable for administration twice a day to the patient. Dosage form provides a mean ratio12/Smaxaverage of from 0.55 to 0.85, and the specified dosage form provides a therapeutic effect for at least 12 hours. The invention provides improved efficiency and quality of pain management in patients experiencing moderate pain. 12 c. and 30 C.p. f-crystals, 3 ill., 24 table.

Due to the difficulty taking place in the pharmacological treatment of pain, in particular chronic pain, the ideal drugs are opioid analgesics, need to be instituted as a preparative forms with controlled release.

The goal of all preparative forms with controlled release is ensuring longer period pharmacolo is to testify. Such longer periods of response have many therapeutic benefits that are not achieved by using the appropriate short-acting preparations immediate-release. Thus, therapy can be continued without interrupting the sleep of the patient, which is especially important, for example, in the treatment of the patient to severe pain regulation (for example, a patient after surgery, the patient with a malignant tumour, and so on) or those patients who experience headache type migraine headaches upon awakening, as well as debilitated patients require sleep.

Despite the fact that a common treatment for fast-acting drugs accompanied by careful introduction of small intervals to maintain effective steady concentrations of drugs in plasma, there are peaks and dips in the level of active drug in the plasma because of the rapid absorption, systemic excretion of the compound and due to metabolic inactivation, thus causing problems with maintenance therapy of the patient. Another important advantage of drugs long-term action is to improve compliance with PAC and a method of obtaining compositions which provide controlled release of pharmacologically active substances contained in the compositions, after oral administration to humans and animals. Such compositions with slow release is used to delay the absorption of the medicinal product to achieve its particular quantity in the digestive tract. Such controlled release of the drug in the digestive tract supports further the desired concentration of the specified drug in the bloodstream for a longer time than what occurs with the introduction of conventional dosage forms quick release.

The known prior methods of preparation and use of compositions that provide controlled release of the active compounds of the media, mainly relates to the release of the active substance in a physiological fluid of the digestive tract. However, it is recognized that the mere presence of active substances in the fluids of the gastrointestinal tract does not in itself guarantee bioavailability.

For absorption of the active drug must be in solution. The time required for raspado substances, released from a standard dosage forms over time, based on testing conducted in standardized conditions. The physiological fluids of the gastrointestinal tract are environments to determine the time of dissolution. In the prior art there are many satisfactory test procedures to measure the time of dissolution of the pharmaceutical compositions, and these test procedures are described worldwide in the official guides.

Although there are many different factors that affect the time of dissolution of the drug substance from the carrier, the time of dissolution, for certain pharmacologically active substances to their specific composition is relatively constant and reproducible. To various factors that can affect the time of dissolution include the surface area of the drug substance, the wetted solvent, the pH of the solution, the solubility of a substance in a particular solvent environment and driving forces of the saturation concentration of the solute in the solvent environment. Thus, the concentration of the dissolution of the active drug substance is dynamically modified to its stable status is practical conditions, the saturation concentration of dissolved substances is filled from the reserve of the dosage form to maintain universal and constant concentration of dissolving in the solvent environment, that provides a stable suction.

Transport through tissue sites of absorption in the gastrointestinal tract is subject to the forces of osmotic equation of Donana (Donnan) on both sides of the membrane, since the direction of the driving force is the difference between the concentrations of the active substance on each side of the membrane, i.e., between the amount dissolved in the fluids of the gastrointestinal tract, and the amount present in the blood. Since the concentration in the blood is constantly changing due to the dissolution, circulatory changes, accumulation in tissues, metabolic transformation and systemic excretion, the flow of the active substance is sent from the gastrointestinal tract into the bloodstream.

To get dosage forms with controlled release is used in different ways. In this area known special coated pills, tablets and capsules, where a slow release of the active drug is due to selective destruction of the coating of the preparation or by blending with a special matrix for the impact on drug release. Known formulations of controlled release asperity after injection.

Specific examples of opioid preparative forms of controlled release, are reported in the patent literature include, for example, described in U.S. patent No. 4990341 and 4844909 (Goldie et al.), transferred to the assignee of the present invention and included in the description as a reference, and they describe the composition of hydromorphone, where the dissolution rate in vitro of the dosage form when measured ways “blades” (Paddle) or basket (Basket) according to USP at 100 rpm in 900 ml aqueous buffer (pH between 1.6 and about 7.2) at 37With is between 12.5 and 42.5% (by weight) hydromorphone released after 1 hour, between 25 and 55% (by weight) release after 2 hours, between 45 and 75% (by weight) released after 4 hours and between 55 and 85% (by weight) release after 6 hours, and the rate of release in vitro was independent of pH between 1.6 and 7.2 and was chosen so that the peak concentration of hydromorphone in plasma obtained in vivo, took place in the interval between 2 and 4 hours after administration of the dosage form. Using these formulations of hydromorphone was achieved at least 12 hours of pain relief.

Providing dosed drugs controlled release for other SOS is highly desirable. In addition, highly desirable to provide such drugs controlled release with pharmacokinetic properties that provide the most effective management of pain in patients who require pain treatment.

The INVENTION

The aim of the present invention is to substantially improve the efficiency and quality of pain management in patients experiencing moderate pain.

The aim of the present invention is to provide bioavailable formulations of hydrocodone, which significantly enhance the efficiency and quality of pain management in patients experiencing moderate pain.

Another objective of the present invention is to provide bioavailable formulations of hydrocodone controlled release, providing a substantial increase in the duration of action compared to preparative forms of hydrocodone immediate-release, but which provide early analgesia.

A further purpose of the invention is the provision of the input oral formulations of hydrocodone with controlled release formulation suitable for administration twice a day to the AI in the interval dosing provide a relatively smooth profile in plasma, meaning that the level of opioid plasma provides the ratio of C12/Cmaxfrom 0.55 to 0.85, and which provide effective anesthesia of the patient. In alternative embodiments, dosage form provides a ratio of C12/Cmax0, 65 to 0.75.

The above and other objectives reach thanks to the present invention, which in some embodiments relates to solid oral dosage forms with controlled release, including effective for analgesia amount of hydrocodone or its pharmaceutically acceptable salt and a sufficient amount of material for controlled release in order to make a dosage form suitable for administration twice a day, and the dosage form after a single injection to a patient or group of patients provides the time to reach peak concentration of hydrocodone in plasma in vivo, preferably in the range of from about 2 to 8 hours (Tmaxand after reaching the maximum concentration provides the ratio of C12/Cmaxfrom 0.55 to 0.85.

In some preferred embodiments, dosage form with controlled release provides release in vitro from about 18% to 42.5% on the under USP at 100 rpm in 700 ml of artificial gastric juice (SGF) for 55 min at 37With, and then switching to 900 ml of artificial intestinal juice (SIF) at 37C.

In some preferred embodiments, the dissolution rate in vitro of the dosage form of hydrocodone when measuring method “basket” (Basket) according to USP at 100 rpm in 900 ml aqueous buffer at a pH of 1.2 and 7.5 at 37With is from about 25 to 65% by weight hydrocodone or salt released after 2 hours, from about 45 to 85% by weight hydrocodone or salt released after 4 hours and more than about 60% by weight hydrocodone or salt released after 8 hours. Although the rate of release in vitro may be at the request of pH-independent or pH-dependent, in preferred embodiments of the invention the release of the hydrocodone is pH-independent.

Some preferred variations include the prescription forms for controlled release comprising a therapeutically effective amount of hydrocodone, where the dosage form provides a concentration of hydrocodone in the plasma is equal to at least 5 or 6 ng/ml, 12 hours after administration, and is the concentration of hydrocodone in the plasma is equal to at least about 8 ng/ml, approximately 2-8 casarme hydrocodone controlled release for administration twice a day, which provides Withmaxhydrocodone component is less than 50% of themaxwith the introduction of equivalent dose control formulation of hydrocodone immediate-release (e.g., Lortab®), and which provides effective analgesia during the 12-hour interval between doses.

Other preferred variants of the invention relates to an oral dosage form of hydrocodone controlled release for administration twice a day, where the dosage form provides a time to reach 80% Withmaxapproximately 90 to 150%, preferably from 90 to 110% of the time 80% Withmaxwith the introduction of equivalent dose control hydrocodonebuy formulation comparison with immediate-release (e.g., Lortab). Preferably the time to reach 80% Withmaxhydrocodone for dosage forms with controlled release of approximately from 0.5 to 1.5 hours, most preferably about 0.8 to 1.2 hours. In alternative embodiments, the time to reach 80% Withmaxhydrocodone for dosage forms with controlled release is from about 0.75 to 2 hours, most preferably from about 0.9 to 1.5 hours is on controlled release for administration twice a day, where the dosage form provides a time to reach 90% Withmaxapproximately from 150 to 400%, preferably from 150 to 250%, the time to reach 90% Cmaxwith the introduction of equivalent dose control hydrocodonebuy formulation comparison with immediate-release. Preferably the time to reach 90% Cmaxhydrocodone for dosage forms with controlled release of approximately 1.5 to 2.5 hours, most preferably about 1.8 to 2.2 hours. In alternative embodiments, the time to reach 90% Cmaxhydrocodone for dosage forms with controlled release of approximately 1.5 to 4 hours, most preferably from about 1.8 to 2.5 hours.

Other preferred variants of the invention relates to an oral dosage form of hydrocodone controlled release for administration twice a day, where the dosage form maintains a plasma concentration within 80% Cmaxfrom about 0.5 to 10 hours, preferably about 1 to 9 hours, or about 4 to 8 hours.

Other preferred variants of the invention relates to an oral dosage form of hydrocodone controlled release Elah 90% Cmaxfrom about 1 to 6.5 hours, preferably from about 2 to 5 hours or from about 2 to 6.5 hours.

Other preferred variants of the invention relates to an oral dosage form of hydrocodone controlled release introduction to two times daily, which provides the average rate of absorption in vivo from the introduction to Tmaxapproximately from 1.5 to 5 mg/hour, and delivers an average absorption rate in vivo from Tmaxuntil the end of the interval between doses, comprising less than about 0.5 mg/hour, based on oral administration of the dosage form, containing 15 mg of hydrocodone bitartrate. Preferably the dosage form provides an average absorption rate in vivo from the introduction to Tmaxapproximately 2 to 4 mg/hour, and delivers an average absorption rate in vivo from Tmaxuntil the end of the 12-hour interval between doses of approximately from 0.08 to 0.4 mg/hour, based on oral administration of the dosage form, containing 15 mg of hydrocodone bitartrate.

Other preferred variants of the invention relates to an oral dosage form of hydrocodone controlled release for administration twice a day to the high injection dosage forms, which is from about 55 to 85% of the speed of elimination (eliminatia) during the same period of time.

The above variants of the invention, as well as other options, preferably provide the time up to Tmax3-4 times greater than Tmaxequivalent dose reference hydrocodonewapa drug immediate-release. Preferably Tmaxpreparative forms with prolonged release is in the range of from about 2 to 8 hours, from 3 to 7 hours, or 4 to 6 hours after oral administration.

The present invention also relates to a preparative forms of hydrocodone, which providemaxhydrocodone component of less than about 50%, preferably less than 40% from smaxthat provides an equivalent dose of the reference product with immediate-release.

For example, unexpectedly found that when received medication hydrocodone with delivery system, as described in U.S. patent No. 4861598 and 4970075,maxhydrocodone, which were provided by the delivery system, expressed as a percentage Withmaxreference product with the immediate-release was significantly lower than the same value calculated for the drug oxetine form of oxycodone and hydrocodone controlled release showed similar parameters of dissolution in vitro.

When the formulations of the present invention is obtained using the delivery systems described in U.S. patent No. 4861598 and 4970075,maxdelivery system, expressed as a percentage Withmaxreference product with immediate-release formulation is less than about 50% and less than about 40% in the preferred embodiments, while oxycodone is characterized by a calculated value, constituting more than 50%.

The term “hydrocodone” is defined for purposes of the invention as comprising a free base hydrocodone, as well as pharmaceutically acceptable salts and complexes of hydrocodone.

The term “the way of the blade (Paddle) and baskets (Basket) per USP” represents the way of the blade (Paddle) and baskets (Basket), as described, for example, in the US Pharmacopoeia XXII (1990), included in the description by reference.

The term “pH-dependent” for the purposes of the present invention is defined as having characteristics (e.g., dissolution), which vary depending on the pH of the environment.

The term “pH independent” for the purposes of the present invention is defined as having characteristics (e.g., dissolution), in which the pH of the environment is not significantly affected.

The term “byodo the example, hydrocodone) is drawn from a standard dosage forms.

The term “controlled release” is defined for purposes of the present invention as the release of drugs (eg, hydrocodone) with such speed that the concentration in the blood (e.g., plasma) are maintained within therapeutic range, but below toxic concentrations, over a period of time approximately equal to 12 hours or more.

The term “Cmax” means the maximum concentration in plasma, which is achieved during the interval between the doses.

The term “Tmax” mean time to reach maximum plasma concentration (Cmax).

The term T1/2(abs) means the time required to transfer into the plasma half absorbed dose of opioid.

The term “steady state” means that the plasma concentration of this drug achieved and maintained consistent doses of drug at or above the minimum effective therapeutic concentration below the minimum toxic plasma concentrations of this drug. For opioid analgesics minimum effective therapeutic concentration partially is well understood, the measurement of pain is highly subjective, and among patients there may be large individual differences.

The terms “maintenance therapy” and “chronic treatment” are defined for purposes of the present invention as a drug therapy that is assigned to the patient after the patient was subjected to titration of opioid analgesics to a certain higher steady state.

The term “minimum effective analgesic concentration or “MEAC” in relation to the concentrations of opioids, such as hydrocodone, it is very difficult to quantify. However, in General this means the minimum effective analgesic concentration of hydrocodone in the plasma at concentrations below which analgesia is provided. While there is an indirect relationship between, for example, concentrations of hydrocodone in plasma and analgesia, higher and prolonged concentration of hydrocodone in plasma in General is associated with better pain relief. Between the time of the peak concentration of hydrocodone in the plasma and the time of peak effect of the medicinal product have a time lag or hysteresis. This holds true for the treatment of opioid analgesics in General.

The term ‾ means remains in the body. This calculated value, which is a function of absorption, distribution and excretion depends in part on the dosage form containing the active ingredient.

For the purposes of the invention, except the following cases, the term “patient” means that the description (or claim) refers to the pharmacokinetic parameters of an individual patient or subject.

The term “patient” means that the description (or claim) refers to the mean pharmacokinetic parameters of at least two patients or subjects.

The term “breakthrough pain” (breakthrough pain) refers to pain experienced by the patient, despite the fact that the patient was administered effective in the General sense of the amount of solid dosage forms according to the invention with a long release, containing hydromorphone.

The term “deliverance” (rescue) refers to the dose of the analgesic, which is administered to a patient experiencing breakthrough pain.

The term “effective pain management” means an objective assessment, which gives the doctor the response of a patient suffering pain against the side effects) on analgesic treatment, as well as a subjective assessment therapeuticestablishment depending on many factors, including individual variability of patients.

The term “control hydrocodonebuy preparative form with immediate release” for the purposes of the present invention represents an equivalent amount of hydrocodone from Lortab®, commercially available from USB Pharma, Inc., or pharmaceutical product, which provides an immediate release of the hydrocodone or salt.

For the purposes of the invention described formulations of controlled release and control formulations of immediate-release correspond to each other in terms of dose. Pharmacokinetic parameters such preparative forms (e.g., AUC and Cmax) grow linearly from one dose to another. Therefore, the pharmacokinetic parameters of a specific dose can be derived from the settings of another dose of the same formulation.

For the purposes of the invention, if nothing else is stated, described the pharmacokinetic parameters based on the single dose formulation of hydrocodone an individual patient. Pharmacokinetic parameters based on the study group of patients will be marked as “medium” data.

The term “first introduction” means single, etc>Oral solid dosage forms with controlled release of the present invention can contain surprisingly little opioid. It is possible that oral solid dosage forms with controlled release of the present invention can have a significantly lower dose compared with conventional products with immediate-release without distinction on the effectiveness of analgesia. At comparable daily dosages with the use of oral solid dosage forms with controlled release of the present invention is to obtain greater efficiency compared to conventional products with immediate-release.

BRIEF DESCRIPTION of FIGURES

The attached figures illustrate variants of the invention and are not meant to restrict the scope of the invention covered by the claims.

Figure 1 is a graphical representation of the average concentration of hydrocodone in the plasma of example 1, example 2, example 3 and an equivalent dose of hydrocodone immediate-release.

Figure 2 is a graphical representation of the average plasma concentrations of example 1, example 2 and example 3 against different samples orfina controlled release obtained according to the procedures of example 5.

Figure 3 is a graphical representation of % share of hydrocodone that is absorbed over a period of time for example 1, example 2, example 3, and an equivalent dose of hydrocodone immediate-release.

DETAILED DESCRIPTION

The above variants of the invention can be provided with a wide variety of preparative forms of controlled release, known to specialists in this field. For example, suitable dosage forms with controlled release described in patimah U.S. No. 4861598 and 4970075 included in the description by reference.

In some embodiments of the present invention an effective amount of opioid in the form of immediate-release included in the preparative form. Form of opioid immediate-release is included in an amount that is effective to reduce the time to reach the maximum concentration of the opioid in the blood (e.g., plasma), somaxreduced, for example, until the time of from about 2 to 5 hours or from about 2 to 4 hours. Found that by incorporating an effective amount of opioid immediate-release in the standard dose significantly reduced considers the slow release can cover the substrates of the present invention. For example, where a prolonged release of the opioid from the preparative form is a consequence of the presence of the coating for the controlled release layer for immediate release may be applied over the coating for controlled release. On the other hand, the layer for immediate release may cover the surface of the substrate, in which the opioid is included in the matrix for controlled release. Where many substrates for long-term release, including effective standard dose of opioid (e.g., system multimechanistic, including pellets, spheres, beads and the like), part hard gelatin capsule, part of the dose of opioid immediate-release can fit in the composition of the gelatin capsule via inclusion in the capsule sufficient opioid immediate-release in the form of powder or granules. Alternative gelatin capsule itself may be coated with a layer of opioid immediate-release. The specialist in this area there are other, alternative methods include a part of the opioid with immediate release as part of the standard dose. Such alternatives are considered to be covered by the supplied formula that therapeutic concentrations in General are achieved essentially without significantly increasing the intensity and/or degree related side effects, such as nausea, vomiting or drowsiness, which are often associated with high concentrations of opioids in the blood. Also it is obvious to assume that use of these dosage forms leads to reducing the risk of development of drug dependence.

The ACTIVE AGENT

Oral solid dosage forms with controlled release of the present invention preferably include from about 0.5 to 1250 mg of hydrocodone or equivalent amount of its pharmaceutically acceptable salts. In the preferred inventions dosage form can include about 5 to 60 mg, for example 15 mg. Suitable pharmaceutically acceptable salts of hydrocodone includes hydrocodone bitartrate, of hydrocodone bitartrate hydrate, hydrocodone hydrochloride, hydrocodone p-toluensulfonate, hydrocodone phosphate, hydrocodone thiosemicarbazone, hydrocodone sulfate, hydrocodone triptorelin, hydrocodone hemipentahydrate, hydrocodone pentafluoropropionate, hydrocodone p-nitrophenylhydrazone, hydrocodone on-methyloxime, hydrocodone semicarbazone, hydrocodone hydrobromide, hydrocodone the mukat, the hydrocodone oleate, hydrocodone dibasic phosphate, hydrocodone monobasic phosphate, inorganic salt GI is hydrocodone bis(methylcarbamate), hydrocodone bis(pentafluoropropionate), hydrocodone bis(pyridinecarboxylic), hydrocodone bis(triptorelin), hydrocodone hydrochloride and hydrocodone sulfate pentahydrate. Preferably hydrocodone presented as the bitartrate salt.

Dosage forms of the present invention may also include one or more additional drugs that may act synergistically with hydrocodonebuy analgesics according to the present invention or do not act thus. Examples of such additional drugs include non-steroidal anti-inflammatory drugs, including ibuprofen, diclofenac, naproxen, benoxaprofen, flurbiprofen, fenoprofen, fluvirin, Ketoprofen, indoprofen, pirprofen, carprofen, oxaprozin, pranoprofen, miroprofen, tioxaprofen, suprofen, alminoprofen, tiaprofenic acid, fluprofen, bulokovu acid, indomethacin, sulindac, tolmetin, zomepirac, tiopinac, zidometacin, acemetacin, fentiazac, clinatec, exping, mefenamico acid, meclofenamic acid, flufenamic acid, niflumova acid, tolfenamic acid, diflunisal, flufenisal, piroxicam, sudoxicam or isoxicam and the like. Such non-steroidal protivo the P-28238), meloxicam, 6-methoxy-2-naphthyloxy acid (6-MNA), Vioxx (MK-966), nabumetone (proletarienne substance for 6-MNA), nimesulide, NS-398, SC-5766, SC-58215, T-614, such as amantadine (1-aminoguanidine), memantine (3,5-dimethylaminoethanol), their mixtures and their pharmaceutically acceptable salts.

Other additional drugs include non-toxic NMDA receptor antagonists, such as dextrorphan, dextromethorphan,

3-(1-naphthalenyl)-5-(phosphonomethyl)-L-phenylalanine;

3-(1-naphthalenyl)-5-(phosphonomethyl)-DL-phenylalanine;

1-(3, 5dimethylphenyl)naphthalen and 2-(3, 5dimethylphenyl)naftalin;

2SR,4RS-4-(((1H-tetrazol-5-yl)methyl)oxy)piperidine-2-carboxylic acid;

2SR,4RS-4 -(((( 1H-tetrazol-5-yl)methyl)oxy)methyl)piperidine-2-carboxylic acid;

E and Z 2SR-4-(O-(1H-tetrazol-5-yl)methyl)ketoxime)piperidine-2-carboxylic acid;

2SR,4RS-4-((1H-tetrazol-5-yl)thio)piperidine-2-carboxylic acid;

2SR,4RS-4-((1H-tetrazol-5-yl)thio)piperidine-2-carboxylic acid;

2SR,4RS-4-(5-mercapto-1H-tetrazol-1-yl)piperidine-2-carboxylic acid;

2SR,4RS-4-(5-mercapto-2H-tetrazol-2-yl)piperidine-2-carboxylic acid;

2SR,4RS-4-(5-mercapto-1H-tetrazol-1-yl)piperidine-2-carboxylic acid;

2SR,4RS-4-(5-mercapto-2H-tetrazol-2-yl)piperidine-2-carboxylic acid;

2SR,4RS-4-(((1H-tetrazol-5 the acid or

2SR,4RS-4-((5-mercapto-2H-tetrazol-2-yl)methyl)piperidine-2-carboxylic acid,

their mixtures and their pharmaceutically acceptable salts.

Other suitable additional drugs which may be included in the dosage forms of the present invention include acetaminophen, aspirin, neuroactive steroids (as those described in U. S. Serial No. 09/026520 dated February 20, 1998, included in the description by reference) and other non-opioids.

For example, if the second (non -) drug included in the dosage form, such medicinal products may be included in the form of a controlled release or in the form of immediate-release.The additional drug may be included in the matrix for controlled release with opioid, be included in the coating composition for controlled release, be included as a separate layer for controlled release or layer for immediate release, or may be included in the form of powder, granules, etc. in the composition of the gelatin capsules with the substrates of the present invention.

In some preferred embodiments of the present invention an effective amount hydroco the planned release, subject to introduction. Preparative form of hydrocodone immediate-release is included in an amount that is effective to reduce the time taken To reach amaxhydrocodone in the blood (e.g., plasma). In such embodiments, an effective amount of hydrocodone in the form of immediate-release can cover the substrates of the present invention. For example, where long-term release of hydrocodone from the preparative form is a consequence of the presence of the coating for the controlled release layer for immediate release may be applied over the coating for controlled release. On the other hand, the layer for immediate release may be applied to the surface of the substrate, in which the opioid is included in the matrix for controlled release. Where many substrates for long-term release, including effective standard dose of hydrocodone (for example, a system of many particles, including balls, spheres, granules and the like), part hard gelatin capsule, part of the dose of opioid for immediate release may fit in the composition of the gelatin capsule via inclusion in the capsule sufficient quantity which itself may be covered with a layer of hydrocodone immediate-release. The specialist in this area there are other, alternative methods include a part hydromorphone immediate-release part of the standard dose. Such alternatives are considered to be covered by the attached claims. Found that by incorporating an effective amount of hydrocodone immediate-release in a single dose significantly reduced the relative strengths of the pain felt by the patient.

DOSAGE FORMS

Dosage forms with controlled release may not necessarily include material for controlled release, which is part of the matrix together with hydrocodone or applied in the form of a coating for a long release on the substrate, comprising the medicinal substance (the term “substrate” encompasses beads, granules, spheroids, tablets core tablets and so on). The agent for controlled release can be hydrophobic or hydrophilic. Oral dosage forms according to the invention can be provided, for example, in the form of granules, spheroids, beads (hereinafter collectively referred to as “multitrajectory”; multiparticulates). The number of multimicrocomputer, effective to obtain the desired coverdoll dosage forms, for example, compressed into a tablet. On the other hand, the oral dosage form of the present invention can be obtained in the form of a core tablet surrounded by a coating for controlled release, or in the form of a tablet comprising a matrix of medicinal substance, the substance for controlled release and optional other required from the point of view of the pharmaceutical ingredients (e.g., solvents, binders, dyes, lubricants, and so on).

PREPARATIVE FORM WITH a MATRIX FOR CONTROLLED RELEASE

In some preferred embodiments of the present invention formulations of controlled release is obtained by applying the matrix (for example, tablets matrix), which includes material for controlled release as described above. Dosage form comprising a matrix, which provides a dissolution rate in vitro opioid lying in a preferred range, and it releases the drug at a pH-dependent or pH-independent type. Substances suitable for inclusion in the matrix for controlled release, depending on the method used to obtain the matrix. Oral dosage form may content is osvobojdenie.

A non-limiting list of suitable substances for controlled release, which can be included in the matrix for controlled release according to the invention include hydrophilic and/or hydrophobic substances, such as rubber, ethers, cellulose, acrylic resins, protein substances of origin, waxes, shellac, and oils such as gidrirovannoe castor oil, gidrirovannoe vegetable oil. However, the present invention can be any pharmaceutically acceptable hydrophobic or hydrophilic substance capable of providing controlled release of the opioid. Preferred polymers for controlled release include alkylaryl, such as ethylcellulose, polymers and copolymers of acrylic and methacrylic acids, and ethers of cellulose, especially hydroxyethylcellulose (especially hypromellose) and karboksimetsiltsellyulozy. Preferred polymers and copolymers of acrylic and methacrylic acid include methyl methacrylate, copolymers of methyl methacrylate, ethoxyethylacetate, cyanoethylation, a copolymer of aminoalkylsilane, poly(acrylic acid), poly(methacrylic acid), a copolymer of methacrylic CI, poly(anhydride methacrylic acid) and copolymers of glycidylmethacrylate. In some preferred embodiments, the matrices according to the invention apply a mixture of any of the above substances for controlled release.

The matrix can also include a binder. In such embodiments, the binder facilitates controlled release of hydrocodone from the matrix for controlled release.

Preferred hydrophobic binders are insoluble in water, with more or less pronounced tendency to hydrophilicity and/or hydrophobicity. Preferably hydrophobic binders that can be used according to the invention are characterized by a melting point of from about 30 to 200C, preferably from about 45 to 90C. When a hydrophobic substance is a hydrocarbon, the hydrocarbon is preferably characterized by a melting point of from 25 to 90S. Of long-chain hydrocarbon (C8-C50products are preferred fatty (aliphatic) alcohols. Oral dosage form may contain more than 80% (by weight) of at least one who keeps up to 80% (by weight) of at least one polyalkyleneglycol. Specifically, the hydrophobic binder may include natural or synthetic waxes, fatty alcohols (such as lauric, ministerului, stearyl, cetyl or preferably cetosteatil alcohol), fatty acids, without limitation including esters of fatty acids, glycerides of fatty acids (mono-, di - and triglycerides), hydrogenated fats, hydrocarbons, normal waxes, stearic acid, stearyl alcohol and hydrophobic and hydrophilic compounds having a hydrocarbon skeleton. Suitable waxes include, for example, beeswax, glycophos, castor wax and Carnauba wax. For the purposes of this invention, a wax-like substance is defined as any substance, which at room temperature is normally solid and has a melting point from about 30 to 100C.

Preferred hydrophobic binders that can be used in the present invention include digestible long chain (C8-C50preferably12-C40) substituted or unsubstituted hydrocarbons, such as fatty acids, fatty alcohols, glyceriae esters of fatty acids, mineral and vegetable oils,soumise melting point between 25 and 90S. Of long-chain hydrocarbon binders are preferred in some embodiments are fatty (aliphatic) alcohols. The oral form may contain up to 80% (by weight) of at least one digestible long chain hydrocarbon.

In some preferred invention in matrix composition includes a combination of two or more hydrophobic binders. If you include additional binder, it is preferably selected from natural and synthetic waxes, fatty acids, fatty alcohols and mixtures thereof. Examples include beeswax, Carnauba wax, stearic acid and stearyl alcohol. This list should not be considered exclusive.

One particular suitable matrix for controlled release includes at least one water-soluble hydroalkylation at least one C12-C36- preferably With14-C22-aliphatic alcohol, and optionally at least one polyalkyleneglycol. Hydroxyethylcellulose preferably represents hydroxyethylcellulose with alkyl from C1to C6such as hydroxypropylcellulose, hypromellose and especially the Hydra is public form will be determined, among other things, an exact rate of release of the opioid. The aliphatic alcohol may be, for example, lauralover alcohol, militiajim alcohol or stearyl alcohol. However, in especially preferred embodiments of the present oral dosage form of at least one aliphatic alcohol is cetyl alcohol or cetosteatil alcohol. The amount of at least one aliphatic alcohol in the present oral dosage form will be determined, as described above, an exact rate of release of the opioid. It will also depend on whether there is or is not in the oral dosage form of at least one polyalkyleneglycol. In the absence of at least one polyalkyleneglycol oral dosage form preferably contains from 20 to 50% (by weight.) aliphatic alcohol. When polyalkyleneglycol present in the oral dosage form, the joint weight aliphatic alcohol and polyalkyleneglycol preferably ranges from 20 to 50% (by weight.) of the total dosage.

In one preferred implementation, the ratio of, for example, at least one hydraulically or acrylic resin, and it is aware of the opioid from the preparative form. Preferred is a ratio of at least one hydraulically and at least one aliphatic alcohol/polyalkyleneglycol lying between 1:2 and 1:4, especially preferred is a ratio between 1:3 and 1:4.

Polyalkyleneglycol may, for example, be polypropylenglycol or polyethylene glycol, which is preferred. It is preferable average molecular weight of polyethylene glycol, lying between 1000 and 15000, especially between 1500 and 12000.

Other suitable matrix for controlled release includes alkylsalicylate (especially ethylcellulose)12-C36-aliphatic alcohol and not necessarily polyalkyleneglycol.

In addition to the above ingredients matrix for controlled release may also contain suitable quantities of other substances, such as solvents, lubricants, binders, tools, promotes granulation, dyes, flavorings and moving substances which are conventional in the pharmaceutical field.

In order to facilitate the preparation of solid oral dosage forms with controlled release of truly sobriety forms with controlled release of the present invention, including the introduction of opioids or their salts in a matrix for controlled release.

Introduction to matrix can be performed, for example, by

(a) forming granules comprising at least one hydrophobic or hydrophilic substance, as described above (for example, water-soluble hydroxyethylcellulose), together with hydrocodone;

(b) mixing the granules containing at least one hydrophobic and/or hydrophilic substance, at least one C12-C36aliphatic alcohol and

(c) optionally compressing and shaping the granules.

The granules may be formed by any of the methods well known to experts in the field of pharmaceutical preparations. For example, one of the preferred ways granules may be formed by wet granulating water hydraulically/opioid. In the most preferred embodiment of this method the amount of water added during the stage of wet granulation, preferably 1.5 to 5 times more, especially 1.75 and 3.5 times, the dry weight of the opioid.

The matrices of the present invention can also be obtained by the process of granulation of the melt. In this case, the opioid in a small Fort and and then the mixture is crushed, for example, by mechanical processing in intensively mixing device for the formation of particles (granules, spheres). After that, particles, granules, spheres) can pass the sieve to obtain particles of the desired size. The binder preferably is in the form of particles having a melting point greater than about 40C. Suitable binders include, for example, gidrirovannoe castor oil, gidrirovannoe vegetable oil, other hydrogenated fats, fatty alcohols, esters of fatty acids, glycerides of fatty acids, and the like.

The matrices for controlled release can be obtained, for example, by means of melt granulation or melt extrusion. In General, methods of pelletizing the melt include melting solid under normal conditions, a hydrophobic binder, such as wax, and the introduction of powdered drugs. To obtain a dosage form with controlled release may be necessary to introduce hydrophobic substances for controlled release, such as ethyl cellulose or water-insoluble acrylic polymer, in a molten vosloorus ways granulating the melt, described, for example, in U.S. patent No. 4861598 transferred to the assignee of the present invention and included in the description by reference.

Additional hydrophobic binder may include one or more water-insoluble wax-like thermoplastic substances, possibly mixed with one or more wax-like thermoplastic substances, less hydrophobic than the wax-like thermoplastic substances. To achieve controlled release of individual wax-like substance in the composition should not essentially disintegrate and dissolve in the gastrointestinal fluids during the initial phases of the release. Applicable water-insoluble wax-like binder may have a solubility less than about 1:5000 (wt./wt.).

In addition to the above ingredients matrix for controlled release may also contain suitable quantities of other materials such as solvents, lubricants, binders, tools, promotes granulation, dyes, corrigentov and moving substances which are conventional in the pharmaceutical field, in quantities about which ensure the desired effect of the desired pharmaceutical form.

Specific examples of pharmaceutically acceptable carriers and excipients that may be used for making oral dosage forms are described in Handbook of Pharmaceutical Excipients, American Pharmaceutical Association (1986), included here as a reference.

Obtain a suitable matrices melt extrusion of the present invention can, for example, include the stage of mixing opioid analgesic together with substance for controlled release and preferably with a binder to obtain a homogeneous mixture. Then the homogeneous mixture is heated to a temperature sufficient to at least soften the mixture to a degree sufficient for its extrusion. Then, the resulting homogeneous mixture is extruded using, for example, an extruder with two screws, with the formation of filaments. Product extrusion is preferably cooled and cut on multitrajectory by any means known in this field. The filaments are cooled and cut on multitrajectory. Then multitrajectory divided into separate doses. The product of the extrusion process preferably has a diameter of from about 0.1 to 5 mm and provides controlled release of therapeutically active agent in use the Ohm melt extrusion according to the present invention includes a direct measurement in an extruder a hydrophobic substances for controlled release, therapeutically active funds, and an optional binder; heating the homogenous mixture; extruding the homogeneous mixture formation thus strands; cooling the strands containing the homogeneous mixture; cutting the strands into particles of a size from about 0.1 to 12 mm, and the separation of these particles into individual doses. This aspect of the invention is relatively long production procedure.

Plasticizers, such as those described above may be included in the matrices obtained by extrusion of the melt. The plasticizer is preferably included in an amount of about from 0.1 to 30% by weight of the matrix. Other pharmaceutical excipients such as talc, mono - or polysaccharides, dyes, corrigentov, lubricants and the like may be included in the matrices for controlled release according to the present invention. Include the number depends on the desired characteristics to be achieved.

The diameter of the hole of the extruder or output port can be configured to change the thread thickness of the extrusion. Furthermore, the output portion of the extruder should not be circular; it may be oblong, rectangular, etc. System cartoon is from the opening of the extruder. For the purposes of the present invention the terms “multimechanistic(s) melt extrusion” and “system(s) multimechanistic melt extrusion” and “particles melt extrusion” will be treated to many units, preferably within a similar size and/or shape and containing one or more active agents and one or more excipients, preferably including a hydrophobic substance for controlled release. Preferably multitrajectory melt extrusion have a length in the range from about 0.1 to 12 mm in length and have a diameter of from about 0.1 to 5 mm, In addition, it should be understood that multitrajectory melt extrusion can be any geometrical shape within the size, such as, for example, bulbs, seeds, pellets, etc. Alternative products extrusion can simply be cut to the desired length, and divided into separate doses therapeutically active substances without the need of phase stereopathy.

In one preferred implementation receive oral dosage forms that include an effective amount of multimicrocomputer obtained by the method of extrusion of the melt inside the capsule. For example, many Multimineral for controlled release by ingestion and contact with gastric juice.

In another preferred implementation of an appropriate number of multimicrocomputer product extrusion compressed into an oral tablet using conventional equipment for tabletting using standard methods. Methods and compositions for making tablets (compressed and molded), capsules (hard and soft gelatin capsules and pills are also described in Remington''s Pharmaceutical Sciences (Arthur Osol, editor), 1553-1593 (1980), included in the description by reference.

In another preferred embodiment of the product of extrusion can be formed tablets, as described in U.S. patent No. 4957681 (Klimesch et al.), described in more detail above and included in the description by reference.

Optional matrix system multimechanistic controlled release can be covered with a coating for controlled release, such as coatings for controlled release described above, or they may further be coated with a gelatin capsule. Such coatings preferably include a sufficient amount of a hydrophobic and/or hydrophilic substances for controlled release of obtaining level of weight gain from about 2 to 25%, while coverage can vary greatly etica and the desired rate of release.

Dosage forms of the present invention may further include combinations of multimicrocomputer obtained by the method of melt extrusion containing one or more opioid analgesics. Moreover, the dosage form may also include some amount of therapeutically active funds immediate release for rapid therapeutic action. Therapeutically active agent for immediate release may include, for example, in the form of separate globules in a gelatin capsule, or may, for example, to cover the surface of the granules or multimechanistic melt extrusion. Individual dosage forms of the present invention may also contain, for example, a combination of pellets for controlled release matrix and multimechanistic to achieve the desired effect.

Formulations of controlled release according to the present invention preferably slowly release therapeutically active agent when administered and the influence of gastric juice, and then intestinal juice. Profile for controlled release compositions of melt extrusion according to the invention may vary, for example, by variation of the amount prophetic is Allaudin matrix, hydrophobic material, by the inclusion of additional ingredients or excipients, by altering the method of manufacture, etc.

In other embodiments of the invention formulations of melt extrusion is obtained without inclusion of therapeutically active funds, which is added after the product extrusion. Such preparative forms typically contain a therapeutically active agent, mixed with matrix product extrusion, and then the mixture is subject to pelletizing to obtain formulations of slow release. Such formulation can be useful, for example, in cases where therapeutically active agent included in the preparative form, sensitive to the temperature required to soften the hydrophobic substance and/or inhibiting substances.

Typical production system to obtain by melt extrusion, suitable for use in the present invention include a suitable motor of the extruder, with variable speed and constancy control rotation, controls the start-stop” and ammeter. In addition, the system of products includes console temperature control, the cooling device and temperature indicators along the length of the extruder. the uh protivovirusnaya interconnected augers, inside the cylinder or drum having at its end a hole or a matrix. Downloadable materials are introduced through the inlet funnel and moved through the drum with screws, and force pushed through a die to form strands, which are then transferred by type long conveyor belt in order to let them cool off and send them to the shredder or other suitable device for converting yarn extrusion system multimechanistic. The shredder may consist of rollers, a fixed knife, rotary cutter, and the like. Appropriate tools and systems available from distributors such as C. W. Brabender Instruments, Inc., South Hackensack, New Jersey. Other suitable devices known to specialists in this field.

A further aspect of the invention relates to the above-described receiving multimechanistic way melt extrusion, controlling the amount of air included in the product extrusion. When controlling the amount of air included in the product extrusion, it was unexpectedly found that the rate of release of therapeutically active means, for example, from multimechanistic product extrusion can vary considerably. In the.

Thus, in a further aspect of the invention, the product melt extrusion receive method, which essentially eliminates the air during the extrusion phase of the process. This can be done, for example, using an extruder Lastica (Leistritz) with a vacuum attachment. Unexpectedly, it was found that multitrajectory, obtained according to the invention using an extruder Lastrina in vacuum, are the product of melt extrusion with other physical characteristics. In particular, the product of the extrusion process, is essentially non-porous, which can be seen when zooming in, for example, using a scanning electron microscope, which provides EMC (electronic micrograms scan). Contrary to conventional wisdom, it was found that such essentially non-porous formulation ensure the speedy release of therapeutically active remedies in respect of the same composition obtained without vacuum. EMC multimechanistic obtained using the extruder in a vacuum, are very homogeneous, and multitrajectory tend to be more durable than multitrajectory obtained without vacuum. There is observation, strazii as multimechanistic, which is more pH dependent than the corresponding preparada form received without vacuum.

METHODS of OBTAINING MATRIX GRANULES

Dosage forms with controlled release of the present invention can also be obtained in the form of matrix balls. Matrix balls include stereobase tool and hydrocodone.

Hydrocodone is preferably from about 0.1 to 99% by weight of the matrix ball. Preferably hydrocodon included in the amount of from about 0.1 to 50% by weight of the matrix ball.

Sporoobrazuyushchie tools that can be used to obtain a matrix of balls of the present invention include any known in the field stereobase tool. Preferred are derivatives of cellulose and particularly preferred is microcrystalline cellulose. Suitable microcrystalline cellulose is a substance, which is sold as Avicel PH 101 (trade mark of FMC Corporation). Stereobase means preferably included in an amount of about from 1 to 99% by weight of the matrix ball.

In addition to the active ingredient and sporoobrazujushchimi tool spirometry low viscosity, well-known specialists in the field of pharmaceutics. However, preferred are water-soluble nizkokatsestvennii alkylsilanes, such as hydroxypropylcellulose.

In addition to the opioid analgesic and sporoobrazujushchimi means of preparative forms of matrix balls of the present invention may include a substance for controlled release, such as those described here above. Preferred substances for controlled release for inclusion in the formulations of matrix balls include polymers or copolymers of acrylic and methacrylic acids and ethylcellulose. If it preparative form the substance for controlled release is included in an amount of about 1 to 80% by weight of the mass matrix of the ball. The agent for controlled release preferably included in the composition of matrix balls in amounts effective to provide for a controlled release opioid analgesic of the ball.

In the preparative form of matrix balls can be included tools to help pharmaceutical processing, such as binders, solvents and the like. The number of these to provide the preparative form.

In matrix balls can be covered with a coating for controlled release comprising a substance for controlled release, such as those described above. Coating for controlled release is used in an amount constituting a gain in weight from about 5 to 30%. The number of coatings for controlled release, to be applied varies depending on various factors such as the composition of the matrix of balls and a chemical and/or physical properties of opioid analgesic (i.e. hydrocodone).

Matrix granules are mainly produced by granulating sferoobraznogo tool together with an opioid analgesic, for example, by wet granulation. The product is then subjected to granulation stereopathy with obtaining a matrix of balls. Then the matrix beads optional cover coating for controlled release means, such as those described above.

Another way to obtain the matrix of the granules is carried out, for example, by (a) forming granules comprising at least one hydroxyethylcellulose and opioid or salt of the opioid; (b) mixing the granules containing hydroxyethylcellulose, with at mariepascale granules formed by wet granulation hydroxyethylcellulose/opioid water. In a particularly preferred implementation of this method, the amount of water added during the stage of wet granulation, preferably 1.5 to 5 times more, especially 1.75 and 3.5 times, the dry weight of the opioid.

In other alternative embodiments, the means for stereopathy together with the active ingredient may be stereopathy with the formation of spheroids. Preferred is microcrystalline cellulose. Suitable microcrystalline cellulose is a substance, which is sold as Avicel PH 101 (trade mark of FMC Corporation). In such embodiments, in addition to the active ingredient and sporoobrazujushchimi tool, the spheroids may also contain a binding agent. Suitable binders such as water-soluble polymers with low viscosity, well known to experts in the field of pharmaceutics. However, preferred are water-soluble nizkokatsestvennii alkylsilanes, such as hydroxypropylcellulose. Additionally (or alternatively), the spheroids may also contain water-insoluble polymer, especially an acrylic polymer, acrylic copolymer, such as copolymer of methacrylic acid-acrylate, or ethylcellulose. the, is such an approach as (a) a wax, one or a mixture of fatty alcohol, or (b) shellac or Zein.

PREPARATIVE FORM BALLS CONTROLLED RELEASE

In one particularly preferred implementation of the oral dosage form comprises an effective amount of spheroids for controlled release contained within a gelatin capsule.

In another preferred implementation of the present invention, the dosage form with controlled release includes the active ingredient, coated by a coating for controlled release comprising a substance for controlled release. The term “spheroid” is known in the pharmaceutical field, and means, for example, a spherical granule having a diameter of between 0.1 and 2.5 mm, especially between 0.5 and 2 mm

The spheroids are preferably covered with a film material for controlled release, which provides release of the opioid (or salt) with a controlled rate in an aqueous environment. Film coating is selected so that, other things being constant properties, is achieved the rate of release in vitro specified above (e.g., at least about 12.5% release within 1 hour). Formulations of controlled release for elegant, ability to hold the pigments and other coating additives, non-toxic, inert and non-sticky.

COVER

Dosage forms of the present invention can be optionally covered with one or more coatings, suitable for the regulation of the release and protection of the drug. In one embodiment, there are coatings that provide or pH-dependent or pH-independent release, for example, under the influence of gastrointestinal fluid. When required a pH-independent coating, coated for optimal release regardless of changes in pH in the surrounding liquid, i.e. in the LCD tract. Other preferred variants include pH-dependent coating that releases the drug in the desired areas of the gastro-intestinal (LCD) tract, such as stomach or small intestine, so that the profile suction, is able to provide the patient for at least about twelve hours and preferably up to twenty-four hours of analgesia. It is also possible to make the preparative form, which releases part of the dose in the desired area of the LCD tract, for example in the stomach, and the remainder of the dose release in another area of the LCD tract, for example in thin cichecki the t repeated actions, when unprotected, the drug is applied over the inner cover and is released in the stomach, while the remainder, being protected internal coating is released in the gastrointestinal tract below. the pH-dependent coating that can be used in the present invention include a substance for controlled release, such as, for example, shellac, phthalate cellulose acetate (CAP), polyvinyl acetate phthalate (PVAP), the phthalate of hydroxypropylmethylcellulose and ester copolymers of acrylic acid, Zein and the like.

In another preferred implementation of the present invention relates to a stabilized solid controlled dosage forms comprising an opioid coated with a hydrophobic substance to a controlled release, selected from (i) alkylaryl; (ii) an acrylic polymer; or (iii) mixtures thereof. The coating may be applied in the form of organic or aqueous solution or dispersion.

In some preferred embodiments, the coating for controlled release is made from aqueous dispersions of hydrophobic substances for controlled release. Coated substrate that contains an opioid(s) (e.g., tablet core or inert harakterizuetsya stable dissolution. Point the end of curing can be determined by comparison of the profile (curve) dissolution of the dosage form immediately after curing profile (curve) dissolution of the dosage form after exposure to accelerated conditions of storage, for example, at least one month at 40 ° C and a relative humidity of 75%. These compositions are described in detail in U.S. patent No. 5273760 and 5286493 transferred to the assignee of the present invention and included in the description by reference. Other examples of preparative forms with controlled release and coatings that can be used in the present invention include U.S. patent No. 5324351, 5356467 and 5472712, owned by the assignee of the present invention, included in the description by reference in its entirety.

In preferred embodiments, coatings for controlled release include a plasticizer, such as those described here below.

In some embodiments, there is a need to cover the substrate, comprising an opioid analgesic, a sufficient amount of aqueous dispersions, for example, alkylaryl or acrylic polymer, to obtain the level of weight gain from about 2 to 50% greater or lesser extent dependent on the physical properties of therapeutically active funds and the required speed of release, included in the aqueous dispersion of the plasticizer and, for example, how to turn them on.

The POLYMERS ALKYLARYL

Cellulose materials and polymers, including alkylaryl represent substances for controlled release, are well-suited for coating substrates, such as beads, tablets and so on, according to the invention. For example, one preferred alkylaromatic polymers is ethylcellulose, although the person skilled in the art will understand that other polymers cellulose and/or alkylaryl can be used, alone or in any combination, as all or part of a hydrophobic coating according to the invention.

One commercially-available aqueous dispersion of ethyl cellulose is Aquacoat® (FMC Corp., Philadelphia, Pennsylvania, USA). Aquacoat® is produced by dissolving ethyl cellulose in water-immiscible organic solvent and subsequent emulsification in water in the presence of a surfactant and a stabilizer. After homogenization with obtaining submicron droplets of the organic solvent is evaporated in vacuum to form pseudolites. During the production phase in pseudolarix not add softener. Thus, before the by ATOR.

Another aqueous dispersion of ethyl cellulose is commercially available as Surelease® (use, Inc., West point, Pennsylvania, USA). The product is obtained by introducing a plasticizer into the dispersion during the manufacturing process. Hot melt polymer, plasticizer (dibutylsebacate) and stabilizer (oleic acid) are obtained in the form of a homogeneous mixture, which is then diluted with an alkaline solution to obtain a water dispersion, which can directly be applied to substrates.

ACRYLIC POLYMERS

In other preferred embodiments of the present invention, the agent for controlled release comprising a coating for controlled release is a pharmaceutically acceptable acrylic polymer, including as non-limiting examples of copolymers of acrylic acid and methacrylic acid, copolymers of methyl methacrylate, ethoxyethylacetate, cyanoethylation, poly(acrylic acid), poly(methacrylic acid), a copolymer of methacrylic acid and alkylamine, polymethylmethacrylate, polymethacrylate, a copolymer of polymethyl methacrylate, polyacrylamide, copolymer of aminoalkylsilane, poly(anhydride methacrylic acid) and copolymers of glycidylether of aminosalicylate. Copolymers of aminomethylated well known in this field and are described in NF XVII as fully polymerized copolymers of esters of acrylic and methacrylic acid with a low content of Quaternary amine groups.

To obtain the desired dissolution profile may be necessary to include two or more copolymers aminosalicylate with different physical properties, such as different molar ratio of Quaternary amine groups and a neutral (meth)acrylic esters.

Some type polymers of esters of methacrylic acid can be used to obtain a pH-dependent coatings, applicable according to the present invention. For example, there is a family of copolymers synthesized from diethylaminoethylmethacrylate and other neutral methacrylic esters, also known as methacrylic acid or polymeric methacrylates, commercially available as EudragitTech, Inc. There are several different types of Eudragit. For example, Eudragit E is an example of a methacrylic acid copolymer which swells and dissolves in the acidic environment. Eudragit L is a copolymer meremere at pH<6.5 and is soluble at about pH>7. Eudragit RL and Eudragit RS swell in water, and the amount of water absorbed by these polymers depends on the pH, however, the dosage form coated with Eudragit RL and RS are pH-independent.

In some preferred embodiments, the acrylic coating comprises a mixture of two varnishes based on acrylic resins, commercially available from Rohm Pharma under the trade names Eudragit RL30D and Eudragit RS30D, respectively. Eudragit RL30D and Eudragit RS30D are copolymers of acrylic and methacrylic esters with a low content of Quaternary amino groups, and the molar ratio of amine groups and the remaining neutral (meth)acrylic esters is 1:20 in Eudragit RL30D and 1:40 in Eudragit RS30D. The average molecular weight equal to approximately 150,000. Code RL (high permeability) and RS (low permeability) belong to the permeability properties of these funds. A mixture of Eudragit® RL/RS insoluble in water and digestive juices.

Dispersion of Eudragit® RL/RS according to the present invention can be mixed together in any desired ratio to obtain ultimately formulations of controlled release, characterized by the desired dissolution profile. The required composition of controlled release can be perceived by the® RS. The person skilled in the art will certainly understand that they may also use other acrylic polymers, such as, for example, Eudragit® L.

PLASTICIZERS

In embodiments of the present invention, where the coating comprises an aqueous dispersion of hydrophobic substances for controlled release, the inclusion of an effective amount of plasticizer in the aqueous dispersion will further improve the physical properties of the coating for controlled release. Because, for example, ethylcellulose characterized by a relatively high transition temperature in the glassy state and does not form flexible films under normal coating, it is preferable to include a plasticizer in ethylcellulose coatings containing coatings for controlled release, prior to their use as a covering material. Typically, the amount of plasticizer included in a coating solution, based on the concentration of the foaming agent, for example, more often from about 1 to 50% by weight of the weight of foaming agent. However, to correctly determine the concentration of plasticizer is possible only after careful experimentation with a specific coating solution and method of application.

Use utilizacin, diethylphthalate, triethylcitrate, tributyltin and triacetin, although it is possible that can be applied to other water-insoluble plasticizers (such as acetylated monoglycerides, esters phthalate, castor oil, and so on). Especially preferred plasticizer for aqueous dispersions of ethyl cellulose of the present invention is triethylcitrate.

Examples of suitable plasticizers for the acrylic polymers of the present invention include as non-limiting examples of esters of citric acid such as methylcitrate NF XVI, tributyltin, dibutyl phthalate, and possibly 1,2-propylene glycol. Other plasticizers which have been suitable for enhancing the elasticity of the films formed acrylic films such as lacquer solutions of Eudragit® RL/RS include polyethylene glycols, propylene glycol, diethylphthalate, castor oil, and triacetin. Especially preferred plasticizer for aqueous dispersions of ethyl cellulose of the present invention is triethylcitrate.

It was further discovered that the addition to the coating for controlled release of small quantities of talc reduces the tendency of the water dispersion of the adhesion during processing, and talc Dagda aqueous dispersion of hydrophobic substances used for coating of substrates, for example, an inert pharmaceutical granules, such as balls, nu pariel 18/20, many obtained stable solid beads for controlled release can then be placed in a gelatin capsule in an amount sufficient to provide effective dose controlled release by ingestion and contact with the surrounding fluid, such as gastric acid in the quality of the environment dissolution.

Stabilized compositions of beads for controlled release according to the present invention slowly release opioid analgesic, for example, the ingestion and exposure to gastric juices and then intestinal juices. Profile for controlled release compositions according to the invention may vary, for example, by variation of the amount of the coating aqueous dispersion of hydrophobic substances for controlled release, by changing the way in which the plasticizer is added to aqueous dispersions of hydrophobic substances for controlled release, by variation of the amount of plasticizer relative to the number of hydrophobic substances for controlled release by the inclusion of additional ingredients or excipients, pucker, by increasing or decreasing the thickness of the coating for controlled release.

Substrates coated with a therapeutically active agent, receive, for example, by dissolving therapeutically active funds in the water and subsequent spraying of the solution on the substrate, for example on the balls nu pariel 18/20, using insert Worcester (Wuster insert). Optional additional ingredients are also added prior to coating the beads in order to facilitate the binding of opioid with balls and/or to color the solution, etc., for Example, a product that includes hypromellose, etc. with a dye (e.g., Opadry®, commercially available from use, Inc.) or without it, can be added to the solution and mixed with a solution (e.g., within approximately 1 hour) before applying it against the substrate. The obtained substrate with the coating may optionally be coated on top of the barrier means to separate therapeutically active funds from hydrophobic coatings for controlled release.

An example of a suitable barrier means is a means that includes hypromellose. However, you may apply any foaming agent, investitute.

Then the substrates can be covered with a hydrophobic substance for controlled release. Aqueous dispersion of hydrophobic substances for controlled release, moreover, preferably includes an effective amount of plasticizer, such as triethylcitrate. Can be used pre-obtained water dispersion of ethyl cellulose, such as Aquacoat® and Shurelease®. When using Shurelease® there is no need to separately add a plasticizer. An alternative can be applied to aqueous dispersions of acrylic polymers, such as Euragit®.

Covering the solutions of the present invention preferably contain, in addition to the foaming agent, plasticizer and solvent (i.e. water), dye to provide an elegant appearance and the ability to distinguish the product. The dye may be added to the solution of therapeutically active means instead of or in addition to adding it to the aqueous dispersion of hydrophobic substances. For example, the dye may be added to Aquacoat® by the application based on alcohol or propylene glycol dye dispersions, milled aluminum coloring lacquers and oxide, such as titanium dioxide, with the addition of the dye to the solution is water-soluble is quacoat®. An alternative may use any reasonable method of dyeing compositions according to the present invention. Suitable ingredients for coloring composition when using a water dispersion of acrylic polymer include titanium dioxide and color pigments, such as pigments of iron oxides. The inclusion of pigments may, however, increase the inhibiting effect of the coating.

Plasticized aqueous dispersion of hydrophobic substances for controlled release can be applied to a substrate, comprising a therapeutic agent, by spraying using any suitable spraying equipment, known in the field. In the preferred method, the fluidized bed system of Wurster (Wurster fluidized-bed system), in which a jet of air emitted from the bottom, pseudogiant the core material and has a drying effect during spraying acrylic polymer coating. Taking into account the physical characteristics of therapeutically active funds, method of use, plasticizer, etc. are preferably used amount of the aqueous dispersion of hydrophobic substances, sufficient to obtain pre-installed for controlled the spending of aqueous solutions, for example gastric juice. After coating a hydrophobic substance to a controlled release beads optionally be further coated with the foaming agent, such as Opadry®. If the coating takes place in order to essentially reduce the agglomeration of beads.

The release of therapeutically active means of preparative forms with controlled release of the present invention may, additionally, be exposed to, i.e., be brought to the desired speed, by adding one or more means, modulating the release, or by providing one or more openings in the floor. The ratio of hydrophobic substances for controlled release and water-soluble substances is determined, among other factors, the desired rate of release and solubility characteristics of the selected substances.

Means, modulating the release, which act as pore-formers can be organic or inorganic, and include substances that can be dissolved, extracted or vydeliajutsia of the coating in the environment of use. The pore-formers can include one or more hydrophilic Vessey may also include means, contributing to erosion, such as starch or resin.

Coatings for controlled release according to the present invention can also include substances that are applicable to obtain a thin microporous layer in the environment of use, such as polycarbonates comprised of linear polyesters of carbonic acid in which carbonate groups recur in the polymer chain.

Agent modulating the release, may also include semi-permeable polymer. In some preferred embodiments, the agent modulating the release, selected from hydroxypropylmethylcellulose, lactose, metal stearates, and mixtures of any of the foregoing.

Coatings for controlled release according to the present invention may also include means output, including at least one passageway, orifice, or the like. The passage can be formed by such methods described in U.S. patent No. 3845770; 3916889; 4063064 and 4088864, which are all included in the description by reference. The passageway can have any shape, either round or triangular, square, elliptical, irregular, etc.

Another way to get balls controlled release, suitable for around 24 hours wedenesday in the description by reference in its entirety, contains guidance for the preparation of 24-hour formulations of morphine, obtained by means of stratifying powder, attracting funds from the treatment, consisting essentially of fine particles of lactose hydrate. Balls of powder layering is produced by spraying the aqueous binding solution onto inert beads to create a sticky surface and subsequent spray on sticky balls of powder, representing a homogeneous mixture of morphine sulfate and tiny particles of lactose hydrate. Then the balls are dried and cover with a hydrophobic substance, such as those described above, to obtain the desired release of the drug when exposed to the final composition of the surrounding fluid. A suitable number of balls controlled release then, for example, encapsulate to obtain the final dosage form, which provides an effective concentration of morphine in plasma within 12 hours.

A DETAILED description of the PREFERRED OPTIONS

The following examples illustrate various aspects of the present invention. They in no way imply an interpretation limiting the invention.

Example 1

Tablets �.gif">

Tablets were obtained by the following procedure.

1. Slow-wave dispersion: mix Eudragit RS30D and triacetin using mixer instantaneous mixing.

2. Melt stearyl alcohol.

3. Spray slow down the release of the variance on hydrocodone bitartrate, spray dried lactose and povidone using a granulator, fluidized bed.

4. Dry the party on the baking sheet from stainless steel for 15 minutes, or until constant weight.

5. Make a batch of molten stearyl alcohol, using a Hobart mixer (Hobart).

6. Dry waxed granular mass on the pan stainless steel for 30 minutes, or until a temperature of mass, equal to or less than 35C.

7. Grind the cooled granular mass through a CoMil.

8. Process the granulated mass as a lubricant talc and magnesium stearate using a Hobart mixer (Hobart).

9. Pressed granulated mixture into tablets using a press for tableting.

Then tablets were tested for dissolution using the following procedure.

1. Device: method 1 according to USP (basket), 100 rpm

2. Wednesday: 700 ml IH (SGF) for 55 min, and then 900 ml of IR is cromatografia. The dissolution parameters are given below in table II.

Then defined Cmaxand Tmaxfor example 1 and for the control standard immediate-release in the bioavailability study comparing the effect on healthy people 15 mg of hydrocodone, introduced in the form of formulations of immediate-release (Lortab 7.5 mg2), and the above composition with KB (controlled release), which is shown below in table III.

Example 2

Tablets, sustained-release hydrocodone got the recipe given below in table IV, following the procedure of example 1.

Then determine the parameters of the dissolution, using the procedure of example 1. The results are shown below in table V.

Example 3

Capsule delayed release of hydrocodone get prescription listed below in table VI.

Capsules receive the following procedure.

1. Mix milled stearyl alcohol, Eudragit RLPO, hydrocodone bitartrate and Eudragit RSPO by using a Hobart mixer (Hobart).

2. Granularit �"https://img.russianpatents.com/chr/215.gif">1 mm), conveyor, laser micrometer (lasermike) and mill under the following conditions:

The feed rate of powder 40 g/min, the speed of the screw 185 rpm, vacuum 980 mbar.

The conveyor corresponding to the diameter of the product extrusion, equal to 1 mm

Shredder - providing cutting particles 1 mm in length.

3. Sift the particles through the sieve No. 16 and No. 20. Collect the material that passed through the sieve No. 16 and stranded on a sieve No. 20.

4. Fill particles, empty gelatin capsules No. 2. Range: NLT 114 mg and NMT 126 mg.

The dissolution parameters were then determined using the procedure of example 1. The results are shown below in table VII.

Example 4

Tablets, sustained-release oxycodone was obtained according to the recipe given below in table VIII.

Tablets will receive the following procedure.

1. Granulation: spray the dispersion of Eudragit/triacetin on the oxycodone HCl, spray dried lactose and povidone using a granulator with a movable bottom.

2. Grinding: select granular mass and passed through a mill.

3. Waxing: melt stearyl alcohol and add in ground granulirovannye mass through the mill.

5. Grease: handle granular mass as a lubricant talc and magnesium stearate using a mixer.

6. Pressing: press granulated mixture into tablets using a press tabletting.

7. Floor tape: put the water film coating on tablets.

Then the tablets are tested for dissolution using the following procedure.

1. Device: method 2 according to USP (blade), 150 rpm

2. Wednesday: 700 ml IH (SGF) for the first hour, then gave 900 ml of phosphate buffer to pH 7.5.

3. Time sampling: 1, 2, 4, 8, 12, 18 and 24 hours.

4. Analysis: high performance liquid chromatography. The dissolution parameters are shown below in table IX.

Then define Cmaxand Tmaxfor example 4, and for the control standard immediate-release in the investigation of bioavailability, which is shown below in table X.

Example 5

Tablets, sustained-release morphine was obtained according to the recipe given below in table XI.

Tablets were obtained by the following procedure.

1. Granulation: add water to morphine sulfate, dried by spraying. receivina: select granular mass and pass through a sieve.

3. Waxing: melt cetosteatil alcohol and add in ground granulated mass using a mixer. Allowed to cool.

4. Screening: select granular mass and pass through a sieve.

5. Grease: handle granular mass as a lubricant talc and magnesium stearate using a mixer.

6. Pressing: press granulated mixture into tablets using a press tabletting.

7. The coating film: handle pills aqueous film coating.

Then the tablets are tested for dissolution using the following procedure.

1. Device: method 1 according to USP (cart), 50 rpm

2. Medium: 900 ml of pure water 37C.

3. Time of sampling: 1, 2, 3, 4, and 6 hours.

4. Analysis: UV detection, 285 nm and 305 nm, mode 2 points using a 5-cm cell.

The dissolution parameters are shown below in table XII.

Then define Cmaxand Tmaxfor example 5 and control standard immediate-release in the investigation of bioavailability, which is shown below in table XIII.

what Anno was detected, even though the dissolution of tablets with controlled-release hydrocodone-Hcl as in example 1 was very similar to the dissolution of tablets with controlled release oxycodone according to example 4 and tablets with controlled-release morphine in example 5, the ratio of CmaxKB to that of HB for the composition of hydrocodone is 38%, whereas the tablets of oxycodone and morphine tablets correspond to values above 50%. The comparison results are given in table XIV below.

Example 7

Conducted a pharmacokinetic comparison of the actions of a single dose formulation of hydrocodone immediate-release formulation of example 1, example 2, example 3 and the two tablets of hydrocodone bitartrate (7.5 mg/acetaminophen (500 mg) of immediate-release (example HB) in healthy volunteers, on an empty stomach, with four treatment with open-label. Plasma concentrations corresponding to the compositions shown in tables XV-XVIII below.

Example 8

Tablets with delayed you the

Tablets were obtained by the following procedure.

1. Grinding: miss flakes stearyl alcohol through the mill.

2. Mixing: mix hydrocodone bitartrate, secondary acidic calcium phosphate, glycerinated and microcrystalline cellulose in a suitable mixer.

3. Extrusion: gradually load the mixed material into an extruder with two screws at an elevated temperature to soften and product education extrusion.

4. Cooling: provide product extrusion to cool down the pipeline.

5. Grinding: miss cooled extrudate through the mill with obtaining a granular mass with a suitable particle size.

6. Mixing: mix ground product extrusion with stearate.

7. Pressing: mix the resulting granular mass with the use of a press to tablets.

8. Coverage: get solution covering film by dispersing Opadry in purified water and applying it to the core tablets.

Then tablets were tested for dissolution using the following procedure.

1. Device: method 2 according to USP (basket), 100 rpm

2. Wednesday: 700 ml IH (SGF without enzymes) for 55 minutes, then gave 900 ml fo the Naya chromatography. The dissolution parameters are given in table XXI.

Example 9

Pharmacokinetic study of 3 ways, representing a comparison of the actions of a single dose tablets controlled release 15 mg of hydrocodone (example 8) after eating and fasting and 15 mg of hydrocodone immediate-release (27.5 mg, tablet), were performed for two doses Q6H in healthy volunteers, on an empty stomach.

Then defined Withmaxand Tmaxfor example 8 and control standard immediate-release in the investigation of bioavailability, which is shown below in tables XXII and XXIII.

Claims

1. Solid oral dosage form with controlled release formulation comprising from 0.5 to 1250 mg of hydrocodone or its pharmaceutically acceptable salt and a substance for controlled release to bring the specified dosage form in a condition suitable for administration twice a day patient (man), and specified dosage form after the first injection, the patient provides the relationship With12/Smaxconstituting about, the specified de hydrocodone dispersed in a matrix containing a specified substance for controlled release.

3. Dosage form under item 2, where this matrix is in the form of multimicrocomputer.

4. Dosage form under item 3, where these multitrajectory compressed into a tablet.

5. Dosage form under item 3, where these multitrajectory placed in a pharmaceutically acceptable capsule.

6. Dosage form under item 1, which provides a relationship With12/Smaxaverage of from 0.65 to 0.75.

7. Dosage form under item 1, which provides an in vitro release from the dosage form, is equal to one hour from about 18% to 42.5% by weight hydrocodone or salt, in the measurement method of the basket (Basket) at USP at 100 rpm in 700 ml of artificial gastric juice (SGF) for 55 min at 37With, and then switching to 900 ml of artificial intestinal juice (SIF) at 37C.

8. Dosage form under item 6, which provides an in vitro release from the dosage form, comprising over one hour from about 18% to 42.5% by weight hydrocodone or salt, in the measurement method of the basket (Basket) at USP at 100 rpm in 700 ml of artificial VC is echnolo juice (SIF) at 37C.

9. Dosage form under item 1, which provides an in vitro dissolution rate of the dosage form of hydrocodone, in the measurement method of the basket (Basket) at USP at 100 rpm in 900 ml aqueous buffer with a pH of 1.2 at 37With approximately 25 to 65% by weight hydrocodone or salt released after 2 hours, from about 45 to 85% by weight hydrocodone or salt released after 4 hours and more than about 60% by weight hydrocodone or salt released after 8 hours

10. Dosage form under item 1, which provides an in vitro dissolution rate of the dosage form of hydrocodone, in the measurement method of the basket (Basket) at USP at 100 rpm in 900 ml aqueous buffer, pH 7.5, at 37With approximately 25 to 65% by weight hydrocodone or salt released after 2 hours, from about 45 to 85% by weight hydrocodone or salt released after 4 hours and more than about 60% by weight hydrocodone or salt released after 8 hours

11. Dosage form under item 1, which provides Tmaxhydrocodone in the specified patient, comprising from about 2 to 8 h after oral administration of the dosage form.

12. Dosage form under item 1, which is the checksum of the dosage form.

13. Dosage form under item 1, which provides Tmaxhydrocodone in the specified patient, approximately 4 to 6 h after oral administration of the dosage form.

14. Dosage form under item 1, which is the concentration of hydrocodone in the plasma is equal to at least 8 ng/ml within about 2 to 8 h after injection, and provides the concentration of hydrocodone in the plasma is equal to at least 6 ng/ml, approximately 12 h after injection, based on oral administration of the dosage form, containing 15 mg of hydrocodone bitartrate.

15. Dosage form under item 14, which provides a concentration of hydrocodone in the plasma is equal to at least 8 ng/ml after approximately 3 to 7 h after injection.

16. Dosage form under item 1, which provides Withmaxhydrocodone, which is less than 50% of themaxequivalent dose control formulation of hydrocodone immediate-release.

17. Dosage form under item 1, which provides Withmaxhydrocodone, which is less than 40% from smaxequivalent dose control formulation of hydrocodone immediate-release.

18. Dosage form under item 1, where drug I achieve 80% of medianmaxequivalent dose control formulation of hydrocodone immediate-release.

19. Dosage form under item 1, which provides the time to reach 80% of medianmaxapproximately from 0.5 to 1.5 hours

20. Dosage form under item 1, where the dosage form provides a time to reach 90% of the averagemaxthat is approximately from 150 to 250 percent of the time to reach 90% of the averagemaxequivalent dose control formulation of hydrocodone immediate-release.

21. Dosage form under item 1, which provides the time to reach 90% of the averagemaxapproximately 1.5-2.5 hours

22. Dosage form under item 1, which provides the time to reach 90% of the averagemaxapproximately from 1.8 to 2.2 hours

23. Dosage form under item 1, which supports the plasma concentration in the range of 80% Withmaxapproximately during the period from 1 to 9 hours during the 12-hour interval between doses.

24. Dosage form under item 1, which supports the plasma concentration in the range of 80% Withmaxapproximately during the period from 4 to 8 hours during the 12-hour interval between doses.

25. Dosage form under item 1, which is spot interval between the doses.

26. Dosage form under item 1, which supports the plasma concentration in the range of 90% Tomaxfrom about 2 to 5 hours during the 12-hour interval between doses.

27. Dosage form under item 1, which provides Tmaxat the time, 3-4 times later than Tmaxprovided the equivalent dose control formulation of hydrocodone immediate-release.

28. Dosage form under item 1, which provides the average rate of absorption in vivo from inception tomaxapproximately from 1.5 to 5 mg/h and delivers an average absorption rate from Tmaxuntil the end of the interval between doses, comprising less than about 0.5 mg/h, based on oral administration of the dosage form, containing 15 mg of hydrocodone bitartrate.

29. Dosage form on p. 28, which provides the average rate of absorption in vivo from inception tomaxapproximately 2 to 4 mg/hour,

30. Dosage form on p. 28, which provides the average rate of absorption in vivo from Tmaxuntil the end of the 12-hour interval between doses of approximately from 0.08 to 0.4 mg/HR

31. Solid oral dosage form with controlled, vysvobojdenie release to bring the specified dosage forms in the condition, suitable for injection twice per day to a patient (human), and specified dosage form after the first injection, the patient provides the rate of absorption during the time period from Tmaxto about 12 hours after oral administration of the dosage form, which comprises from about 55 to 85% of the elimination rate during the same time period, and the specified dosage form provides a therapeutic effect for at least approximately 12 hours

32. Solid oral dosage form with controlled release formulation comprising from 0.5 to 1250 mg of hydrocodone or its pharmaceutically acceptable salt with a substance for controlled release to bring the specified dosage form in a condition suitable for administration twice a day patient (man), and specified dosage form after the first injection the group of patients provides Tmaxhydrocodone in vivo, approximately from 2 to 8 h, and provides a relationship With12/Smaxaverage of from 0.55 to 0.85, and the specified dosage form provides a therapeutic effect for at least 12 hours

33. Solid oral dosage form with kontroliruemost for controlled release to bring the specified dosage forms in the condition, suitable for injection twice per day to a patient (human), and specified dosage form after the first injection provides Withmaxhydrocodone constituting less than 50% of themaxequivalent dose control formulation of hydrocodone immediate-release, and specified dosage form provides a therapeutic effect for at least 12 hours

34. Solid oral dosage form with controlled release formulation comprising from 0.5 to 1250 mg of hydrocodone or its pharmaceutically acceptable salt and a substance for controlled release to bring the specified dosage form in a condition suitable for administration twice a day patient (man), and specified dosage form after the first injection provides the time to reach 80% of medianmaxthat is about 90 to 110% of the time 80% of medianmaxequivalent dose control formulation of hydrocodone immediate-release, and specified dosage form provides a therapeutic effect for at least 12 hours

35. Solid oral dosage form with controlled vislobokova release to bring the specified dosage forms in the condition, suitable for injection twice per day to a patient (human), and specified dosage form after the first injection delivers an average absorption rate in vivo from the time of oral administration of up to Tmaxapproximately 2 to 4 mg/h, and delivers an average absorption rate in vivo from Tmaxapproximately 12 h after injection, comprising from about 0.08 mg/h to about 0.4 mg/h, with the specified dosage form provides a therapeutic effect for at least 12 hours, based on oral administration of the dosage form, containing 15 mg of hydrocodone bitartrate.

36. A way to provide effective anesthesia of the patient for at least 12 h, including oral administration of the dosage form, comprising from 0.5 to 1250 mg of hydrocodone or its pharmaceutically acceptable salt and a substance for controlled release to bring the specified dosage form in a condition suitable for administration twice a day patient (man), and specified dosage form after the first injection, the patient provides the relationship With12/Smaxaverage of from 0.55 to 0.85, and a therapeutic effect for at least 12 hours

37. Spoot 0.5 to 1250 mg of hydrocodone or its pharmaceutically acceptable salt in substance for controlled release to get dosage forms, suitable for injection twice a day patient (person) where the specified dosage form after the first injection, the patient provides the relationship With12/Smaxaverage of from 0.55 to 0.85, and a therapeutic effect for at least 12 hours

38. Solid oral dosage form with controlled release formulation comprising from 0.5 to 1250 mg of hydrocodone or its pharmaceutically acceptable salt and a substance for controlled release to bring the specified dosage form in a condition suitable for administration twice a day patient (man), and specified dosage form after the first injection the group of patients provides the average ratio12/Smaxaverage of from 0.55 to 0.85, and the specified dosage form provides a therapeutic effect for at least 12 hours

39. Solid oral dosage form with controlled release formulation comprising from 0.5 to 1250 mg of hydrocodone or its pharmaceutically acceptable salt and a substance for controlled release to bring the specified dosage form in a condition suitable for administration twice a day patient (man), and this lekarstvennaya 18% to 42.5% by weight hydrocodone or salt, when measuring method baskets (Basket) at USP at 100 rpm in 700 ml of artificial gastric juice (SGF) for 55 min at 37With, and then switching to 900 ml of artificial intestinal juice (SIF) at 37C.

40. Solid oral dosage form with controlled release formulation comprising from 0.5 to 1250 mg of hydrocodone or its pharmaceutically acceptable salt and a substance for controlled release to bring the specified dosage form in a condition suitable for administration twice a day patient (man), and specified dosage form provides a dissolution rate of the dosage form of hydrocodone in vitro, when measured by way of the blade (Paddle) or baskets (Basket) at USP at 100 rpm in 900 ml aqueous buffer with a pH of 1.2 at 37With approximately 25 to 65% by weight hydrocodone or salt released after 2 hours, from about 45 to 85% by weight hydrocodone or salt released after 4 hours and more than about 60% by weight hydrocodone or salt released after 8 hours

41. Solid oral dosage form with controlled release formulation comprising from 0.5 to 1250 mg of hydrocodone or pharmaceutically state, suitable for injection twice a day to the patient, and the specified dosage form provides a dissolution rate of the dosage form of hydrocodone in vitro, when measured by way of the blade (Paddle) or baskets (Basket) at USP at 100 rpm in 900 ml aqueous buffer, pH 7.5, at 37With approximately 25 to 65% by weight hydrocodone or salt released after 2 hours, from about 45 to 85% by weight hydrocodone or salt released after 4 hours and more than about 60% by weight hydrocodone or salt released after 8 hours

42. Solid oral dosage form with controlled release according to any one of the preceding paragraphs, comprising from 5 to 60 mg of hydrocodone or its pharmaceutically acceptable salt.

 

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