CN101578096A

CN101578096A - Robust sustained release formulations

Info

Publication number: CN101578096A
Application number: CNA2006800560384A
Authority: CN
Inventors: A·R·拜奇沃; K·菲茨莫里斯; S·拉布齐斯基
Original assignee: Penwest Pharmaceuticals Co
Current assignee: Penwest Pharmaceuticals Co
Priority date: 2006-10-10
Filing date: 2006-10-10
Publication date: 2009-11-11
Also published as: CA2652981C; JP5422388B2; EP2079453A1; KR20090113243A; BRPI0621947A2; CA2652981A1; IL198168A0; WO2008045060A1; AU2006349402A1; JP2010505949A; MX2009003771A

Abstract

Robust sustained release formulations, solid dosage forms comprising robust sustained release formulations, and methods for making and using these fopnulations and solid dosage forms are provided. Robustness of the sustained release formulation is related to the particle size of the hydrophilic gum. Sustained release formulations resist dose-dumping when ingested with alcohol. The formulations areuseful for treating a patient suffering from a condition, e.g., pain. The formulations comprise at least one drug. In one embodiment, the drug is an opioid, e.g., oxymorphone.

Description

Sane slow releasing preparation

1. invention field

The invention provides sustained release pharmaceutical formulation and the preparation and the using method of sane (robust).Saturated at least a medicine of preparation of the present invention and slow release delivery system.

2. background of invention

Sustained release pharmaceutical formulation usually comprises more multiple medicines thing than quick releasing formulation.The function of slow releasing preparation and safety were based in the persistent period interior (for example 8-24 hour) that prolongs after the administration, the known controllable rate that medicine discharges from preparation.The preparation medicine release profiles usually depends on the chemical environment of slow releasing preparation, for example pH, ionic strength and solvent such as alcoholic acid existence.

In some cases, if the release ratio of preparation of Chinese medicine specifies controlled release speed faster, a large amount of relatively medicine that exists in the slow releasing preparation may be harmful to the patient.If preparation discharges medicine being lower than to specify under the controllable rate, then the treatment of medicine is renderd a service and is reduced.

In most of the cases, the inefficacy of slow releasing preparation causes the medicine rapid release to enter blood flow.Rapid release is faster from the appointment slow release of preparation than medicine usually, is sometimes referred to as " dosage come down in torrents (dose dumping) ".

Dosage comes down in torrents and can cause serious result, comprises possible permanent damage, even dead.For example by dosage come down in torrents cause surpass the useful dosage of treatment the time may lethal medicine example comprise analgesic, opium kind analgesics for example.

Peroral dosage form usually with conventional beverage, for example water, fruit juice, soda pop or be that alcoholic beverages is taken together sometimes.Alcoholic beverages usually is called the ethanol beverage, alcoholic beverage or abbreviate wine as.As used herein, " wine " is meant ethanol or contains ethanol (" spirituosity ") beverage, as medicated beer, wine and ardent spirits such as Little water., rum or Whiskey.There is the dosage down generation safety issue of coming down in torrents in ethanol because exist the patient with pick-me-up with preparation take possible.When medicine and ethanol interaction, may increase the weight of this effect.Another safety issue is that the patient absorbs pick-me-up when with the medicine in the preparation patient being treated, even preparation and pick-me-up do not absorb simultaneously.

The patient who thirsts for excessive use medicine (for example producing the medicine of glad effect) may wish deliberately to bring out dosage comes down in torrents to amplify the glad effect of medicine.And, thirst for excessively using the people of medicine may have the excessive drinking problem, make may increasing that medicine in the slow releasing preparation and pick-me-up absorb simultaneously or take.

2005, because ethanol is to the influence of medicament slow release preparation, some medicines or withdraw from the market or stick alarm tag more.

For example, FDA (Food and Drug Adminstration) (FDA) requires Pu Du drugmaker (Purdue Pharma)

(hydrochloric acid hydromorphone) slow releasing capsule undercarriage, because studies show that when Palladone takes with ethanol, its slow releasing preparation is impaired and may cause dosage come down in torrents (referring to the FDA communique on July 13rd, 2005).FDA also warns with single spirituosity beverage and takes

Shi Keneng causes the death final result.

The press release report of Alpharma, FDA has required the said firm to exist

Label on enlarge warning message (referring to the Alpharma press release on July 22nd, 2005) about ethanol.Strengthening warning is the result of in vitro study, and this existence that studies show that ethanol causes Sustained releasing character impaired.

Find to work as

When taking with ethanol, the risk that dosage comes down in torrents increases (morphine sulfate slow release).The in vitro study that FDA carries out shows, when 30 milligrams of AVINZA contain alcoholic acid buffer solution (20% and 40%) when mixing with 900 milliliters, the dosage of the morphine that discharges is that determining alcohol is dependent, causes the faster release of morphine, may cause the absorption of potential fatal dose morphine in the body.As a result, during in October, 2005 or about October, a part has been revised by part pharmaceutical Co. Ltd (Ligand Pharmaceuticals Inc.)

Prescription information, outstanding and emphasize that the patient should not take with ethanol

Warning.In addition, for acceptance

The patient of treatment warns it can not use alcoholic prescription or over-the-counter drug.

FDA also points out, for the slow release product in future, suggestion with the testing in vitro of the weakening of the inductive sustained releasing character of ethanol as conventional characteristic test.And the position of FDA is, for some drugs (the narrow medicine of therapeutic index or have high C for example _MaxOr low C _MinExtreme result's medicine), should not ratify the responsive slow releasing preparation of alcohol.FDA is partial to design the preparation of ethanol tolerance, rather than proves simply by in vitro study dosage come down in torrents (summary that goes up the position that the FDA that submits to comes down in torrents to alcohol-induced dosage referring to pharmaceutical science Advisory Board on the 26th meeting October in 2005 (Pharmaceutical Sciences Advisory Committee Meeting)) can not take place.

According to the position of FDA, pure tolerance test is not a preferable methods in the body, because this test may cause potential harmful result to human body.According to FDA, preferable methods is the external dissolution test in the presence of 40% ethanol.This method may be preferred, because the intensity of great majority " ardent spirits " commonly used is about 80 normal intensities, or contains 40% ethanol of having an appointment.FDA proposes preparation is divided into three classes: firmly (rugged), frangible and uncertain.In the pharmaceutical science Advisory Board meeting on October 26th, 2005, OPS (pharmaceutical science office) staff of CDER (drug evaluation and research center) proposes data, show in frangible preparation, the ethanol of higher concentration (as, 40%) than the ethanol of low concentration (as, 20% or 4%) may faster startup drug release.In the example of the firm preparation of FDA, the drug release that is dissolved in the preparation in 40% ethanol is in fact than the control formulation slow (but similar) slightly that is dissolved in the no ethanol medium.(statement of pharmaceutical science Advisory Board on the 26th meeting October in 2005).

The change of Product labelling (promptly increasing the danger warning of taking medicine with ethanol) not only acts on limited, and can not stop the patient of intentional Drug abuse.

Pain is the symptom of normal report, is the general clinical problem that the clinicist faces.Millions of American suffers from the serious pain that long-term treatment is not enough or improper processing causes.Clinical serviceability to opioid analgesia character has been approved the centuries, and morphine and derivant thereof be extensive use decades in the analgesia therapy of many clinical pain statuses.

Oxymorphone hydrochloride (14-hydroxyl paramorphane hydrochlorate) is the deutero-opiates agonist of semi-synthetic phenanthrene, is easy to acute and treatment chronic pain, and analgesic effect is equivalent to other opium kind analgesicses.Oxymorphone is the at present commercially available injection (1 mg/ml, 1ml ampoule) that is used for intramuscular, subcutaneous and intravenous administration.Once sold 10 milligrams oral quick release tablet preparation of persalt oxymorphone.Mainly metabolism in liver of oxymorphone hydrochloride is with the glucuronic acid coupling and be reduced into 6-α and 6-β hydroxyl epimer.

A free-revving engine of analgesia therapy is the continuous alleviation that realizes chronic pain.The effect disappearance that the conventional administration of analgesic requires to guarantee pro-one dosage usually gives before next dosage.Opioid compliance increases with the reduction of administration frequency.It is relatively poor that poor compliance causes not reaching the pain control and quality of life of optimality criterion.The suggestion of present guilding principle in chronic non-pernicious treatment of pain is used, according to plan rather than " as required " give opioid.Unfortunately, the evidence of past clinical trial and clinical experience prompting, the acting duration of rapid release oxymorphone is short, may need per 4 hours to carry out administration to keep the optimum level of analgesic in chronic pain patient.And, because oxymorphone extensively metabolism in liver causes the oral administration biaavailability of rapid release oxymorphone low.

Because when slow releasing preparation lost efficacy, many medicines (as opioid, as oxymorphone) may cause serious adverse or even cause death, this area need with can obtain slow releasing preparation at present and compare, more sane or firm, thereby safer pharmaceutical preparation.

United States Patent (USP) 5,399,358 have reported some slow releasing preparation, its content is included into this paper as a reference.Be surprised to find that the robustness of the particle size influences slow releasing preparation of hydrophilic gel (as xanthan gum) and stripping character now.

Quoting in the application's part 2 is not that these lists of references of approval are prior aries.

3. summary of the invention

The solid dosage forms that the invention provides sustained release pharmaceutical formulation and comprise slow releasing preparation.The present invention also provides with slow releasing preparation treatment patient's method and has prevented the method that dosage comes down in torrents, and for example, this method comprises the sustained release pharmaceutical formulation that the treatment effective dose is provided to the patient.Compare with conventional sustained-release, the probability that pharmaceutical preparation generation dosage as herein described comes down in torrents is lower, and they are more firm, safer and be applicable to the medicine of many types.

The present invention also provides anti-alcoholic acid pharmaceutical preparation, and improves drug safety and reduce the possible method of drug dependence.This can realize by the anti-alcoholic acid pharmaceutical preparation that provides, writes out a prescription and/or give patient's effective dose.Compare with the commercial preparation, anti-alcoholic acid pharmaceutical preparation is safer and abuse potential is lower, because it is basic identical at aqueous solution or the slow release stripping scattergram that contains in the alcoholic solution.In one embodiment, anti-alcoholic acid preparation of Chinese medicine comprises the opioid compounds or derivatives thereof.

The present invention also provides anti-alcoholic acid pharmaceutical preparation and has prevented the method that dosage comes down in torrents.This can realize by the anti-alcoholic acid pharmaceutical preparation that provides, writes out a prescription and/or give patient's effective dose.Dosage can not take place and come down in torrents in anti-alcoholic acid pharmaceutical preparation as herein described in the presence of dense alcohol drink.In one embodiment, the medicine in the anti-alcoholic acid preparation comprises opioid compounds, opioid compounds pharmaceutically acceptable salt or derivatives thereof.

In one aspect, the invention provides a kind of slow releasing preparation, it comprises: medicine; With the slow release delivery system, this system comprises hydrophilic gel, homopolysaccharide glue and medicinal diluent, wherein, can pass through the #270 mesh screen, absorb medicine that the back slow releasing preparation discharged less than about 70% in 2 hours with no ethanol or alcoholic beverages at least about 30% hydrophilic gel that is used to prepare slow releasing preparation.

On the other hand, the invention provides a kind of slow releasing preparation, it comprises: medicine; With the slow release delivery system, this system comprises hydrophilic gel, is selected from univalent cation, the cationic crosslinked chemical compound and the medicinal diluent of polyvalent cation or salt, wherein, can pass through the #270 mesh screen at least about 30% hydrophilic gel that is used to prepare slow releasing preparation, absorb medicine that the back slow releasing preparation discharged less than about 70% in 2 hours with no ethanol or alcoholic beverages.

In some embodiments, hydrophilic gel is a heteropolysaccharide glue.In some embodiments, hydrophilic gel is an xanthan gum.

In one embodiment, the slow release delivery system also comprises the cationic crosslinked chemical compound that is selected from univalent cation, polyvalent cation or salt.In one embodiment, cationic crosslinked dose is sodium salt.

Aspect another, the invention provides a kind of slow releasing preparation, it comprises: medicine; With the slow release delivery system, this system comprises hydrophilic gel, homopolysaccharide glue and medicinal diluent, wherein, less than 53 microns, the medicine that slow releasing preparation discharged in 2 hours after no ethanol or alcoholic beverages absorb is less than about 70% at least about the 30% particulate diameter of hydrophilic gel that is used to prepare slow releasing preparation.

On the other hand, the invention provides a kind of slow releasing preparation, it comprises: medicine; With the slow release delivery system, this system comprises hydrophilic gel, is selected from univalent cation, the cationic crosslinked chemical compound and the medicinal diluent of polyvalent cation or salt, wherein, less than about 53 microns, the medicine that slow releasing preparation discharged in 2 hours after no ethanol or alcoholic beverages absorb is less than about 70% at least about the 30% particulate diameter of hydrophilic gel that is used to prepare slow releasing preparation.In some embodiments, the slow release delivery system also comprises hydrophobic polymer.In some embodiments, slow releasing preparation also comprises coat.In some embodiments, coat comprises hydrophobic polymer and/or plasticizer.

In some embodiments, medicine is a water soluble drug.In some embodiments, medicine is antidepressants, is used for the treatment of the medicine of the many moving attention deficit hyperactivity disorders of bipolar disorder, panic disorder, epilepsy, migraine and/or companion.In some embodiments, medicine is selected from: the dextroisomer and the d of alprazolam, lithium carbonate, divalproex sodium, dexamphetamine and amphetamine and amphetamine saccharate, other pharmaceutically acceptable salts of neutral sulfatase, tramadol hydrochloride and the active pharmaceutical ingredient of 1-amphetamine aspartic acid monohydrate.

In some embodiments; Medicine is opioid; For example, alfentanil; Allylprodine; Alphaprodine; Anileridine; Benzyl morphine; Bezitramide; Buprenorphine; Butorphanol; Clonitazene; Codeine; Cyclazocine; Desomorphine; Dextromoramide; Dezocine; Diampromide; Paracodin; Paramorphane; Dimenoxadol; Dimepheptanol; Dimethylthiambutene; Amidalgon; Dipipanone; Eptazocine; Ethoheptazine; Ethylmethylthiambutene; Dionin; Etonitazene; Fentanyl; Heroin; Hydrocodone; Hydromorphone; Hydroxypethidine; Isomethadone; Ketobemidone; Levallorphan; Levorphanol; Levophenacylmorphan; Lofentanil; Pethidine; Meptazinol; Metazocine; Methadone; Metopon; Morphine; Myrophine; Nalbuphine; Narceine; Nicomorphine; Norlevorphanol; Normethadone; Nalorphine; Normorphine; Norpipanone; Opium; Oxycodone; Oxymorphone; The 6-hydroxy-oxymorphone for use; Narsco; Pentazocine; Phenadoxone; Phenomorphan; Phenazocine; Phenoperidine; Piminodine; Pirinitramide; Proheptazine (propheptazine); Trimeperidine; Properidine; Propiram; Dextropropoxyphene; Sufentanil; C16H25NO2; Tilidine; Its stereoisomer; Its metabolin; Its ether; Its ester; With and derivative and pharmaceutically acceptable salt. In addition, the present invention also provides preparation sustained release pharmaceutical formulation and the method that comprises the solid dosage forms of slow releasing preparation.

In one aspect, the invention provides the method for preparing slow releasing preparation, said preparation comprises: medicine; With the slow release delivery system, wherein said slow release delivery system comprises hydrophilic gel, homopolysaccharide glue and medicinal diluent, and described method comprises: hydrophilic gel is provided, and the particulate diameter of at least a portion is less than about 53 microns; Hydrophilic gel, homopolysaccharide glue and medicinal diluent are carried out pelletize to form granule; With this granule and medicament mixed to form particulate compositions; With particulate compositions is exerted pressure with the preparation preparation.

On the other hand, the invention provides the method for preparing slow releasing preparation, described preparation comprises: medicine; With the slow release delivery system, wherein, described slow release delivery system comprises hydrophilic gel, is selected from univalent cation, the cationic crosslinked chemical compound and the medicinal diluent of polyvalent cation or salt, and described method comprises: hydrophilic gel is provided, and the particulate diameter of at least a portion is less than about 53 microns; Hydrophilic gel, homopolysaccharide glue and medicinal diluent are carried out pelletize to form granule; With this granule and medicament mixed to form particulate compositions; With particulate compositions is exerted pressure with the preparation preparation.

In some embodiments, provide step to comprise acceptance, make and/or the processing hydrophilic gel.In some embodiments, procedure of processing comprises the mensuration particulate granularity of at least a portion hydrophilic gel and/or makes at least a portion hydrophilic gel by sieve.In some embodiments, sieve is the #270 mesh screen.

In some embodiments, the method for preparing slow releasing preparation and solid dosage forms also is included at least a portion slow releasing preparation and applies coat.

In some embodiments, granulation step comprises each composition is mixed with aqueous solution.In other embodiments, granulation step comprises each composition and alcoholic solution, for example contains alcoholic acid solution and mixes.

In one aspect, the invention provides the method for preparing slow releasing preparation, described preparation comprises: medicine; With the slow release delivery system, wherein, described slow release delivery system comprises hydrophilic gel, homopolysaccharide glue and medicinal diluent, and described method comprises: intermediate value and/or average (average and/or mean) granularity are mixed with aqueous solution to form granule greater than about 53 microns hydrophilic gel, homopolysaccharide glue and medicinal diluent; With this granule and medicament mixed to form particulate compositions; With particulate compositions is exerted pressure with the preparation preparation.

On the other hand, the invention provides the method for preparing slow releasing preparation, described preparation comprises: medicine; With the slow release delivery system, wherein, described slow release delivery system comprises hydrophilic gel, is selected from univalent cation, the cationic crosslinked chemical compound and the medicinal diluent of polyvalent cation or salt, and described method comprises: intermediate value and/or particle mean size are mixed with aqueous solution to form granule greater than about 53 microns hydrophilic gel, cationic crosslinked chemical compound and medicinal diluent; With this granule and medicament mixed to form particulate compositions; With particulate compositions is exerted pressure with the preparation preparation.

In one embodiment, provide the method for preparing slow releasing preparation, this method also comprises the record slow releasing preparation or comprises the stripping scattergram of solid dosage forms in containing alcoholic solution of slow releasing preparation.

In one embodiment, the invention provides lenitive method, this method comprises the solid dosage forms that gives patient treatment effective dose slow releasing preparation as herein described or comprise slow releasing preparation.

In another embodiment, the invention provides the patient's who suffers from disease method, this method comprises the solid dosage forms that gives patient treatment effective dose slow releasing preparation as herein described or comprise slow releasing preparation.On the other hand, the invention provides and reduce the method that sustained release pharmaceutical formulation generation dosage comes down in torrents, this method comprises to the patient provides slow releasing preparation as herein described.

Aspect another, the invention provides the solid dosage forms that comprises slow releasing preparation as herein described.In some embodiments, solid dosage forms is powder agent, granule, tablet or capsule.

In one aspect, slow releasing preparation comprises the slow release delivery system of about 5-80 milligram oxymorphone hydrochloride and about 80-360 milligram; Wherein said slow release delivery system comprises: about 8.3-41.7 weight % locust bean gum, about 8.3-41.7 weight % xanthan gum, wherein can pass through the #270 mesh screen at least about 30% xanthan gum granule, about 20-55 weight % dextrose, about 5-20 weight % calcium sulfate dihydrate and about 2-10% ethyl cellulose absorb the described slow releasing preparation in back with no ethanol or alcoholic beverages and are released in the medicine of release in 2 hours less than 70%.

In one aspect, slow releasing preparation comprises the slow release delivery system of about 5-80 milligram oxymorphone hydrochloride and about 300-420 milligram; Wherein said slow release delivery system comprises: about 8.3-41.7 weight % locust bean gum, about 8.3-41.7 weight % xanthan gum, at least about the particulate diameter of 30% xanthan gum less than about 53 microns; About 20-55 weight % dextrose, about 5-20 weight % calcium sulfate dihydrate and about 2-10% ethyl cellulose absorb the described slow releasing preparation in back with no ethanol or alcoholic beverages and are released in the medicine of release in 2 hours less than 70%.

In one embodiment, slow releasing preparation comprises about 20 milligrams of oxymorphone hydrochlorides.In another embodiment, slow releasing preparation comprises about 160 milligrams of slow release delivery systems.In another embodiment, slow releasing preparation comprises about 360 milligrams of slow release delivery systems.In another embodiment, the slow release delivery system comprises about 25% locust bean gum, about 25% xanthan gum, about 35% dextrose, about 10% calcium sulfate dihydrate and about 5% ethyl cellulose.

On the other hand, the invention provides and prevent to issue the method that crude drug agent amount is come down in torrents in alcoholic acid existence, this method comprises: may take in the medicine that alcoholic acid patient provides the anti-alcoholic acid slow releasing preparation form of effective dose when carrying out Drug therapy, described preparation comprises: medicine; With the slow release delivery system, this delivery system comprises at least a hydrophilic gel, at least a homopolysaccharide glue and at least a medicinal diluent, wherein, can pass through the #270 mesh screen at least about 30% hydrophilic gel that is used to prepare slow releasing preparation, absorb medicine that the back slow releasing preparation discharged less than about 70% in 2 hours with no ethanol or alcoholic beverages.

In one aspect, the invention provides and prevent to have the method that crude drug agent amount is come down in torrents that issues at ethanol, this method comprises: may take in the medicine that alcoholic acid patient provides the anti-alcoholic acid slow releasing preparation form of effective dose when carrying out Drug therapy, described preparation comprises: medicine; With the slow release delivery system, described delivery system comprises at least a hydrophilic gel, at least a cationics that is selected from univalent cation, polyvalent cation or salt quantizes compound and at least a medicinal diluent, wherein, can pass through the #270 mesh screen at least about 30% hydrophilic gel that is used to prepare slow releasing preparation, absorb medicine that the back slow releasing preparation discharged less than about 70% in 2 hours with no ethanol or alcoholic beverages.

On the other hand, the invention provides the method that improves the pharmaceutical preparation safety, this method comprises: may take in the medicine that alcoholic acid patient provides the anti-alcoholic acid slow releasing preparation form of effective dose when carrying out Drug therapy, described preparation comprises: medicine; With the slow release delivery system, described slow release delivery system comprises at least a hydrophilic gel, at least a homopolysaccharide glue and at least a medicinal diluent, and the raising of wherein said safety is the controlled hydrophilic gel granularity and the result of the anti-alcoholic acid sustained release property of preparation.

On the other hand, the invention provides the method that improves the pharmaceutical preparation safety, this method comprises: may take in the medicine that alcoholic acid patient provides the anti-alcoholic acid slow releasing preparation form of effective dose when carrying out Drug therapy, described preparation comprises: medicine; With the slow release delivery system, described delivery system comprises at least a hydrophilic gel, at least a cationics that is selected from univalent cation, polyvalent cation or salt quantizes compound and at least a medicinal diluent, and the raising of wherein said safety is the controlled hydrophilic gel granularity and the result of the anti-alcoholic acid sustained release property of preparation.

In one aspect, the invention provides a kind of slow release Numorphan, it comprises slow release delivery system and about 5-80 milligram oxymorphone, wherein, after single oral dose gives the patient simultaneously with the ethanol of the about 4-40% of about 200-300 milliliter, and about 12 hours preparations provide oxymorphone blood drug level secondary peak after the administration, and preparation provides analgesia at least about 12 hours to the patient after the administration.

In some embodiments, preparation comprises about 20-60 milligram oxymorphone or about 40 milligrams of oxymorphones.In one embodiment, preparation is a solid dosage forms, for example tablet, granule, capsule or powder agent.

On the other hand, the invention provides a kind of slow release Numorphan, said preparation comprises slow release delivery system and about 5-80 milligram oxymorphone, wherein, after the administration of patient's single oral dose, when the maximum plasma concentration of oxymorphone is less than no alcohol panning when about 200-300 milliliter is up to about 40% ethanol and absorbs about 5 times, preparation provides analgesia at least about 12 hours to the patient after the administration.

When in one embodiment, the maximum plasma concentration of oxymorphone is less than no alcohol panning when about 200-300 milliliter is up to about 40% ethanol and absorbs about 2.5 times.

In another embodiment, the invention provides a kind of slow release Numorphan, it comprises slow release delivery system and about 5-80 milligram oxymorphone, wherein, after the administration of patient's single oral dose, the ratio of the maximum plasma concentration of oxymorphone is about 0.5-2 when absorbing preparation after the maximum plasma concentration of oxymorphone and the no ethanol high fat diet when the ethanol of about 200-300 milliliter about 40% absorbs preparation, and preparation provides analgesia at least about 12 hours to the patient after the administration.

The ratio of the maximum plasma concentration of oxymorphone is about 0.8-1.5 when in one embodiment, absorbing preparation after the maximum plasma concentration of oxymorphone and the no ethanol high fat diet when the ethanol of about 200-300 milliliter about 40% absorbs preparation.

In one aspect, the invention provides a kind of slow release Numorphan, said preparation comprises slow release delivery system and about 5-80 milligram oxymorphone, wherein, after the ethanol single oral dose of the about 4-40% of about 200-300 milliliter gives the patient, the maximum plasma concentration of oxymorphone is about the 0.1-15 nanograms/milliliter, and preparation provides analgesia at least about 12 hours to the patient after the administration.

In some embodiments, the maximum plasma concentration of oxymorphone is about 0.5-7.5 nanograms/milliliter or about 1-4 nanograms/milliliter.

In one embodiment, preparation comprises about 10-20 milligram oxymorphone, and the maximum plasma concentration of oxymorphone is about 0.3-3.2 nanograms/milliliter or about 0.4-2.8 nanograms/milliliter.

In some embodiments, preparation comprises about 10 milligrams of oxymorphones, and the maximum plasma concentration of oxymorphone is about 0.3-1.8 nanograms/milliliter or about 0.5-1.5 nanograms/milliliter.

In another embodiment, preparation comprises about 20-40 milligram oxymorphone, and the maximum plasma concentration of oxymorphone is about 0.5-7 nanograms/milliliter or about 0.9-6 nanograms/milliliter.

In another embodiment, preparation comprises about 20 milligrams of oxymorphones, and the maximum plasma concentration of oxymorphone is about 0.5-3.2 nanograms/milliliter or about 0.75-2.8 nanograms/milliliter.

In one embodiment, preparation comprises about 40-80 milligram oxymorphone, and the maximum plasma concentration of oxymorphone is about 1-15 nanograms/milliliter or about 1.9-12 nanograms/milliliter.

In another embodiment, preparation comprises about 40 milligrams of oxymorphones, and the maximum plasma concentration of oxymorphone is about 1-7 nanograms/milliliter or about 1.4-5 nanograms/milliliter.

In another embodiment, preparation comprises about 80 milligrams of oxymorphones, and the maximum plasma concentration of oxymorphone is about 3.5-15 nanograms/milliliter or about 4-13 nanograms/milliliter.

In one aspect, the invention provides a kind of slow release Numorphan, said preparation comprises slow release delivery system and about 5-80 milligram oxymorphone, after the ethanol single oral dose of the about 4-40% of about 200-300 milliliter gives the patient, locating preparation in about 12 hours provides the minimum blood drug level of oxymorphone to be at least about 0.013 nanograms/milliliter, and preparation provides analgesia at least about 12 hours to the patient after the administration.

In one embodiment, preparation comprises about 5 milligrams of oxymorphones, and the minimum blood drug level of oxymorphone is at least about 0.07 nanograms/milliliter.

In another embodiment, preparation comprises about 10 milligrams of oxymorphones, and the minimum blood drug level of oxymorphone is at least about 0.15 nanograms/milliliter.

In another embodiment, preparation comprises about 20 milligrams of oxymorphones, and the minimum blood drug level of oxymorphone is at least about 0.3 nanograms/milliliter.

In one embodiment, preparation comprises about 40 milligrams of oxymorphones, and the minimum blood drug level of oxymorphone is at least about 0.6 nanograms/milliliter.

In another embodiment, preparation comprises about 80 milligrams of oxymorphones, and the minimum blood drug level of oxymorphone is at least about 1.2 nanograms/milliliter.

In some embodiments, preparation is a solid dosage forms, for example tablet, capsule, granule or powder agent.

In one aspect, the invention provides a kind of lenitive method, this method comprises and gives the patient a kind of slow release Numorphan, described preparation comprises slow release delivery system and about 5-80 milligram oxymorphone, after the ethanol single oral dose of the about 4-40% of 200-300 milliliter gives the patient, provided oxymorphone blood drug level secondary peak in about 12 hours after the administration, preparation provides analgesia at least about 12 hours to the patient after the administration.

On the other hand, the invention provides lenitive method, this method comprises and gives the patient a kind of slow release Numorphan, said preparation comprises slow release delivery system and about 5-80 milligram oxymorphone, after single oral dose gives the patient, when the maximum plasma concentration of oxymorphone is less than no alcohol panning when the 200-300 milliliter is up to about 40% ethanol and absorbs about 5 times, described preparation provides analgesia at least about 12 hours to the patient after the administration.

When the maximum plasma concentration of oxymorphone was less than no alcohol panning when in one embodiment, the about 200-300 milliliter of picked-up was up to about 40% ethanol about 2.5 times.

On the other hand, the invention provides lenitive method, this method comprises and gives the patient a kind of slow release Numorphan, said preparation comprises slow release delivery system and about 5-80 milligram oxymorphone, after single oral dose gives the patient, the ratio of the maximum plasma concentration of oxymorphone is about 0.5-2 when absorbing after the maximum plasma concentration of hydromorphone and the no ethanol high fat diet when the ethanol of about 200-300 milliliter about 40% absorbs, and preparation provides analgesia at least about 12 hours to the patient after the administration.

The ratio of the maximum plasma concentration of oxymorphone is about 0.8-1.5 when absorbing after the maximum plasma concentration of hydromorphone and the no ethanol high fat diet when the ethanol of about 200-300 milliliter about 40% absorbs in one embodiment.

In some embodiments, preparation comprises about 20-60 milligram oxymorphone or about 40 milligrams of oxymorphones. and in one embodiment, preparation is a solid dosage forms, for example tablet, granule, capsule or powder agent.

In one aspect, the invention provides lenitive method, this method comprises and gives the patient a kind of slow release Numorphan, said preparation comprises slow release delivery system and about 5-80 milligram oxymorphone, after the ethanol single oral dose of the about 4-40% of 200-300 milliliter gives the patient, the maximum plasma concentration of oxymorphone is about the 0.1-15 nanograms/milliliter, and preparation provides analgesia at least about 12 hours to the patient after the administration.

On the other hand, the invention provides lenitive method, this method comprises and gives the patient a kind of slow release Numorphan, said preparation comprises slow release delivery system and about 5-80 milligram oxymorphone, after the ethanol single oral dose of the about 4-40% of 200-300 milliliter gives the patient, the minimum blood drug level of oxymorphone is at least about 0.013 nanograms/milliliter in the time of about 12 hours, and preparation provides analgesia at least about 12 hours to the patient after the administration.

In another embodiment, preparation comprises about 80 milligrams of oxymorphones, and the minimum blood drug level of oxymorphone is at least about 1.2 nanograms/milliliter.Slow releasing preparation as herein described can be used in treatment.And slow releasing preparation as herein described can be used for making sanatory medicine.In one embodiment,

Slow releasing preparation as herein described can be used for making lenitive medicine.

In some embodiments, preparation is a solid dosage forms, for example tablet, capsule, granule or powder agent.This paper will describe these and other aspects of the present invention and embodiment in detail.

4. detailed Description Of The Invention

4.1. definition

As described herein, except as otherwise noted, the inclusive connotation of conjunction " or " expression " and/or ", rather than the exclusiveness connotation of " perhaps/or ".

As described herein, term " steadily and surely " represents that the character of slow releasing preparation makes its stripping scattergram that significantly change, impaired or inefficacy unlikely take place.The example that slow releasing preparation takes place to lose efficacy is that dosage comes down in torrents." steadily and surely " and " firmly " is synonym.

As used herein, term " meticulous " expression diameter is less than about 53 microns, and perhaps particle can pass through the granularity of the polymer of #270 mesh screen.

As used herein, term " dosage " is come down in torrents " be meant that medicine or active component enter blood flow from the slow releasing preparation rapid release.This rapid release is faster from the preparation slow release than medicine usually.Dosage comes down in torrents and also represents the peak concentration high release of the peak concentration of medicine in blood plasma than medicine appointment slow release.In some cases, the overdose that dosage comes down in torrents and may cause danger causes dead final result.

As used herein, term " slow release " expression medicine discharges from preparation with controllable rate, thereby keeps the useful level of treatment (but being lower than toxic level) of medicine in the persistent period that prolongs.

As used herein, term " slow release ", " postponing to discharge " and " controlled release " are synonyms, promptly have identical connotation.

As used herein, medicine discharged from preparation at short notice after term " rapid release " expression gave preparation, in for example about 4 hours.

As used herein, area under term " AUC " indicated concentration-time graph.

As used herein, term " C _Max" the maximum observation of expression concentration.

As used herein, term " RSD " expression relative standard deviation.

As used herein, term " CI " expression confidence interval.

As used herein, the total heat content of term " high fat diet " expression about 50% is from the diet of fat.The example of high fat diet is that two butter fried eggs, two bacon, two toast breads add butter, four ounces of broken cinnamon soil beans and eight ounces of whole milks.

As used herein, term " liquid " for example comprises, gastro-intestinal Fluid, aqueous solution (as be used for external dissolution test those) and mucus (as, the mucus of oral cavity, nasal cavity, pulmonary and esophagus etc.).

As used herein, term " anti-alcoholic acid " represents according to USP drug release rules USP23, carries out the stripping scattergram when measuring in 0.1NHCl and 40% alcoholic solution, and the active component that discharges in 1 hour is less than 50%.

As used herein, term " medicine " comprises any pharmaceutically active compound or biologic artifact and the pharmaceutically acceptable salt thereof that is used for relief of symptoms, treatment or prevention disease.

The medicine that is applicable to sane slow releasing preparation as herein described includes but not limited to: alprazolam (XANAX

), lithium carbonate

Divalproex sodium The dextroisomer of dexamphetamine and amphetamine and amphetamine saccharate and d, the neutral sulfatase (ADDERALL of 1-amphetamine aspartic acid monohydrate

), tramadol hydrochloride (TRAMADOL

) and opioid such as morphine (

With

) and oxycodone

As used herein, term " opiates " comprises its stereoisomer, metabolite, salt, ether, ester and/or its derivant (as, pharmaceutically acceptable salt) .Opiates can be μ-exemplary opioid of antagonist and/or blended μ-agonist/antagonist. comprises: alfentanil; Allylprodine; Alphaprodine; Anileridine; Benzyl morphine; Bezitramide; Buprenorphine; Butorphanol; Clonitazene; Codeine; Cyclazocine; Desomorphine; Dextromoramide; Dezocine; Diampromide; Paracodin; Paramorphane; Dimenoxadol; Dimepheptanol; Dimethylthiambutene; Amidalgon; Dipipanone; Eptazocine; Ethoheptazine; Ethylmethylthiambutene; Dionin; Etonitazene; Fentanyl; Heroin; Hydrocodone; Hydromorphone; Hydroxypethidine; Isomethadone; Ketobemidone; Levallorphan; Levorphanol; Levophenacylmorphan; Lofentanil; Pethidine; Meptazinol; Metazocine; Methadone; Metopon; Morphine; Myrophine; Nalbuphine; Narceine; Nicomorphine; Norlevorphanol; Normethadone; Nalorphine; Normorphine; Norpipanone; Opium; Oxycodone; Oxymorphone; The 6-hydroxy-oxymorphone for use; Narsco; Pentazocine; Phenadoxone; Phenomorphan; Phenazocine; Phenoperidine; Piminodine; Pirinitramide; Proheptazine; Trimeperidine; Properidine; Propiram; Dextropropoxyphene; Sufentanil; C16H25NO2; Tilidine; Their stereoisomer; Metabolin; Ether; Ester; And/or their derivative. In some embodiments, opioid is morphine, codeine, hydromorphone, hydrocodone, oxycodone, paracodin, paramorphane, oxymorphone, 6-hydroxy-oxymorphone for use (comprising 6-Alpha-hydroxy oxymorphone and/or 6-beta-hydroxy oxymorphone) or tramadol.

As used herein, term " oxymorphone " comprises oxymorphone, its metabolite and derivant thereof.The metabolite of oxymorphone for example comprises, the 6-hydroxy-oxymorphone for use (as, 6-Alpha-hydroxy oxymorphone and/or 6-beta-hydroxy oxymorphone).

As used herein, term " disease " comprises any disease that need treat with medicine or the set of symptom.Exemplary disease comprises: panic disorder (with or without agoraphobia), how moving attention deficit hyperactivity disorder (ADHD), depression and the pain of bipolar disorder (manic depressive illness), the acute mania relevant or mixed type outbreak, epilepsy, migraine, companion with bipolar disorder.

Pain can be light to moderate, or moderate is to severe.Pain can be acute or chronic.Pain also may be lasting and requires ceaselessly alleviating continuously in the time expand scope.Pain may be relevant with (for example) cancer, autoimmune disease, infection, operation wound or unexpected wound.The patient can be animal, mammal or people.

Medicine can be the form of any pharmaceutically acceptable salt known in the art.Exemplary pharmaceutically acceptable salt comprises: hydrochlorate, sulfate, silver nitrate, phosphate, hydrobromate, maleate, malate, Ascorbate, citrate, tartrate, pamoate, laruate, stearate, palmitate, oleate, cinnamate, lauryl sulfate, naphthalene sulfonate, linoleate, linolenate etc.

Give sane medicament slow release preparation, dosage is enough at for example about 8-24 hour, or interior relief of symptoms of the persistent period of about 12-24 hour prolongation, treatment or prevention disease.But sane release oral solid dosage form formulation described herein every day four times, every day three times, twice of every day or administration once a day.

Give opioid slow releasing preparation, dosage is enough at for example about 8-24 hour, or alleviating pain in the persistent period of about 12-24 hour prolongation.But opioid release oral solid dosage form formulation as herein described every day four times, every day three times, twice of every day or the every day of administration thus.

The treatment effective dose of medicine be the amount that is enough to eliminate or alleviate disease symptoms (for example with give the opiates slow releasing preparation before the pain that exists compare reduce pain).

Medicament contg in the compositions is about the 0.5-1000 milligram, about 1-800 milligram, about 1-200 milligram, or about 1-100 milligram.

4.2. granularity is to the influence of slow releasing preparation robustness

Be surprised to find that, hydrophilic gel, as xanthan gum, the particle size influences slow releasing preparation and comprise the stripping character of the solid dosage forms of slow releasing preparation, thereby influence its robustness.Still do not understand this quality-design principle up to now and how to be applied to the stripping scattergram of the slow releasing preparation of medicine (for example opioid).

Specifically, find that the granularity of hydrophilic gel will influence the robustness of ethanol/ethyl cellulose granulating preparation.For example, when diameter is equal to or greater than approximately 30% the time less than 53 microns particle mark, comprising xanthan gum is sane as the ethanol/ethyl cellulose granulating preparation of hydrophilic gel.For other hydrophilic gels, this mark can be higher or lower, for example is about 20-80%, about 40-60%, or about 50%.And if the hydrophilic gel particle can sieve by different mesh screen filters, the particle size distribution that then produces the sane desired hydrophilic gel of slow releasing preparation can be different.The robustness of slow releasing preparation described herein may be the selection of hydrophilic gel and the combination of particle size distribution.Usually, hydrophilic gel is coarse more, and the then sane desired short grained mark of preparation is big more.Similarly, hydrophilic gel is meticulous more, and the sane desired short grained mark of preparation is more little.In some cases, may wish that the percentage composition of hydrophilic gel in the preparation is greater than making the sane required amount of preparation.If hydrophilic gel is an xanthan gum, preparation can comprise and surpass 30% less than 53 microns xanthan gum granule, and is for example about 40%, about 50%, or about 60%.

Do not wish to be subjected to the restriction of any theory, some hydrophilic gel (as, xanthan gum) hydrophilic helps the initial hydration of slow releasing preparation and solid dosage forms, in one embodiment, described preparation or dosage form comprise medicine, one or more heteropolysaccharide glue and one or more homopolysaccharide glue, in another embodiment, described preparation or dosage form comprise medicine, one or more heteropolysaccharide glue and one or more are selected from the cationic crosslinked chemical compound of univalent cation, polyvalent cation or salt.

Discovery comprises the integrity of slow releasing preparation of hydrophilic gel (as xanthan gum) to comprising the prilling process sensitivity of the particulate preparation of xanthan gum.

If select use nonaqueous solvent, carry out the prilling process of wet granulation as alcohol, glycerol, propylene glycol or other nonaqueous solvents, then the granularity of xanthan gum has significance to the hydration of granulating slow releasing preparation and solid dosage forms and integrity influences.

Xanthan gum fast hydrating in cold water helps the integrity of non-particle water slow releasing preparation described herein and final solid dosage forms.The hydration rate of discovery xanthan gum depends on the granularity of xanthan gum.The xanthan gum granule of minor diameter is than the faster hydration of large diameter xanthan gum granule.Therefore, the granulating slow releasing preparation of the xanthan gum bigger with comprising average diameter is compared with solid dosage forms, comprises the non-particle water slow releasing preparation of the less xanthan gum of average diameter and solid dosage forms with faster hydration and more sane.

In some embodiments, the dispersion of a certain amount of one or more hydrophobic materials (for example, the copolymer of alkylcellulose, acrylic acid and methacrylate, wax, lac, zein, hydrogenated vegetable oil and the mixture of above-mentioned substance arbitrarily) of preparation hydration can effectively slow down when the nonaqueous solvent wet granulation comprises the contact environment fluid.

For example, if the prilling process of selecting is that the particulate big young pathbreaker of xanthan gum influences the hydration restriction and the integrity of granulating slow releasing preparation and solid dosage forms with ethanol and ethyl cellulose wet granulation.

When the prilling process of selecting is water or any other aqueous solution wet granulation, be used to realize hydration that the particle diameter of xanthan gum is less to the influence of solid dosage forms hydration, can ignore or even do not exist from the water of aqueous solution.Because their poor solubility in cold water estimate that some homopolysaccharide glue (for example locust bean gum) does not have facilitation to the initial hydration of slow releasing preparation and solid dosage forms.Therefore, the particle mean size of these homopolysaccharide glue can not influence the aqueous restriction and the integrity of slow releasing preparation and solid dosage forms.Granularity can adopt any suitable method known in the art to measure.The method of mensuration granularity that may be the most frequently used comprises makes particle screening pass through mesh screen.Other exemplary methods comprise optical means, for example determination of laser diffraction, light microscopy, surface area test (for example, mercury porosity mensuration, nitrogen adsorption, krypton aspiration are attached).Also can adopt other physical measurement methods to calculate granularity.Even can adopt some, for example the stripping scattergram measures to determine the robustness and the integrity of solid dosage forms (for example tablet, capsule, granule and powder agent).Exemplary stripping scattergram is measured and is comprised that adopting USP I type, II type, III type or IV type dissolving device to carry out drug release measures.

4.3. ethanol is to the influence of slow releasing preparation robustness

Find that slow releasing preparation as herein described keeps its slow release stripping property system in the presence of alcoholic acid.

Do not wish to be bound by any theory, make them be formed on together with the physicochemical properties of cross-linking agent (for example locust bean gum) cross-linked hydrophilic chemical compound (for example xanthan gum) and do not dissolve in the ethanol or the substrate of undissolved basically natural gum or similar natural gum.This solubility properties of preparation helps the hydrophilic of slow release delivery system, in one embodiment, described delivery system comprises one or more hydrophilic gels and one or more homopolysaccharide glue, in another embodiment, described delivery system comprises one or more hydrophilic gels and one or more univalent cations, polyvalent cation and/or salt.A small amount of hydrophobic agents (for example, hydrophobic polymer such as ethyl cellulose) can not cause appreciable impact to the stripping character of preparation in ethanol, may be because the slow release delivery system has kept hydrophilic feature.Pharmaceutical properties unlikely influences the natural gum of substrate or the character of similar natural gum, makes preparation as herein described be fit to and/or adapt to various medicines.

Believe that following factors can influence ethanol and have the release of following medicine from preparation: the dissolubility of medicine ethanol, the dosage form (for example, tablet more tolerates ethanol than capsule) of constituent material of preparation (for example hydrophilic compounds more tolerates ethanol than hydrophobic compound) and preparation.

Other factors also can influence the release of the following medicine of ethanol existence from preparation in detail: the compression degree of dosage form (for example, the softer tablet of harder tablet more tolerates ethanol), tablet (is for example formed, the alcohol resistance of monolithic compositions is not as being wrapped in the multiparticle granule unit dosage forms in the gelatine capsule), and the existing of the similar agglomerative coating of tolerance ethanol stripping (for example, some cellulose).

Therefore, slow releasing preparation described herein can be used for preventing or significantly reducing the harmful effect that ethanol discharges from preparation medicine.Exemplary harmful effect comprises that dosage comes down in torrents and the change of slow release stripping scattergram.

The change of elution profiles can show in (for example) drug bioavailability curve, for example gives or give separately the change of back blood plasma Cot curve with alcoholic beverages.The parameter of conventional determining is drug level peak value (C _Max), C _MaxRising may improve the security risks of medicine; Concentration (C when treatment stage finishes _Min), C _MinReduce may reduce curative effect of medication.Compare the C of slow releasing preparation as herein described when absorbing with 40% ethanol with 0% ethanol _MaxThe average rising about 1.7 times.Think that this is an acceptable, because the C after the individual administration of feed (standard high fat diet) individuality and fasting _MaxRatio can change between about 0.7 to about 3.5, average C _MaxRatio is about 1.5.Therefore, has similar effect with taking medicine after 40% ethanol ingestion of drugs and the high fat diet.Compare C with 20% or 4% ethanol ingestion of drugs and high fat diet _MaxInfluence less, show as average C _MaxRatio is about 1.2 and about 1.1 respectively.

Under exemplary situation, the preparation that ethanol changes elution profiles may discharge relatively large medicine in (for example) after administration (for example in 0-6 hour), causes C _MaxThan specifying C _MaxHigher.If medicine is poisonous, than specifying C _MaxHigher C _MaxMay cause patient's toxic and side effects, comprise death.The result of this rapid release is that follow-up release medicine is less, the C of (just before giving subsequent dose) when causing treatment stage to finish _MinThan specifying C _MinLow.C _MinThan specifying C _MinThe low curative effect that can cause reduces, and perhaps even cause drug failure, causes the patient disease recurrence.

The C that is higher than the specific drug peak concentration _MaxCan for example be than specifying C _MaxHigh four times concentration.Be lower than and specify C _MinConcentration can for example be than specifying C _Min1/3rd lower concentration.

In pharmaceutical science Advisory Board on the 26th meeting October in 2005, the staff of FDA has provided in vivo test result after the approval of known drug.This test shows, can cause C with the beverage ingestion of drugs that contains 40% ethanol _MaxRaise 5 times, can cause C with the beverage ingestion of drugs that contains 20% ethanol _MaxDouble.Less with the average effect that the beverage ingestion of drugs that contains 5% ethanol causes, but the C of at least one object _MaxDouble.

Therefore, the safety of medicine under high concentration that can utilize slow releasing preparation as herein described to improve to have potential illeffects and reduce the abuse of the medicine (for example opioid) that produces glad effect.Reducing (for example being lower than the useful level of treatment) may cause patient health under the dysgenic situation at levels of drugs, and preparation as herein described also can be used for reducing or prevents injury to the patient.Preparation as herein described can be used for preparing the narrower medicine of valid density, is sometimes referred to as the narrower medicine of therapeutic index.

If preparation as herein described absorbs with pick-me-up, perhaps before or after drinking pick-me-up, absorb, said preparation keeps its sustained release property basically, and medicine will slowly discharge from gained hydrophilic gel substrate.

Because dosage can not taking place in the presence of alcoholic acid, preparation as herein described do not come down in torrents, they can be used for existing when absorbing with ethanol the pharmaceutical preparation of risk, the for example medicine of abuse potential and the medicine of drawing to ethanol and/or drug abuser, or will produce when excessive and be harmful to or the medicine of deadly side effect.The example of these medicines comprises opioid.

In addition, with common people's faciation ratio, suffer from panic disorder (with or without agoraphobia), how moving the patient of bipolar disorder (manic depressive illness), the acute mania relevant with bipolar disorder or mixed type outbreak, epilepsy, migraine, companion attention deficit hyperactivity disorder (ADHD), depression and/or the pain diseases probability of drinking higher.This just causes the patient to thirst for by drunk generation sense of euphoria and/or elimination or alleviates disease (for example pain) symptom.

Because medicine is from the slow release of preparation described herein, oral suction/picked-up or the sense of euphoria who produces immediately when patient (for example drug dependence person) can not feel to abuse conventional formulation (for example opiates preparation) during with the pick-me-up orally ingestible.Therefore, pharmaceutical preparation as herein described can not abused by the patient or abuse potential significantly reduces (for example, comparing with conventional opiates preparation).

For example, slow releasing preparation as herein described can be resisted the extraction of preparation of Chinese medicine, and this leaching process comprises the solid dosage forms grind into powder, pours in 95% ethanol, water becomes the ethanol of beverage intensity with the gained solution dilution, filters by coffee filter paper or other filter paper to remove not dissolved substance.Ethanol content in the ardent spirits is generally 40-45%.Think that this leaching process may be utilized by drug dependence person, wish to extract medicine (for example opioid) back abuse, use from the medicine of preparation extraction and inject from slow releasing preparation.

In addition, because the medicine release formulation of postponing slowly discharges in the persistent period that prolongs, many slow releasing preparation comprise the medicine of high level.Compare with the quick releasing formulation that contains a small amount of medicine usually, the slow releasing preparation that contains high amount of drug during inefficacy may be more harmful to the patient.Therefore, pharmaceutical preparation as herein described can improve in the safety that is higher than treatment harmful and/or lethal medicine during useful level.

4.4. slow release delivery system

The slow release delivery system comprises at least a hydrophilic compounds.In some embodiments, hydrophilic compounds is a natural gum, heteropolysaccharide glue for example, when forming contact liq to continue the gel-type vehicle that speed discharges medicine.

Medicine depends on the partition coefficient of medicine between gel-type vehicle assembly and gastrointestinal tract water from the rate of release of gel-type vehicle.In compositions as herein described, the weight ratio of medicine and hydrophilic compounds is about 1: 0.5 to about 1: 25 usually, perhaps is about 1: 0.5 to about 1: 20.The content of hydrophilic compounds is about 20-80 weight % usually in the slow release delivery system, is about 20-60 weight %, is about 40-60 weight %, or about 50 weight %.

Hydrophilic compounds can be any chemical compound known in the art.The example of hydrophilic compounds comprises natural gum, cellulose ether, acrylic resin, polyvinylpyrrolidone, protein derived chemical compound and their mixture.Exemplary natural gum comprises heteropolysaccharide glue and homopolysaccharide glue, for example xanthan gum, Tragacanth, pectin, arabic gum, karaya, alginic acid glue, agar, guar gum, hydroxypropyl guar gum, carrageenin, locust bean gum and gelling carbohydrate gum.Exemplary cellulose ether comprises hydroxy alkyl cellulose and carboxyl alkyl cellulose, for example hydroxyethyl-cellulose, hydroxypropyl cellulose, hydroxypropyl emthylcellulose, carboxymethyl cellulose and their mixture.Exemplary acrylic resin comprises acrylic acid, methacrylic acid, acrylic acid methyl ester. and Polymerization of Methyl thing and copolymer.In some embodiments, hydrophilic compounds is natural gum, for example heteropolysaccharide glue, for example xanthan gum or derivatives thereof.The derivant of xanthan gum for example comprises, takes off the carboxymethyl ester of acetyl xanthan gum, xanthan gum and the propylene glycol ester of xanthan gum.

In another embodiment, the slow release delivery system also comprises at least a cross-linking agent.Described cross-linking agent can be to make hydrophilic compounds be cross-linked to form the chemical compound of gel-type vehicle in the presence of liquid.The content of cross-linking agent is about 0.5-80 weight % usually in the slow release delivery system, is about 2-54 weight %, is about 20-30 weight %, or about 25 weight %.

Exemplary cross-linking agent comprises homopolysaccharide.Exemplary homopolysaccharide comprises galactomannan gum, for example guar gum, hydroxypropyl guar gum and locust bean gum.In some embodiments, cross-linking agent is locust bean gum, guar gum or their derivant.In other embodiments, cross-linking agent is alginate derivatives or hydrocolloid.

When the slow release delivery system comprised at least a hydrophilic compounds and at least a cross-linking agent, the ratio of hydrophilic compounds and cross-linking agent was about 1: 9 to about 9: 1 usually, or about 1: 3 to about 3: 1.In some embodiments, the slow release delivery system also comprises one or more cationic crosslinked chemical compounds.

In some embodiments, can use cationic crosslinked chemical compound replace cross-linking agent or with the cross-linking agent coupling.The consumption of cationic crosslinked chemical compound can make hydrophilic compounds be cross-linked to form gel-type vehicle in the presence of liquid.The cationic crosslinked dose of consumption in the slow release delivery system is about 0.5-30 weight %, or about 5-20 weight %.

Exemplary cationic crosslinked chemical compound comprises monovalent metal cation, multivalent metal cation and inorganic salt, comprises alkali metal and/or alkali earth metal sulfate, chloride, borate, bromide, citrate, acetate, lactate and their mixture.For example, cationic crosslinked mixture can be following one or more: calcium sulfate, sodium chloride, potassium sulfate, sodium carbonate, lithium chloride, tripotassium phosphate, sodium borate, potassium bromide, potassium fluoride, sodium bicarbonate, calcium chloride, magnesium chloride, sodium citrate, sodium acetate, calcium lactate, magnesium sulfate, sodium fluoride or their mixture.

When the slow release delivery system comprised at least a hydrophilic compounds and at least a cationic crosslinked chemical compound, the ratio of hydrophilic compounds and cationic crosslinked chemical compound was about 1: 9 to about 9: 1 usually, or about 1: 3 to about 3: 1.

Contact liq forms chemical compound (for example at least a hydrophilic compounds and at least a cross-linking agent of two kinds of character of gel-type vehicle, or at least a hydrophilic compounds and at least a cationic crosslinked chemical compound) can make chemical compound/cross-linking agent fast hydrating, form gel-type vehicle with high-gel strength.Realize the concrete combination maximization (for example at least a hydrophilic compounds and at least a cross-linking agent, or at least a hydrophilic compounds and at least a cationic crosslinked chemical compound) of these required two kinds of character of sustained-release gel substrate according to chemical compound.For example, hydrophilic compounds (for example xanthan gum) has the moisture wicking character of the excellence of fast hydrating.Hydrophilic compounds with the rigidity spiral ordered structure that can make hydrophilic compounds crosslinked material (for example cross-linking agent and/or cationic crosslinked chemical compound) coupling takes place will produce synergism to improve than the higher gel-type vehicle of expection viscosity.

In some embodiments, the slow release delivery system also comprises one or more medicinal diluents known in the art.Exemplary medicinal diluent comprises monosaccharide, disaccharidase, polyhydroxy-alcohol and their combination, for example starch, lactose, dextrose, sucrose, microcrystalline Cellulose, Sorbitol, xylitol, fructose and their mixture.In other embodiments, medicinal diluent is water miscible, for example lactose, dextrose, sucrose or their mixture.The ratio of medicinal diluent and hydrophilic compounds is about 1: 8 to about 8: 1 usually, or about 1: 3 to about 3: 1.The slow release delivery system comprises content usually and is about 20-80 weight %, one or more medicinal diluents of for example about 35 weight %.In other embodiments, the slow release delivery system comprises one or more medicinal diluents that content is about 40-80 weight %.

In some embodiments, the slow release delivery system also comprises one or more hydrophobic polymers.The consumption of hydrophobic polymer should be enough to slow down the hydration of hydrophilic compounds and can not destroy it.For example, the content of hydrophobic polymer is about 0.5-20 weight % usually in the slow release delivery system, is about 2-10 weight %, is about 3-7 weight %, or about 5 weight %.

Exemplary hydrophobic polymer comprises: alkylcellulose (for example, C _1-6Alkylcellulose, carboxymethyl cellulose), other hydrophobic fiber cellulosic material or chemical compound are (for example, acetic acid-phthalic acid cellulose esters, Hydroxypropyl Methylcellulose Phathalate ester), polyvinyl acetate polymer (for example, polyvinyl acetate phthalate), the polymer of acrylic acid and/or methacrylate or copolymer, zein, wax, lac, hydrogenated vegetable oil and their mixture.Hydrophobic polymer for example can be methylcellulose, ethyl cellulose or propyl cellulose.

Compositions as herein described can be further with one or more wetting agent (for example GREMAPHOR GS32, polyethoxylated hydrogenated castor, be derived from Oleum Ricini the polyethoxylated fatty acid, be derived from the polyethoxy fatty acid of castor oil hydrogenated), one or more lubricants (for example magnesium stearate), one or more buffer agents, one or more coloring agent, and/or other conventional ingredients mix.

In some embodiments, the sane slow releasing preparation that comprises medicine is a solid preparation, oral solid formulation for example, for example tablet, comprise many particulate capsules, Sublingual tablet, powder agent, granule, tablet or capsule or granule.In some embodiments, oral solid formulation is a tablet.Tablet randomly comprises casing or hydrophobic coating.

4.5. comprise the sane slow releasing preparation of oxymorphone

In one embodiment, sane slow releasing preparation as herein described comprises oxymorphone or its pharmaceutically acceptable salt of the effective dose that eases pain.

The giving of oxymorphone usually is subjected to the low-down restriction of oxymorphone oral preparation of quick releasing bioavailability, needs carry out in per 4 hours frequent drug administration.The bioavailability of sane slow releasing preparation described herein is enough high, makes sane slow releasing preparation can be used for treating pain patients, and only need be administered once or twice every day.

The dosage of sane oxymorphone slow releasing preparation is enough at for example about 8-24 hour, or alleviating pain in the persistent period of about 12-24 hour prolongation.

But oxymorphone release oral solid dosage form formulation described herein every day four times, every day three times, twice of every day or administration once a day.

In some embodiments, comprise the sane slow releasing preparation orally ingestible of oxymorphone after, preparation contacts with gastro-intestinal Fluid, sane slow releasing preparation generation swelling and gelling and form hydrophilic gel substrate, oxymorphone discharges from this hydrophilic gel substrate.The swelling of gel-type vehicle causes the preparation bulk density to reduce, and provides gel-type vehicle is swum on the gastric content to realize that oxymorphone slowly discharges required buoyancy.The size of hydrophilic substrate depends on the size of original formulation, significantly near swelling and form obstruction pylorus inlet.Because oxymorphone is dispersed in the whole preparation (thereby being dispersed in whole gel-type vehicle), since the dispersion or the corrosion of hydrophilic gel substrate outside, the oxymorphone of release constant basis in the time per unit body.It is under one's belt floating that gel-type vehicle keeps, and said process continues to take place all to discharge up to oxymorphone.

In some embodiments, some component in the preparation, for example the chemical property of hydrophilic compounds (for example xanthan gum) makes this component be considered from buffer agent, to the dissolubility of oxymorphone and change insensitive basically along the pH in gastrointestinal tract path.And, think that the chemical property of this component is similar to some known mucosal adhesive material, for example polycarbophil.Its mucoadhesive properties is that the oral delivery system is needed.Therefore, loose interaction can take place with the mucin in the gastrointestinal tract in sane slow releasing preparation, thereby the another kind of pattern that realizes the constant delivery rate of oxymorphone is provided.

In one embodiment, according to USP drug release rules USP23 (its content is included into this paper as a reference), the dissolution rate in vitro of sane slow releasing preparation described herein is the about 15-50 weight of a stripping % oxymorphone after 1 hour, the about 45-80 weight of stripping % oxymorphone after 4 hours, stripping is at least about 80 weight % oxymorphones after 10 hours.Release characteristic can utilize one or more different water-fast and/or water soluble compounds in the external and body of sane slow releasing preparation described herein, utilize different plasticizers, change the thickness of slow release thin film, be included in the chemical compound that adjustment release is provided in the coating, and/or provide by the path of coating and regulate.

Some embodiments provide and comprise about 1-200 milligram oxymorphone hydrochloride, or about 5-80 milligram oxymorphone hydrochloride; With about 80-200 milligram slow release delivery system, or about 120-200 milligram slow release delivery system, or the sane slow-release solid dosage formulation of about 160 milligrams of slow release delivery systems; Wherein, described slow release delivery system comprises about 8.3-41.7% locust bean gum, or about 25% locust bean gum; At least about 30% particulate diameter less than about 53 microns about 8.3-41.7% xanthan gum, or at least about 30% particulate diameter less than about 53 microns about 25% xanthan gum; About 20-55% dextrose, or about 35% dextrose; About 5-20% calcium sulfate dihydrate, or about 10% calcium sulfate dihydrate; With about 2-10% ethyl cellulose, or about 5% ethyl cellulose.

Other embodiments provide and comprise about 1-200 milligram oxymorphone hydrochloride, or about 5-80 milligram oxymorphone hydrochloride; With about 80-200 milligram slow release delivery system, or about 120-200 milligram slow release delivery system, or the sane slow-release solid dosage formulation of about 160 milligrams of slow release delivery systems; Wherein, described slow release delivery system comprises about 8.3-41.7% locust bean gum, or about 25% locust bean gum; Xanthan gum granule at least about 30% can perhaps can pass through about 25% xanthan gum of #270 mesh screen by about 25-41.7% xanthan gum of #270 mesh screen at least about 30% granule; About 20-55% dextrose, or about 35% dextrose; About 5-20% calcium sulfate dihydrate, or about 10% calcium sulfate dihydrate; With about 2-10% ethyl cellulose, or about 5% ethyl cellulose.

Some embodiments provide and comprise about 1-200 milligram oxymorphone hydrochloride, or about 5-80 milligram oxymorphone hydrochloride; With about 200-420 milligram slow release delivery system, or about 300-420 milligram slow release delivery system, or the sane slow-release solid dosage formulation of about 360 milligrams of slow release delivery systems; Wherein, described slow release delivery system comprises about 8.3-41.7% locust bean gum, or about 25% locust bean gum; At least about 30% particulate diameter less than about 53 microns about 8.3-41.7% xanthan gum, perhaps at least about 30% particulate diameter less than about 53 microns about 25% xanthan gum; About 20-55% dextrose, or about 35% dextrose; About 5-20% calcium sulfate dihydrate, or about 10% calcium sulfate dihydrate; With about 2-10% ethyl cellulose, or about 5% ethyl cellulose.

Other embodiments provide and comprise about 1-200 milligram oxymorphone hydrochloride, or about 5-80 milligram oxymorphone hydrochloride; With about 200-420 milligram slow release delivery system, or about 300-420 milligram slow release delivery system, or the sane slow-release solid dosage formulation of about 360 milligrams of slow release delivery systems; Wherein, described slow release delivery system comprises about 8.3-41.7% locust bean gum, or about 25% locust bean gum; Xanthan gum granule at least about 30% can perhaps can pass through about 25% xanthan gum of #270 mesh screen by about 8.3-41.7% xanthan gum of #270 mesh screen at least about 30% granule; About 20-55% dextrose, or about 35% dextrose; About 5-20% calcium sulfate dihydrate, or about 10% calcium sulfate dihydrate; With about 2-10% ethyl cellulose, or about 5% ethyl cellulose.

During orally give, patient's sane slow releasing preparation as herein described has with feature in the lower body: the peak serum concentration that (a) occurs oxymorphone after the administration in about 2-6 hour; (b) persistent period of oxymorphone analgesic effect is about 8-24 hour; (c) compare with the aqueous solution of the oxymorphone of oral administration, the relative bioavailability of oxymorphone is about 0.5-1.5.

Though oxymorphone compositions as herein described can the form with the single-activity medical compounds give in method as herein described, they also can with effectively one or more chemical compound couplings of known antagonism pain therapy.

In one embodiment, provide medicine box, medicine box comprises one or more containers, and one or more sane slow release Numorphans as herein described are housed in the container.Medicine box also can comprise the effective other drug chemical compound of known antagonism pain therapy in this area, and operation instruction.

4.6. the preparation of sane slow releasing preparation

Sane slow releasing preparation as herein described can be prepared by wet granulation.Solid dosage forms as herein described can be prepared by direct compacting or wet granulation.

In some embodiments, slow releasing preparation can be prepared by wet granulating technique.In wet granulating technique, each component (for example hydrophilic compounds (as xanthan gum), cross-linking agent, medicinal diluent, cationic crosslinked chemical compound, hydrophobic polymer etc.) is mixed, use one or more liquid (for example water, propylene glycol, glycerol, ethanol) moistening with preparation moistening material then, and then dry.Exsiccant improved grinding is become the granule of slow release delivery system with conventional equipment.Then, with the slow release delivery system with institute's expense and medicine, one or more optional wetting agent, one or more lubricants, one or more buffer agents, one or more coloring agent, or other conventional ingredients mix with the preparation particulate compositions.Available high speed shear mixer mixing slow release delivery system and medicine.Medicine can be meticulous and be evenly dispersed in the slow release delivery system.(promptly 2,000-16 000psi.) carries out tabletting to a certain amount of particulate compositions that will be enough to prepare even batch tablet with common press power in the preparative scale tablet machine of routine.The degree that is difficult to hydration in the time of mixture should not being pressed into follow-up contact liq.The illustrative methods of preparation slow release delivery system can be referring to United States Patent (USP) 4,994, and 276,5,128,143,5,135,757,5,455,046,5,512,297 and 5,554,387, its content is included into this paper as a reference.

Be surprised to find that, with non-aqueous solution (for example ethanol/ethyl cellulose suspension) when wet granulation prepares the slow release delivery system, the particle size influences preparation of hydrophilic compounds (for example xanthan gum) and the robustness and the integrity of solid dosage forms.

Specifically, the mark of granule hydrophilic compounds (for example xanthan gum) (for example, diameter is less than 53 microns) influences with the slow releasing preparation of the wet prilling process preparation of nonaqueous solvent and the robustness and the integrity of solid dosage forms.For example, be lower than a certain mark (for example about 30%) if be used to prepare the granule xanthan gum that the xanthan gum of preparation comprises, then slow releasing preparation is easy to lose efficacy.When the mark of the granule xanthan gum that is used to prepare preparation meets or exceeds a certain threshold value, preparation is sane and be difficult for losing efficacy.For example, if meet or exceed about 30% xanthan gum granular preparation less than 53 microns score threshold, the then robustness of preparation and solid dosage forms and integrity no change (referring to table 4).

It will be understood by those skilled in the art that other that also can adopt xanthan gum granular size and threshold score make up makes sane slow releasing preparation described herein.For example, when threshold score less than about 30%, for example be about 5-25%, or during about 10-20%, comprising diameter is sane less than the particulate preparation of 45,38,32,25 or 20 microns xanthan gum.When threshold score greater than about 30%, for example be about 30-100%, or during about 50-90%, comprising diameter is sane less than the particulate preparation of 63,75,90,106,125 or 150 microns xanthan gum.Can control by the particle size distribution of control hydrophilic compounds (for example xanthan gum) with the slow releasing preparation of non-aqueous solution pelletize and the robustness and the integrity of solid dosage forms.The control of the particle size distribution of hydrophilic compounds can realize in the following manner, for example by the granularity of mesh screen (for example #270 mesh screen) screening hydrophilic compounds (for example xanthan gum), makes granularity pass through mesh screen less than the granule of a certain standard (for example diameter is 53 microns).Have required fractional required size batch, batch and the combination can be used for mixing to prepare sane slow releasing preparation with other components.

Perhaps, hydrophilic compounds (for example xanthan gum) be can prepare, screening or other courses of processing need not in this case with desired particle size distribution.And the hydrophilic compounds (for example, particle mean size, minimum particle size, maximum particle size or its compositions) with desired particle size distribution can obtain by extraneous, for example buys from manufacturer or distributor.

When water or any other aqueous solution wet granulation prepared the slow release delivery system, the granularity of hydrophilic compounds (for example xanthan gum) can not impact (referring to table 5) to the robustness and the integrity of slow releasing preparation and solid dosage forms.

The particle mean size of pharmaceutical preparation is about the 50-400 micron before the tabletting, or about 185-265 micron.The average density of pharmaceutical preparation is about 0.3-0.8g/ml, or about 0.5-0.7g/ml.Usually the hardness of the tablet that is formed by pharmaceutical preparation is about 6-8kg.

When utilizing wet granulation rather than direct compression process to carry out the tabletting step in the process of preparation solid dosage forms, the granularity of hydrophilic compounds (for example xanthan gum) can not impact the robustness and the stripping character of solid dosage forms.

In some embodiments, the sustained release coating on the inner core comprises at least a medicine.For example, available slow release film wrapped pastille inner core will be in case contact liq will discharge medicine from inner core to continue speed.

In one embodiment, sustained release coating comprises at least a water-fast chemical compound.Water-fast chemical compound can be a hydrophobic polymer.Hydrophobic polymer can be identical or different with the hydrophobic polymer that adopts in the slow release delivery system.Exemplary hydrophobic polymer comprises: alkylcellulose (for example, C _1-6Alkylcellulose, carboxymethyl cellulose), other hydrophobic fiber cellulosic material or chemical compound are (for example, acetic acid-O-phthalic acid cellulose, Hydroxypropyl Methylcellulose Phathalate), polyvinyl acetate polymer (for example, polyvinyl acetate phthalate), the polymer of acrylic acid and/or methacrylate or copolymer, zein, wax (use separately or with aliphatic alcohol coupling), lac, hydrogenated vegetable oil and their mixture.Hydrophobic polymer for example can be methylcellulose, ethyl cellulose or propyl cellulose.The sane slow releasing preparation of available water-fast chemical compound parcel, weight increases about 1-20 weight %.

Sustained release coating also can comprise at least a plasticizer, for example triethyl citrate, dibutyl phthalate, propylene glycol, Polyethylene Glycol or their mixture.

Sustained release coating also can comprise at least a water soluble compound, for example polyvinylpyrrolidone, hydroxypropyl emthylcellulose or their mixture.The slow release delivery system can comprise at least a water soluble compound, and content is about 1-6 weight %, for example about 3 weight %.

Can be sprayed onto by aqueous dispersion on the medicated core and sustained release coating is applied on the medicated core water-fast chemical compound.Medicated core can be the particulate compositions by the dried of blended drug powder and at least a binding agent or wet granulation preparation; by wrapping up the inertia beadlet, perhaps by blended drug powder and at least a spheroid reagent are carried out the particulate compositions that spheroidization obtains with medicine and at least a binding agent.Exemplary binding agent comprises hydroxypropyl emthylcellulose.Exemplary spheroid reagent comprises microcrystalline Cellulose.Inner core can be by compressed granulate or by suppressing the tablet of pastille powder preparation.

In other embodiments, the available sustained release coating parcel as herein described compositions that comprises at least a medicine and slow release delivery system described herein.In other embodiments, the available hydrophobic polymer parcel as herein described compositions that comprises at least a medicine and slow release delivery system described herein.In other embodiments, available casing, for example acetic acid-phthalic acid cellulose esters, Hydroxypropyl Methylcellulose Phathalate ester, polyvinyl acetate phthalate, methacrylic acid copolymer, lac, succinic acid hydroxypropyl emthylcellulose ester, acetic acid-trimellitic acid cellulose esters or their the mixture parcel compositions that contains at least a medicine and slow release delivery system described herein.In other embodiments, available hydrophobic polymer parcel as herein described further wraps up the compositions that comprises at least a medicine and slow release delivery system described herein with casing as herein described.In any embodiment as herein described, can be randomly with the hydrophilic coating parcel compositions that comprises medicine and slow release delivery system described herein, this hydrophilic coating can be applied to above the release membranes or below, on hydrophobic coating or below, and/or on casing or below.Exemplary hydrophilic coating comprises hydroxypropyl emthylcellulose.

Be not subjected to the restriction of any theory of the present invention, behind the orally ingestible sustained release pharmaceutical formulation, preparation contacts with gastro-intestinal Fluid, slow releasing preparation swelling and gelling and form hydrophilic gel substrate, and medicine discharges from hydrophilic gel substrate.The swelling of gel-type vehicle causes the preparation bulk density to reduce, and provides gel-type vehicle is swum on the gastric content to realize that drug slow discharges required buoyancy.The size of hydrophilic substrate depends on the size of original formulation, significantly near swelling and form obstruction pylorus inlet.Because medicine is dispersed in the whole preparation (thereby being dispersed in whole gel-type vehicle),, can in the time per unit body, discharge the medicine of constant basis owing to the dispersion or the corrosion of hydrophilic gel substrate outside.This phenomenon is called as zero level release profiles or zero order kinetics.It is under one's belt floating that gel-type vehicle keeps, and said process continues to take place all to discharge up to medicine.

Do not wish to be subjected to the constraint of any theory of the present invention, some component in the preparation, for example the chemical property of hydrophilic compounds (for example xanthan gum) makes this component be considered from buffer agent, to the dissolubility of medicine and change insensitive basically along the pH in gastrointestinal tract path.And, think that the chemical property of this component is similar to some known mucosal adhesive material, for example polycarbophil.Its mucoadhesive properties is that the oral delivery system is needed.Therefore, slow releasing preparation potentially with gastrointestinal tract in mucin loose interaction takes place, thereby the another kind of pattern that realizes the constant delivery rate of medicine is provided.

Above-mentioned two kinds of phenomenons (hydrophilic gel substrate and mucosal adhesive restriction) are sane slow releasing preparation and mucin in the gastrointestinal tract and fluid interaction described herein and provide the possibility of constant drug delivery rate machine-processed.

4.7. the purposes of sane slow releasing preparation

When sane slow releasing preparation described herein and solid dosage forms can be used for the formulated inefficacy patient is caused dangerous medicine.When preparation as herein described can be used for providing preparation to lose efficacy with the solid dosage forms that comprises preparation the patient is caused dangerous (for example write out a prescription, give) medicine.The example of this medicine comprises for example opioid, for example oxymorphone.

Sane slow releasing preparation described herein and solid dosage forms can be used for treating disease (for example pain), by taking alcoholic acid patient's prescription when treating and/or treating the sane sustained release pharmaceutical formulation (for example, opioid such as oxymorphone) of effective dose with medicine.The treatment effective dose be the amount that is enough to eliminate or alleviate disease (that is, with give sane slow releasing preparation before the symptom that exists compare mitigation symptoms).

Though preparation as herein described and solid dosage forms can the form with the single-activity pharmaceutical composition give in method as herein described, they also can with effectively one or more chemical compounds and/or the compositions coupling of known antagonism treatment of diseases.

Medicine box is provided, and medicine box comprises one or more pharmaceutical preparation as herein described.Medicine box for example can comprise one or more containers, and one or more sane slow releasing preparation as herein described and/or solid dosage formss are housed in the container.Medicine box also can comprise the effective other drug chemical compound of known antagonism treatment of diseases in this area, and operation instruction.

5. embodiment

The following examples only are for the purpose of setting forth, rather than in order to limit the scope of appended claims.

Some experiments are carried out with salbutamol sulfate, and the dosage of salbutamol sulfate, dissolubility and other physicochemical properties are similar to opioid, for example oxymorphone and oxycodone.

Embodiment 1

Prepare TIMERx-with ethanol/ethyl cellulose granulation liquid

The slow release delivery system

According to United States Patent (USP) 4,994, the correlation technique of institute's discrimination method prepares many crowdes of TIMERx-in 276,5,128,143 and 5,554,387 (content of these patents is included into this paper as a reference)

The slow release delivery system.

(the Bu Lai company that accounts for of Australian general literary composition (Jungbunzlauer, Perhoven, Austria) or the CP Kelco of CPK company in Chicago, Illinois, Chicago, IL)) carries out testing graininess to many batches of xanthan gum to utilize a series of mesh screens.These mesh screens comprise the #270 mesh screen, and its permission diameter passes through (particulate) less than 53 microns particle.Measure by the particulate weight fraction of the xanthan gum of mesh screen (being the mark of xanthan gum particulate).Prepare the known batch of material of xanthan gum particulate weight fraction then.Xanthan gum, locust bean gum, calcium sulfate and the dextrose of necessary amounts done blending 3 minutes with preparation TIMERx-in high-speed mixer/comminutor

Ethyl cellulose is dissolved in prepares hydrophobic polymer (ethyl cellulose) serosity in the ethanol.This serosity is added in the above-mentioned dried blended mixture, in chipper/impeller operation, this material was carried out pelletize 4 minutes then.In fluidized bed dryer, granulation liquid is dried to LOD (drying loss) less than 9 weight % (for example, LOD is about 3-5% usually).Use 1.0mm (0.040 ") sieve abrasive grains then.The sustained release excipient composition is as shown in table 1:

Table 1

^*Remove in the course of processing

Embodiment 2

The water granulation liquid prepares TIMERx- The slow release delivery system

According to United States Patent (USP) 5,399, the correlation technique of institute's discrimination method prepares many crowdes of TIMERx-in 358 (content of this patent is included into this paper as a reference) The slow release delivery system.

According to the known xanthan gum batch of material of embodiment 1 preparation particulate mark.Xanthan gum, locust bean gum, calcium sulfate and the mannitol of necessary amounts is done blending 3 minutes with preparation TIMERx-in high-speed mixer/comminutor

In chipper/impeller operation, water is added in the dried blended mixture, mixture is carried out pelletize 3 minutes again.In fluidized bed dryer, granulation liquid is dried to drying loss (LOD) less than about 6 weight % then.Usually LOD is about 3-5%." the sieve abrasive grains of using 0.065 then.The composition of this slow release delivery system is as shown in table 2:

Table 2

^*Remove in the course of processing

Embodiment 3

Xanthan gum particulate with variable prepares slow releasing preparation and solid dosage forms

Make salbutamol sulfate, ProSolv

90 (silicified microcrystalline cellulose, the JRS drugmaker of New York Paterson (JRS Pharma LP, Patterson, New York)) and TIMERx-

Or TIMERx- Screening is passed through #20 order mesh screen with the preparation slow releasing preparation respectively.With salbutamol sulfate, ProSolv 90 and respectively according to embodiment 1 and 2 the preparation TIMERx-

Or TIMERx-

In the P/K Blendmaster V-mixer of Paterson-Kerry (Patterson-Kelley), mixed 11 minutes.With Pruv ^TM(sodium stearyl fumarate, NF, the JRS drugmaker of New York Paterson (JRS Pharma LP, Patterson, New York)) adds in this mixture, and mixture was mixed 5 minutes." circular standard concave hypotenuse device is pressed into the tablet that 224.0 milligrams, hardness are about 11Kp with the granulation liquid of blending with 5/16 on tablet machine.The composition of gained tablet is as shown in table 3.

Table 3

Embodiment 4

Stripping scattergram with the solid dosage forms of the xanthan gum particulate of variable preparation is measured

According to embodiment 3 described preparation TIMERx-

And TIMERx-

The salbutamol sulfate tablet of slow release delivery system.Adopt USP device 2 strippings test, in the kaliumphosphate buffer (pH4.5) of 900 milliliters of 50mM, estimate the stripping scattergram of tablet.Solution stirs under 50r.p.m..Take a sample at interval at preset time, sample volume is about 1.5 milliliters, continues about 14 hours always.

Adopt Waters The C18 post (before 4.6 * 250mm) (or equivalent form of values) and this post

SecurityGuard ^TM(4 * 3.0mm) guard columns are monitored the drug release of all tablets to C18 by RP-HPLC.The mensuration wavelength set is 226nm.Mobile phase is 85: 10: 5 acetonitrile by volume ratio: the methanol buffer constitutes.Buffer is made of 1 milliliter of triethylamine and the 1 milliliter of trifluoroacetic acid in 1 premium on currency.Column temperature is 30 ℃, and flow velocity is set at 1.5 ml/min.In order to be determined at each time point drug release percentage ratio, the concentration and the concentration of standard solution that are obtained sample each time period compare.The preparation of standard solution comprises: 45 milligrams of flow velocity albuterol are dissolved in the kaliumphosphate buffer (pH4.5) of 100 milliliters of 50mM, get 5 ml solns then and use the kaliumphosphate buffer (pH4.5) of more 50mM to be diluted to 50 milliliters.

Table 4 has shown the TIMERx-with the ethanol/ethyl cellulose pelletize of the xanthan gum that comprises the different grain size distribution

The stripping experimental result of the tablet of preparation.

Table 4

The TIMERx-of pelletize in ethanol/ethyl cellulose

The tablet that comprises 13.7% and 27.9% xanthan gum particulate almost discharge immediately near whole drug qualities.This is the example that undesirable dosage comes down in torrents.Contain 31.6% and the tablet of above xanthan gum particulate with the slow release mode stripping of expection.The data of table 4 show, contain to have an appointment 31.6% and the stripping scattergram there was no significant difference of the preparation of about 88.8% xanthan gum particulate.

Table 5 has shown the TIMERx-with the water pelletize of the xanthan gum that comprises the different grain size distribution

The stripping experimental result of the tablet of preparation.

Table 5

Water-pelletize the TIMERx-that comprises xanthan gum

The direct compressed tablet of preparation is insensitive to the xanthan gum granularity.The data of table 5 show, when water carries out pelletize to xanthan gum in the preparation process of preparation, with granularity less than 180 microns and granularity less than there was no significant difference between the stripping scattergram of the tablet of 75 microns xanthan gum preparation.

Tablet that table 6 has shown the straight pressing preparation and stripping scattergram with the slow releasing preparation of the particulate ethanol/ethyl cellulose of different fractional #270 (particulate) icteric sclera virgin rubber-pelletize.

Table 6

In the tabletting step with the TIMERx-that comprises of straight pressing or wet granulation preparation

Comparison shows that of stripping scattergram of tablet, when preparing tablet by straight pressing the robustness of tablet as if to the granularity sensitivity of xanthan gum, and insensitive to granularity by the tablet of wet granulation preparation.When preparing tablet, with the TIMERx-of the ethanol/ethyl cellulose pelletize that contains 27.9% particulate with wet granulation

The tablet of preparation has required stripping scattergram, and does not have this result with the tablet of straight pressing preparation.When xanthan gum particulate mark surpasses approximately 30% the time, the direct compacting of the preparation of ethanol/ethyl cellulose-pelletize produces the tablet with required stripping scattergram.

Embodiment 5

Anti-ethanol with the solid dosage forms of the xanthan gum particulate of variable preparation

TIMERx-according to embodiment 3 described preparation salbutamol sulfates The tablet of preparation.Stripping scattergram according to every kind of preparation of embodiment 4 described mensuration.The medium that adopts 40% ethanol and 60%0.1M HCl is as the stripping model under the ethanol existence.Select the biotic environment of 0.1M HCl simulation upper digestive tract/stomach, slow releasing preparation begins to discharge medicine at these positions.

Carry out the stripping experiment according to employing USP II type dissolving device mentioned above.Table 7 has shown the TIMERx-with the alcohol/ethyl cellulose pelletize of the xanthan gum that comprises the different grain size distribution

The stripping experimental result of the tablet of preparation.

Table 7

The TIMERx-of pelletize in ethanol/ethyl cellulose

The tablet that comprises 28% xanthan gum particulate almost discharge immediately near whole drug qualities.This is the example that undesirable dosage comes down in torrents.Contain 35% and the tablet of above xanthan gum particulate with the slow release mode stripping of expection.Data in the table 7 show, contain there was no significant difference between the stripping scattergram of preparation of the 35-86% xanthan gum particulate of having an appointment, though the stripping of preparation in 40% ethanol that contains 86% xanthan gum particulate is than slow slightly in standard buffer solution.

Therefore, contain 30% and the preparation of above xanthan gum particulate have sane stripping character, no matter whether exist the ethanol of beverage intensity can both be with the mode stripping that continues to discharge.

Embodiment 6

The sane slow release Numorphan and the preparation of solid dosage forms

Xanthan gum, locust bean gum, calcium sulfate dihydrate and dextrose are done blending a few minutes with the preparation controlled release delivery system in high-speed mixer/comminutor.Ethyl cellulose is mixed with ethanol with the preparation serosity.In the operation of chipper/impeller, above-mentioned serosity added do in the blended mixture, and carry out pelletize a few minutes.Then granulation liquid is dried to LOD (drying loss) less than about 10 weight %.Use the sieve abrasive grains then.The relative consumption of each composition that is used to prepare the slow release delivery system is shown in table 8A.

Table 8A

Excipient	Account for preparation percentage ratio
Excipient	Account for preparation percentage ratio	Locust bean gum, FCC	25.0
Xanthan gum, NF	25.0	Locust bean gum, FCC	25.0
Xanthan gum, NF	25.0	Dextrose, USP	35.0
Calcium sulfate dihydrate, NF	10.0	Dextrose, USP	35.0
Calcium sulfate dihydrate, NF	10.0	Ethyl cellulose, NF	5.0
Alcohol, SD3A (anhydrous)	(10)	Ethyl cellulose, NF	5.0
Alcohol, SD3A (anhydrous)	(10)	Total amount	100.0

Controlled release delivery system preparation shown in the utilization table 8A contains the tablet of 40 milligrams of oxymorphone hydrochlorides.The content of each composition is shown in table 8B in each tablet.

Table 8B

Embodiment 7

The anti-extractability of powdered slow release oxymorphone tablet

Test contains the TIMERx-of 40 milligrams of oxymorphones

The tablet of slow releasing preparation is through the abuse potential of intravenous route administration.The patients such as drug dependence person that attempt to abuse preparation may attempt extracting opioid and injecting gained solution from tablet.

The TIMERx-that contains 40 milligrams of oxymorphones according to the method preparation of embodiment

The tablet of slow releasing preparation also is ground into powder.In water extraction test, be dispersed in the gained powder in 30 ml waters and stirred 5 seconds.Extract in the test at 95% ethanol/water, the gained powder is distributed in 15 milliliter of 95% ethanol, stir in 5 seconds, dilute with 15 other ml waters then.In 95% ethanol extraction test, the gained powder is distributed in 30 milliliter 95 the ethanol and stirred 5 seconds.In various tests, made the gained solution left standstill 15 minutes, use filter paper filtering then.Adopt HPLC, 40 ℃, utilization

XDB-C18 post and UV detector are measured the oxymorphone that reclaims from filtrate at 230nm.The response rate of oxymorphone is as shown in table 9 in each test.

Table 9

Can pass through the TIMERx-of the xanthan gum preparation of #270 mesh screen with at least 30% granule

Preparation contains the slow releasing tablet of 40 milligrams of oxymorphones, and this slow releasing tablet grind into powder is also used water extraction, and about 3-4% oxymorphone is discharged in the water after 15 minutes.Be simulation abuse, tablet is added drop-wise in 95% ethanol, be diluted to then and can absorb concentration that the tablet of powdered at first is suspended in 95% ethanol and kept 5 seconds, dilute with water is to provide 47.5% alcoholic solution then.In this test, about 11-15% oxymorphone is discharged in water/alcoholic solution after 15 minutes.Therefore, with at least 30% granule can be by the #270 mesh screen slow release oxymorphone tablet anti-extraction under more than one potential abuse condition of 40 milligrams of powdered of xanthan gum preparation.

Embodiment 8

The stripping scattergram of slow release oxymorphone sheet under the alcoholic acid existence of beverage intensity

According to 40 milligrams of oxymorphone slow releasing tablet of embodiment 6 described preparations.Respectively 12 tablets are put into 500 milliliters of 0.1N HCl and concentration of alcohol and be ethanol/0.1N HCl solution of 4%, 20% and 40%, carry out dissolution test.As mentioned above, measure the release of oxymorphone by HPLC.

Tablet is kept perfectly in All Media in whole dissolution test process.The mean concentration of the oxymorphone that discharges is shown in table 10A.Calculate the similarity coefficient (f of ethanol dissolution medium and 0.1N HCl medium with standard method ₂), the result shows, the ethanol content inverse relationship in drug release rate and the dissolution medium.The increase of ethanol content moderately reduces drug release rate in the dissolution medium.

The dissolution test result is shown in table 10A.

Table 10A

^*The RSD=relative standard deviation

The highest 40% alcoholic acid existence can significance influence the stripping scattergram of 40 milligrams of oxymorphone slow releasing tablet.Compare with the stripping scattergram under no ethanol exists, 4% alcoholic acid existence has the significance influence to the stripping scattergram of 40 milligrams of oxymorphone slow releasing tablet.The release of oxymorphone and the ethanol content inverse relationship in the dissolution medium.20% and 40% alcoholic acid existence makes the release of oxymorphone slow down in the dissolution medium, but still discharges in a controlled manner.Concentration of alcohol is not observed dosage and is come down in torrents between 0% to 40%.Therefore, the tablet of slow releasing preparation described herein preparation can discharge oxymorphone in the presence of alcoholic acid in a controlled manner being up to few 40%.

Table 10B

For 4%, 20% and 40% alcoholic solution, contain ethanol medium and be respectively 97,60 and 45 with respect to the similarity coefficient of 0.1N HCl medium (ethanol content is 0%).Therefore, the ethanol of the oxymorphone sheet strength of anti-the beverage is up to and under few 40% alcoholic acid existence dosage can take place and come down in torrents.

Embodiment 9

Ethanol is to the influence of the bioavailability of oxymorphone in the oxymorphone slow releasing tablet

This test adopts the healthy volunteer to estimate and 240 milliliter 40%, 20%, the pharmacokinetic property of 4% and 0% (water) ethanol is parallel when giving 40 milligrams of oxymorphone slow releasing tablet.

Experimental design be in 28 volunteers, carry out at random, the single dose quadravalence section cross matching of open label.Be the opiates effect of blocking-up oxymorphone, after about 12 and 2 hours and administration before each oxymorphone administration 12 hours, give Naltrexone Hydrochloride (50 milligrams).Volunteer's overnight fasting is at least 8 hours before the administration.Except 1 hour, freely intaking after the administration preceding 1 hour of administration.Gave the standardization diet after the administration in 4 hours and 10 hours.

Four different periods, with 240 milliliters of A) 40% ethanol, B) 20% ethanol, C) 4% ethanol, or D) 0% ethanol gives 40 milligrams of oxymorphone slow releasing tablet.Obtained a series of blood samples after the administration in 0-48 hour.Oxymorphone in the analysed for plasma sample.Determine the pharmacokinetic parameter of oxymorphone with the noncompartmental method of data analysis.Calculate the C that natural logrithm transforms with least square average (LS is average) _Max, AUC _0-T and AUC _0-infPoint estimation and 90% confidence interval (CI).Any result that (0-12 hour) object during the dosing interval is taken place in vomiting is got rid of outside elementary pharmacokinetic analysis.

30 volunteers are recruited in test.25 volunteers finish test, and promptly these volunteers finish all four kinds of processing.The result that the object of vomiting takes place in the dosing interval (0-12 hour) is got rid of outside pharmacokinetic analysis.Processing A (40% ethanol) had 10 volunteers to vomit between 0-12 hour, and treatments B (20% ethanol) had 5 to vomit between 0-12 hour.Handling C (4% ethanol) or the no object of D (0% ethanol) vomits.Reject the processing gained data that vomiting takes place object, the average blood drug level-time data of every kind of processing is shown in the table 11.

Table 11

The statistical analysis of pharmacokinetic parameter is shown in the table 12.

Table 12

Object finish test and the geometric average ratio (GMR) of the result that can between 0-12 hour, not take place to vomit and 90%CI shown in the table 13.

Table 13

Mean plasma concentration-the time data of table 11 shows that 40% and 20% Ethanol Treatment is higher than the plasma concentration that 0% Ethanol Treatment produces in initial 4-6 hour.Concentration when the mean plasma concentration of 4% Ethanol Treatment is similar to 0% Ethanol Treatment.16-48 hour all data are suitable after the administration.4% and 0% Ethanol Treatment located to observe secondary peak at 5 hours, all four kinds of processing located all to observe secondary peak at 12 hours.Though the mean plasma concentration of 40% Ethanol Treatment is higher than 0%, 4% or 20% Ethanol Treatment in 0.5-6 hour, its concentration descends subsequently and located to be lower than other three kinds of results at 8-12 hour.C _MaxSeemingly directly related unique a kind of pharmacokinetic parameter (table 12) with Ethanol Treatment.By the ratio shown in the table 13 as can be known, compare with 0% Ethanol Treatment, 40% ethanol, 20% ethanol and 4% Ethanol Treatment cause C _MaxRaise 70%, 31% and 7% respectively.Compare with 0% ethanol, Ethanol Treatment causes AUC _0-tAnd AUC _0-infVariation between 1% to 13% (table 13).Remove C _MaxOutside, each group is not observed the pharmacokinetic parameter significant difference between handling.

Table 14 and 15 shows the analysis result (no matter whether they vomit) of all objects.Mean plasma concentration-the time data of every kind of processing (comprising the object that vomiting takes place) is shown in the table 14.

Table 14

Mean plasma concentration-the time graph (n=25) that comprises the result of the object that vomiting takes place showed (table 14), and 40% Ethanol Treatment located to have secondary peak at 5 hours, and this is also not obvious in table 11, and table 11 has only been summed up the result of 15 objects.The result and the table 11 of 20% Ethanol Treatment (n=25) are similar, have summed up the result of 20 objects in the table 11.4% obtains the result identical with table 11 with 0% Ethanol Treatment.As shown in table 12, C _MaxSeemingly directly related unique a kind of pharmacokinetic parameter (table 15) with Ethanol Treatment.

Table 15

By the GMR data shown in the table 16 as can be known, compare with 0% Ethanol Treatment, 40% ethanol, 20% ethanol and 4% Ethanol Treatment cause C _MaxRaise 62%, 15% and 8% respectively.Compare with 0% ethanol, Ethanol Treatment causes AUC _0-tAnd AUC _0-infVariation between-10% to 7% (table 16).When comprising the object that vomiting takes place, the C of 40% and 20% Ethanol Treatment object _Max, AUC _0-tAnd AUC _0-infIncrease.

Table 16

Embodiment 10

Food is to the influence of the bioavailability of 40 milligrams of oxymorphone slow releasing tablet and 4 * 10 milligrams of oxymorphone fast-release tablets

In the healthy volunteer, test, estimate the influence of food the bioavailability of 40 milligrams of oxymorphone slow releasing tablet and oxymorphone fast-release tablet (4 * 10 milligrams).Experimental design be in 28 volunteers, carry out at random, the single dose quadravalence section cross matching of open label.Estimate 40 milligrams of oxymorphone slow releasing tablet and 4 * 10 milligrams of oxymorphone fast-release tablets down with fasting state on the feed.Be the opiates effect of blocking-up oxymorphone, before each oxymorphone administration about 12 hours, give Naltrexone Hydrochloride (50 milligrams).Volunteer's overnight fasting is at least 8 hours before the administration.High fat breakfast is provided and is eating up administration in 10 minutes after the meal early to the feed process object.Every dosage gives with 240 ml waters.Do not allow object to absorb any other food after administration 4 hours.Obtained a series of blood samples after the administration in 0-72 hour.Oxymorphone in the analysed for plasma sample.Determine the pharmacokinetic parameter of oxymorphone with noncompartmental method.C with the conversion of LS average computation natural logrithm _Max, AUC _0-tAnd AUC _0-infPoint estimation and 90% confidence interval (CI).

25 objects are finished test.Mean plasma concentration-the time data of slow releasing tablet is shown in the table 17 under fasting and the feed treatment conditions.

Table 17

Shown in table 17, feed is handled than fasting and is handled the higher oxymorphone plasma concentration of generation in 8 hours initial processes.After the administration in 10-18 hour the mean plasma concentration of two kinds of processing modes similar.Fasting was handled and was located to observe secondary peak at 5 hours, and two kinds of processing located all to observe secondary peak at 12 hours.The average oxymorphone plasma concentration-time data of fast-release tablet is shown in the table 18 under fasting and the feed treatment conditions.Feed is handled than fasting and is handled the higher oxymorphone plasma concentration of generation in 10 hours initial processes.After the administration in 12-18 hour the mean plasma concentration of two kinds of processing modes similar.Fasting and feed processed group were located all visible secondary peak at 12 hours.

The average oxymorphone plasma concentration-time distribution map of oxymorphone fast-release tablet (4 * 10 milligrams) is shown in the table 18 under fasting and the feed treatment conditions.

Table 18

4 * 10 milligrams of oxymorphone fast-release tablets that feed is handled in 10 hours initial processes are handled than fasting and are produced higher oxymorphone plasma concentration.After the administration in 12-48 hour the mean plasma concentration of two kinds of processing modes similar.Fasting was handled and the feed processed group was located all visible secondary peak at 12 hours.For slow releasing tablet and fast-release tablet, the existence of food all causes C _MaxRaise, the existence of food causes AUC rising (table 19) in the fast-release tablet.By GMR data (table 20) as seen, compare with administration under the fasting state, food causes the C of slow releasing tablet and fast-release tablet _MaxRaise 51% and 38% respectively.For fast-release tablet, food causes AUC _0-tAnd AUC _0-infRaise 43% and 38% respectively.For the slow releasing tablet that gives with food, AUC _0-tAnd AUC _0-infIncrease is less than 10%, and 90%CI is 80-125%.

Table 19

Table 20

By GMR data (table 20) as seen, compare with administration under the fasting state, food causes the C of slow releasing tablet and fast-release tablet _MaxRaise 51% and 38% respectively.For fast-release tablet, food causes AUC _0-tAnd AUC _0-infRaise 43% and 38% respectively.For slow releasing tablet, cause AUC with food _0-tAnd AUC _0-infIncrease less, 90%CI is 80-125%.

In vitro study (embodiment 8) shows that 40% ethanol can not increase the dissolution rate of 40 milligrams of oxymorphone slow releasing tablet.Data show, can not damage mechanisms for drug release at the concentration of alcohol of beverage intensity, can not come in contact concentration oxymorphone too early release in vivo when being up to 40% ethanol.Yet human body ethanol test for data shows, gives 240 milliliter of 40% ethanol can cause 40 milligrams of oxymorphone slow releasing tablet up to low concentration 20% ethanol oxymorphone C simultaneously _MaxRaise, and AUC is had no significant effect (table 12 and 13).The interior result of external and body shows that the ethanol of beverage intensity can directly not influence the integrity of preparation, but may produce other effects, causes the obvious increase of oxymorphone absorption rate.

What is interesting is, when giving 40 milligrams of oxymorphone slow releasing tablet after the high fat diet, also observe the increase (table 19 and 20) of oxymorphone absorption rate.After high fat diet or with ethanol TIMERx-

The preparation the oxymorphone sheet time, the amplitude and the plasma concentration-time graph of increase are similar.This observed result shows, causes C _MaMay there be common mechanism between food that improves and the ethanol.After the high fat diet, the pharmacokinetic parameter of measuring after the oral solution administration behind the oxymorphone fast-release tablet also be affected (table 19 and 20).Except C _MaxOutside the increase, the AUC of fast-release tablet also increases, and this result with slow releasing tablet is different, and the AUC of slow releasing tablet does not significantly change after consume alcohol or the food.These difference promptings, alcoholic acid existence can not cause slow releasing tablet to discharge oxymorphone with accelerated speed, and the level that just is dissolved in the oxymorphone in the gastrointestinal tract is subjected to food or alcoholic acid influence.

In vitro results shows, does not have interaction between oxymorphone slow releasing preparation and the ethanol.The result of bioavailability study shows, have pharmacokinetic interaction when taking 40 milligrams of oxymorphone slow releasing tablet with 240 milligram of 40% ethanol (the expression alcohol panning is excessive), observed result is similar when giving the oxymorphone slow releasing tablet after the increase of gained blood drug level peak value and the standard high fat diet.The mechanism that this phenomenon is possible is unclear as yet at present.

Result based on data in in-vitro evaluation and the body early believes observed C _MaxIncrease be not that the disintegrate of slow release delivery system causes oxymorphone early to discharge (being that dosage comes down in torrents) that causes, but with the result of the remarkable increase of the irrelevant absorption rate of preparation.

Expectation will obtain similar result with other drug, because the character of slow-released system is obviously higher to the influence of stripping character than the character of preparation of Chinese medicine to the influence of preparation stripping character.Consideration with the ethanol dissolution test as the standard method in the open process of new sustained release product.

The content of the patent that this paper quotes, patent application and publication is included into this paper as a reference.

By foregoing, the of the present invention various improved forms except content described herein also are understood by one of ordinary skill in the art.These improved forms also fall within the scope of the appended claims.

Claims

1. slow releasing preparation, it comprises:

Medicine; With

The slow release delivery system, described system comprises hydrophilic gel, homopolysaccharide glue and medicinal diluent,

Wherein, can pass through the #270 mesh screen, absorb medicine that the back slow releasing preparation discharged less than about 70% in 2 hours with no ethanol or alcoholic beverages at least about 30% hydrophilic gel that is used to prepare slow releasing preparation.

2. slow releasing preparation as claimed in claim 1 is characterized in that described hydrophilic compounds is an xanthan gum.

3. slow releasing preparation as claimed in claim 1 is characterized in that, described slow release delivery system also comprises hydrophobic polymer.

4. slow releasing preparation as claimed in claim 1 is characterized in that, described slow release delivery system also comprises the cationic crosslinked chemical compound that is selected from univalent cation, polyvalent cation or salt.

5. slow releasing preparation as claimed in claim 1 is characterized in that described preparation also comprises coat, and described coat comprises hydrophobic polymer.

6. slow releasing preparation as claimed in claim 1 is characterized in that described preparation also comprises coat, and described coat comprises plasticizer.

7. slow releasing preparation as claimed in claim 1 or 2, it is characterized in that, described medicine is selected from: the dextroisomer and the d of alprazolam, lithium carbonate, divalproex sodium, dexamphetamine and amphetamine and amphetamine saccharate, other pharmaceutically acceptable salts of neutral sulfatase, tramadol hydrochloride and these active pharmaceutical ingredients of l-amphetamine aspartic acid monohydrate.

8. slow releasing preparation as claimed in claim 1 or 2 is characterized in that described medicine is an opioid.

9. slow releasing preparation as claimed in claim 8 is characterized in that, described opioid is μ-agonist or blended μ-agonist/antagonist.

10. sustained release preparation as claimed in claim 9; It is characterized in that described opioid is selected from: alfentanil; Allylprodine; Alphaprodine; Anileridine; Benzyl morphine; Bezitramide; Buprenorphine; Butorphanol; Clonitazene; Codeine; Cyclazocine; Desomorphine; Dextromoramide; Dezocine; Diampromide; Paracodin; Paramorphane; Dimenoxadol; Dimepheptanol; Dimethylthiambutene; Amidalgon; Dipipanone; Eptazocine; Ethoheptazine; Ethylmethylthiambutene; Dionin; Etonitazene; Fentanyl; Heroin; Hydrocodone; Hydromorphone; Hydroxypethidine; Isomethadone; Ketobemidone; Levallorphan; Levorphanol; Levophenacylmorphan; Lofentanil; Pethidine; Meptazinol; Metazocine; Methadone; Metopon; Morphine; Myrophine; Nalbuphine; Narceine; Nicomorphine; Norlevorphanol; Normethadone; Nalorphine; Normorphine; Norpipanone; Opium; Oxycodone; Oxymorphone; The 6-hydroxy-oxymorphone for use; Narsco; Pentazocine; Phenadoxone; Phenomorphan; Phenazocine; Phenoperidine; Piminodine; Pirinitramide; Proheptazine; Trimeperidine; Properidine; Propiram; Dextropropoxyphene; Sufentanil; C16H25NO2; Tilidine; Its stereoisomer; Its metabolin; Its ether; Its ester and derivative thereof.

11. slow releasing preparation as claimed in claim 10 is characterized in that, described opioid is an oxymorphone.

12. a slow releasing preparation, it comprises:

Medicine; With

The slow release delivery system, described system comprises hydrophilic gel, is selected from univalent cation, the cationic crosslinked chemical compound and the medicinal diluent of polyvalent cation or salt,

13. slow releasing preparation as claimed in claim 12 is characterized in that, described hydrophilic compounds is an xanthan gum.

14. slow releasing preparation as claimed in claim 12 is characterized in that, described slow release delivery system also comprises hydrophobic polymer.

15. slow releasing preparation as claimed in claim 12 is characterized in that, described preparation also comprises coat, and described coat comprises hydrophobic polymer.

16. slow releasing preparation as claimed in claim 12 is characterized in that, described preparation also comprises coat, and described coat comprises plasticizer.

17. as claim 12 or 13 described slow releasing preparation, it is characterized in that, described medicine is selected from: the dextroisomer and the d of alprazolam, lithium carbonate, divalproex sodium, dexamphetamine and amphetamine and amphetamine saccharate, other pharmaceutically acceptable salts of neutral sulfatase, tramadol hydrochloride and these active pharmaceutical ingredients of l-amphetamine aspartic acid monohydrate.

18., it is characterized in that described medicine is an opioid as claim 12 or 13 described slow releasing preparation.

19. slow releasing preparation as claimed in claim 18 is characterized in that, described opioid is μ-agonist or blended μ-agonist/antagonist.

20. sustained release preparation as claimed in claim 19; It is characterized in that described opioid is selected from: alfentanil; Allylprodine; Alphaprodine; Anileridine; Benzyl morphine; Bezitramide; Buprenorphine; Butorphanol; Clonitazene; Codeine; Cyclazocine; Desomorphine; Dextromoramide; Dezocine; Diampromide; Paracodin; Paramorphane; Dimenoxadol; Dimepheptanol; Dimethylthiambutene; Amidalgon; Dipipanone; Eptazocine; Ethoheptazine; Ethylmethylthiambutene; Dionin; Etonitazene; Fentanyl; Heroin; Hydrocodone; Hydromorphone; Hydroxypethidine; Isomethadone; Ketobemidone; Levallorphan; Levorphanol; Levophenacylmorphan; Lofentanil; Pethidine; Meptazinol; Metazocine; Methadone; Metopon; Morphine; Myrophine; Nalbuphine; Narceine; Nicomorphine; Norlevorphanol; Normethadone; Nalorphine; Normorphine; Norpipanone; Opium; Oxycodone; Oxymorphone; The 6-hydroxy-oxymorphone for use; Narsco; Pentazocine; Phenadoxone; Phenomorphan; Phenazocine; Phenoperidine; Piminodine; Pirinitramide; Proheptazine; Trimeperidine; Properidine; Propiram; Dextropropoxyphene; Sufentanil; C16H25NO2; Tilidine; Its stereoisomer; Its metabolin; Its ether; Its ester and derivative thereof.

21. slow releasing preparation as claimed in claim 20 is characterized in that, described opioid is an oxymorphone.

22. a slow releasing preparation, it comprises:

Medicine; With

Wherein, less than about 53 microns, the medicine that slow releasing preparation discharged in 2 hours after no ethanol or alcoholic beverages absorb is less than about 70% at least about the 30% particulate diameter of hydrophilic gel that is used to prepare slow releasing preparation.

23. slow releasing preparation as claimed in claim 22 is characterized in that, described hydrophilic compounds is an xanthan gum.

24. slow releasing preparation as claimed in claim 22 is characterized in that, described slow release delivery system also comprises hydrophobic polymer.

25. slow releasing preparation as claimed in claim 22 is characterized in that, described slow release delivery system also comprises the cationic crosslinked chemical compound that is selected from univalent cation, polyvalent cation or salt.

26. slow releasing preparation as claimed in claim 22 is characterized in that, described preparation also comprises coat, and described coat comprises hydrophobic polymer.

27. slow releasing preparation as claimed in claim 22 is characterized in that, described preparation also comprises coat, and described coat comprises plasticizer.

28. as claim 22 or 23 described slow releasing preparation, it is characterized in that, described medicine is selected from: the dextroisomer and the d of alprazolam, lithium carbonate, divalproex sodium, dexamphetamine and amphetamine and amphetamine saccharate, the neutral sulfatase of l-amphetamine aspartic acid monohydrate, tramadol hydrochloride and other pharmaceutically acceptable salts of these medicines.

29., it is characterized in that described medicine is an opioid as claim 22 or 23 described slow releasing preparation.

30. slow releasing preparation as claimed in claim 29 is characterized in that, described opioid is μ-agonist or blended μ-agonist/antagonist.

31. sustained release preparation as claimed in claim 30; It is characterized in that described opioid is selected from: alfentanil; Allylprodine; Alphaprodine; Anileridine; Benzyl morphine; Bezitramide; Buprenorphine; Butorphanol; Clonitazene; Codeine; Cyclazocine; Desomorphine; Dextromoramide; Dezocine; Diampromide; Paracodin; Paramorphane; Dimenoxadol; Dimepheptanol; Dimethylthiambutene; Amidalgon; Dipipanone; Eptazocine; Ethoheptazine; Ethylmethylthiambutene; Dionin; Etonitazene; Fentanyl; Heroin; Hydrocodone; Hydromorphone; Hydroxypethidine; Isomethadone; Ketobemidone; Levallorphan; Levorphanol; Levophenacylmorphan; Lofentanil; Pethidine; Meptazinol; Metazocine; Methadone; Metopon; Morphine; Myrophine; Nalbuphine; Narceine; Nicomorphine; Norlevorphanol; Normethadone; Nalorphine; Normorphine; Norpipanone; Opium; Oxycodone; Oxymorphone; The 6-hydroxy-oxymorphone for use; Narsco; Pentazocine; Phenadoxone; Phenomorphan; Phenazocine; Phenoperidine; Piminodine; Pirinitramide; Proheptazine; Trimeperidine; Properidine; Propiram; Dextropropoxyphene; Sufentanil; C16H25NO2; Tilidine; Its stereoisomer; Its metabolin; Its ether; Its ester and derivative thereof.

32. slow releasing preparation as claimed in claim 31 is characterized in that, described opioid is an oxymorphone.

33. a slow releasing preparation, it comprises:

Medicine; With

34. slow releasing preparation as claimed in claim 33 is characterized in that, described hydrophilic compounds is an xanthan gum.

35. slow releasing preparation as claimed in claim 33 is characterized in that, described slow release delivery system also comprises hydrophobic polymer.

36. slow releasing preparation as claimed in claim 33 is characterized in that, described preparation also comprises coat, and described coat comprises hydrophobic polymer.

37. slow releasing preparation as claimed in claim 33 is characterized in that, described preparation also comprises coat, and described coat comprises plasticizer.

38. as claim 33 or 34 described slow releasing preparation, it is characterized in that, described medicine is selected from: the dextroisomer and the d of alprazolam, lithium carbonate, divalproex sodium, dexamphetamine and amphetamine and amphetamine saccharate, the pharmaceutically acceptable salt of neutral sulfatase, tramadol hydrochloride and other active pharmaceutical ingredients of l-amphetamine aspartic acid monohydrate.

39., it is characterized in that described medicine is an opioid as claim 33 or 34 described slow releasing preparation.

40. slow releasing preparation as claimed in claim 39 is characterized in that, described opioid is μ-agonist or blended μ-agonist/antagonist.

41. sustained release preparation as claimed in claim 40; It is characterized in that described opioid is selected from: alfentanil; Allylprodine; Alphaprodine; Anileridine; Benzyl morphine; Bezitramide; Buprenorphine; Butorphanol; Clonitazene; Codeine; Cyclazocine; Desomorphine; Dextromoramide; Dezocine; Diampromide; Paracodin; Paramorphane; Dimenoxadol; Dimepheptanol; Dimethylthiambutene; Amidalgon; Dipipanone; Eptazocine; Ethoheptazine; Ethylmethylthiambutene; Dionin; Etonitazene; Fentanyl; Heroin; Hydrocodone; Hydromorphone; Hydroxypethidine; Isomethadone; Ketobemidone; Levallorphan; Levorphanol; Levophenacylmorphan; Lofentanil; Pethidine; Meptazinol; Metazocine; Methadone; Metopon; Morphine; Myrophine; Nalbuphine; Narceine; Nicomorphine; Norlevorphanol; Normethadone; Nalorphine; Normorphine; Norpipanone; Opium; Oxycodone; Oxymorphone; The 6-hydroxy-oxymorphone for use; Narsco; Pentazocine; Phenadoxone; Phenomorphan; Phenazocine; Phenoperidine; Piminodine; Pirinitramide; Proheptazine; Trimeperidine; Properidine; Propiram; Dextropropoxyphene; Sufentanil; C16H25NO2; Tilidine; Its stereoisomer; Its metabolin; Its ether; Its ester and derivative thereof.

42. slow releasing preparation as claimed in claim 41 is characterized in that, described opioid is an oxymorphone.

43. a method for preparing slow releasing preparation, described slow releasing preparation comprises:

Medicine; With

The slow release delivery system,

Wherein, described slow release delivery system comprises hydrophilic gel, homopolysaccharide glue and medicinal diluent, and described method comprises:

Hydrophilic gel is provided, and at least 30% particulate diameter is less than about 53 microns;

Hydrophilic gel, homopolysaccharide glue and medicinal diluent are carried out pelletize to form granule;

With this granule and medicament mixed to form particulate compositions; With

Particulate compositions is exerted pressure with the preparation preparation.

44. method as claimed in claim 43 is characterized in that, described hydrophilic gel is an xanthan gum.

45. method as claimed in claim 43 is characterized in that, describedly provides step to comprise to accept hydrophilic gel.

46. method as claimed in claim 43 is characterized in that, the described step that provides comprises the manufacturing hydrophilic gel.

47. method as claimed in claim 43 is characterized in that, the described step that provides comprises the processing hydrophilic gel.

48. method as claimed in claim 47 is characterized in that, described procedure of processing comprises measures the particulate size of at least a portion polysaccharide glue.

49. method as claimed in claim 47 is characterized in that, described procedure of processing comprises makes at least a portion hydrophilic gel pass through sieve.

50. method as claimed in claim 49 is characterized in that, described sieve is the #270 mesh screen.

51. method as claimed in claim 43 is characterized in that, described method also is included at least a portion slow releasing preparation and applies coat.

52. method as claimed in claim 51 is characterized in that, described coat comprises hydrophobic polymer.

53. method as claimed in claim 51 is characterized in that, described coat comprises plasticizer.

54. method as claimed in claim 43 is characterized in that, described granulation step comprises mixes each composition with the aqueous solution of bag.

55. method as claimed in claim 43 is characterized in that, described granulation step comprises mixes each composition with alcoholic solution.

56. method as claimed in claim 55 is characterized in that, described alcoholic solution comprises ethanol.

57. method as claimed in claim 43 is characterized in that, described slow release delivery system also comprises the cationic crosslinked chemical compound that is selected from univalent cation, polyvalent cation or salt.

58. as claim 43 or 44 described methods, it is characterized in that, described medicine is selected from: the dextroisomer and the d of alprazolam, lithium carbonate, divalproex sodium, dexamphetamine and amphetamine and amphetamine saccharate, other pharmaceutically acceptable salts of neutral sulfatase, tramadol hydrochloride and these active pharmaceutical ingredients of l-amphetamine aspartic acid monohydrate.

59., it is characterized in that described medicine is an opioid as claim 43 or 44 described methods.

60. method as claimed in claim 59 is characterized in that, described opioid is μ-agonist or blended μ-agonist/antagonist.

61. method as claimed in claim 60; It is characterized in that described opioid is selected from: alfentanil; Allylprodine; Alphaprodine; Anileridine; Benzyl morphine; Bezitramide; Buprenorphine; Butorphanol; Clonitazene; Codeine; Cyclazocine; Desomorphine; Dextromoramide; Dezocine; Diampromide; Paracodin; Paramorphane; Dimenoxadol; Dimepheptanol; Dimethylthiambutene; Amidalgon; Dipipanone; Eptazocine; Ethoheptazine; Ethylmethylthiambutene; Dionin; Etonitazene; Fentanyl; Heroin; Hydrocodone; Hydromorphone; Hydroxypethidine; Isomethadone; Ketobemidone; Levallorphan; Levorphanol; Levophenacylmorphan; Lofentanil; Pethidine; Meptazinol; Metazocine; Methadone; Metopon; Morphine; Myrophine; Nalbuphine; Narceine; Nicomorphine; Norlevorphanol; Normethadone; Nalorphine; Normorphine; Norpipanone; Opium; Oxycodone; Oxymorphone; The 6-hydroxy-oxymorphone for use; Narsco; Pentazocine; Phenadoxone; Phenomorphan; Phenazocine; Phenoperidine; Piminodine; Pirinitramide; Proheptazine; Trimeperidine; Properidine; Propiram; Dextropropoxyphene; Sufentanil; C16H25NO2; Tilidine; Its stereoisomer; Its metabolin; Its ether; Its ester and derivative thereof.

62. method as claimed in claim 43 is characterized in that, described method also comprises the stripping scattergram of the described preparation of record in containing alcoholic solution.

63. method as claimed in claim 62 is characterized in that, described opioid is an oxymorphone.

64. a method for preparing slow releasing preparation, described slow releasing preparation comprises:

Medicine; With

The slow release delivery system,

Wherein, described slow release delivery system comprises hydrophilic gel, is selected from univalent cation, the cationic crosslinked chemical compound and the medicinal diluent of polyvalent cation or salt, and described method comprises:

With this granule and medicament mixed to form particulate compositions; With

Particulate compositions is exerted pressure with the preparation preparation.

65., it is characterized in that described hydrophilic compounds is an xanthan gum as the described method of claim 64.

66. as the described method of claim 64, it is characterized in that, describedly provide step to comprise to accept hydrophilic gel.

67., it is characterized in that the described step that provides comprises the manufacturing hydrophilic gel as the described method of claim 64.

68., it is characterized in that the described step that provides comprises at least a hydrophilic gel of processing as the described method of claim 64.

69., it is characterized in that described procedure of processing comprises measures the particulate size of at least a portion hydrophilic gel as the described method of claim 68.

70., it is characterized in that described procedure of processing comprises makes at least a portion hydrophilic gel pass through sieve as the described method of claim 68.

71., it is characterized in that described sieve is the #270 mesh screen as the described method of claim 70.

72., it is characterized in that described method also is included at least a portion slow releasing preparation and applies coat as the described method of claim 64.

73., it is characterized in that described coat comprises hydrophobic polymer as the described method of claim 72.

74., it is characterized in that described coat comprises plasticizer as the described method of claim 72.

75., it is characterized in that described granulation step comprises mixes each composition with the aqueous solution of bag as the described method of claim 64.

76., it is characterized in that described granulation step comprises mixes each composition with alcoholic solution as the described method of claim 64.

77., it is characterized in that described alcoholic solution comprises ethanol as the described method of claim 76.

78. as claim 64 or 65 described methods, it is characterized in that, described medicine is selected from: the dextroisomer and the d of alprazolam, lithium carbonate, divalproex sodium, dexamphetamine and amphetamine and amphetamine saccharate, other pharmaceutically acceptable salts of neutral sulfatase, tramadol hydrochloride and these active pharmaceutical ingredients of l-amphetamine aspartic acid monohydrate.

79., it is characterized in that described medicine is an opioid as claim 64 or 65 described methods.

80., it is characterized in that described opioid is μ-agonist or blended μ-agonist/antagonist as the described method of claim 79.

81. such as the described method of claim 80; It is characterized in that described opioid is selected from: alfentanil; Allylprodine; Alphaprodine; Anileridine; Benzyl morphine; Bezitramide; Buprenorphine; Butorphanol; Clonitazene; Codeine; Cyclazocine; Desomorphine; Dextromoramide; Dezocine; Diampromide; Paracodin; Paramorphane; Dimenoxadol; Dimepheptanol; Dimethylthiambutene; Amidalgon; Dipipanone; Eptazocine; Ethoheptazine; Ethylmethylthiambutene; Dionin; Etonitazene; Fentanyl; Heroin; Hydrocodone; Hydromorphone; Hydroxypethidine; Isomethadone; Ketobemidone; Levallorphan; Levorphanol; Levophenacylmorphan; Lofentanil; Pethidine; Meptazinol; Metazocine; Methadone; Metopon; Morphine; Myrophine; Nalbuphine; Narceine; Nicomorphine; Norlevorphanol; Normethadone; Nalorphine; Normorphine; Norpipanone; Opium; Oxycodone; Oxymorphone; The 6-hydroxy-oxymorphone for use; Narsco; Pentazocine; Phenadoxone; Phenomorphan; Phenazocine; Phenoperidine; Piminodine; Pirinitramide; Proheptazine; Trimeperidine; Properidine; Propiram; Dextropropoxyphene; Sufentanil; C16H25NO2; Tilidine; Its stereoisomer; Its metabolin; Its ether; Its ester and derivative thereof.

82., it is characterized in that described opioid is an oxymorphone as the described method of claim 81.

83., it is characterized in that described method also comprises the described slow releasing preparation of record or comprises the stripping scattergram of solid dosage forms in containing alcoholic solution of slow releasing preparation as the described method of claim 64.

84. a method for preparing slow releasing preparation, described slow releasing preparation comprises:

Medicine; With

The slow release delivery system,

Intermediate value and/or particle mean size are mixed with aqueous solution to form granule greater than about 53 microns hydrophilic gel, homopolysaccharide glue and medicinal diluent;

With this granule and medicament mixed to form particulate compositions; With

Particulate compositions is exerted pressure with the preparation preparation.

85., it is characterized in that described hydrophilic compounds is an xanthan gum as the described method of claim 84.

86., it is characterized in that described slow release delivery system also comprises the cationic crosslinked chemical compound that is selected from univalent cation, polyvalent cation or salt as the described slow releasing preparation of claim 84.

87., it is characterized in that described method also is included at least a portion slow releasing preparation and applies coat as the described method of claim 84.

88. as the described method of claim 84, it is characterized in that, described medicine is selected from: the dextroisomer and the d of alprazolam, lithium carbonate, divalproex sodium, dexamphetamine and amphetamine and amphetamine saccharate, other pharmaceutically acceptable salts of neutral sulfatase, tramadol hydrochloride and these active pharmaceutical ingredients of l-amphetamine aspartic acid monohydrate.

89., it is characterized in that described medicine is an opioid as claim 84 or 85 described methods.

90., it is characterized in that described opioid is μ-agonist or blended μ-agonist/antagonist as the described method of claim 89.

91. such as the described method of claim 90; It is characterized in that described opioid is selected from: alfentanil; Allylprodine; Alphaprodine; Anileridine; Benzyl morphine; Bezitramide; Buprenorphine; Butorphanol; Clonitazene; Codeine; Cyclazocine; Desomorphine; Dextromoramide; Dezocine; Diampromide; Paracodin; Paramorphane; Dimenoxadol; Dimepheptanol; Dimethylthiambutene; Amidalgon; Dipipanone; Eptazocine; Ethoheptazine; Ethylmethylthiambutene; Dionin; Etonitazene; Fentanyl; Heroin; Hydrocodone; Hydromorphone; Hydroxypethidine; Isomethadone; Ketobemidone; Levallorphan; Levorphanol; Levophenacylmorphan; Lofentanil; Pethidine; Meptazinol; Metazocine; Methadone; Metopon; Morphine; Myrophine; Nalbuphine; Narceine; Nicomorphine; Norlevorphanol; Normethadone; Nalorphine; Normorphine; Norpipanone; Opium; Oxycodone; Oxymorphone; The 6-hydroxy-oxymorphone for use; Narsco; Pentazocine; Phenadoxone; Phenomorphan; Phenazocine; Phenoperidine; Piminodine; Pirinitramide; Proheptazine; Trimeperidine; Properidine; Propiram; Dextropropoxyphene; Sufentanil; C16H25NO2; Tilidine; Its stereoisomer; Its metabolin; Its ether; Its ester and derivative thereof.

92., it is characterized in that described opioid is an oxymorphone as the described method of claim 91.

93., it is characterized in that described method also comprises the described slow releasing preparation of record or comprises the stripping scattergram of solid dosage forms in containing alcoholic solution of slow releasing preparation as the described method of claim 84.

94. a method for preparing slow releasing preparation, described preparation comprises:

Medicine; With

The slow release delivery system,

Intermediate value and/or particle mean size are mixed with aqueous solution to form granule greater than about 53 microns hydrophilic gel, cationic crosslinked chemical compound and medicinal diluent;

With this granule and medicament mixed to form particulate compositions; With

Particulate compositions is exerted pressure with the preparation preparation.

95., it is characterized in that described hydrophilic gel is an xanthan gum as the described method of claim 94.

96., it is characterized in that described method also is included at least a portion slow releasing preparation and applies coat as the described method of claim 94.

97. as claim 94 or 95 described methods, it is characterized in that, described medicine is selected from: the dextroisomer and the d of alprazolam, lithium carbonate, divalproex sodium, dexamphetamine and amphetamine and amphetamine saccharate, other pharmaceutically acceptable salts of neutral sulfatase, tramadol hydrochloride and these active pharmaceutical ingredients of l-amphetamine aspartic acid monohydrate.

98., it is characterized in that described medicine is an opioid as claim 94 or 95 described methods.

99., it is characterized in that described opioid is μ-agonist or blended μ-agonist/antagonist as the described method of claim 98.

100. such as the described method of claim 99; It is characterized in that described opioid is selected from: alfentanil; Allylprodine; Alphaprodine; Anileridine; Benzyl morphine; Bezitramide; Buprenorphine; Butorphanol; Clonitazene; Codeine; Cyclazocine; Desomorphine; Dextromoramide; Dezocine; Diampromide; Paracodin; Paramorphane; Dimenoxadol; Dimepheptanol; Dimethylthiambutene; Amidalgon; Dipipanone; Eptazocine; Ethoheptazine; Ethylmethylthiambutene; Dionin; Etonitazene; Fentanyl; Heroin; Hydrocodone; Hydromorphone; Hydroxypethidine; Isomethadone; Ketobemidone; Levallorphan; Levorphanol; Levophenacylmorphan; Lofentanil; Pethidine; Meptazinol; Metazocine; Methadone; Metopon; Morphine; Myrophine; Nalbuphine; Narceine; Nicomorphine; Norlevorphanol; Normethadone; Nalorphine; Normorphine; Norpipanone; Opium; Oxycodone; Oxymorphone; The 6-hydroxy-oxymorphone for use; Narsco; Pentazocine; Phenadoxone; Phenomorphan; Phenazocine; Phenoperidine; Piminodine; Pirinitramide; Proheptazine; Trimeperidine; Properidine; Propiram; Dextropropoxyphene; Sufentanil; C16H25NO2; Tilidine; Its stereoisomer; Its metabolin; Its salt; Its ether; Its ester and derivative thereof.

101., it is characterized in that described opioid is an oxymorphone as the described method of claim 100.

102. a method for the treatment of the disease patient, described method comprise give described patient treatment effective dose as each described slow releasing preparation in the claim 1,2,12,13,22,23,33 and 34.

103. a lenitive method, described method comprise give the patient treatment effective dose as each described slow releasing preparation in the claim 10,11,20,21,31,32,41 and 42.

104. one kind is reduced the method that sustained release pharmaceutical formulation generation dosage comes down in torrents, described method comprises and gives each described slow releasing preparation in patient such as the claim 1,12,22 and 33.

105. a solid dosage forms, it comprises as each described slow releasing preparation in the claim 10,11,20,21,31,32,41 and 42.

106. as the described solid dosage forms of claim 105, described dosage form comprises powder agent.

107. as the described solid dosage forms of claim 105, described dosage form comprises tablet.

108. as the described solid dosage forms of claim 105, described dosage form comprises capsule.

109. a slow releasing preparation, it comprises the slow release delivery system of about 5-80 milligram oxymorphone hydrochloride and about 80-360 milligram; Wherein said slow release delivery system comprises: about 8.3-41.7 weight % locust bean gum, about 8.3-41.7 weight % xanthan gum, wherein can pass through the #270 mesh screen at least about 30% xanthan gum granule, about 20-55 weight % dextrose, about 5-20 weight % calcium sulfate dihydrate and about 2-10% ethyl cellulose absorb the described slow releasing preparation in back with no ethanol or alcoholic beverages and are released in the medicine of release in 2 hours less than 70%.

110., it is characterized in that described preparation comprises about 20 milligrams of oxymorphone hydrochlorides as the described slow releasing preparation of claim 109.

111., it is characterized in that described preparation comprises about 160 milligrams of slow release delivery systems as the described slow releasing preparation of claim 109.

112., it is characterized in that described slow release delivery system comprises about 25% locust bean gum as the described slow releasing preparation of claim 109, about 25% xanthan gum, about 35% dextrose, about 10% calcium sulfate dihydrate and about 5% ethyl cellulose.

113., it is characterized in that described preparation also comprises coat as the described slow releasing preparation of claim 109.

114. a treatment suffers from the patient's of pain method, described method comprises treats effective dose such as the described slow releasing preparation of claim 109.

115. a slow releasing preparation, it comprises the slow release delivery system of about 5-80 milligram oxymorphone hydrochloride and about 300-420 milligram; Wherein said slow release delivery system comprises: about 8.3-41.7 weight % locust bean gum, about 8.3-41.7 weight % xanthan gum, wherein at least about 30% particulate preparation less than about 53 microns, about 20-55 weight % dextrose, about 5-20 weight % calcium sulfate dihydrate and about 2-10% ethyl cellulose absorb the described slow releasing preparation in back with no ethanol or alcoholic beverages and are released in the medicine of release in 2 hours less than 70%.

116., it is characterized in that described preparation comprises about 20 milligrams of oxymorphone hydrochlorides as the described slow releasing preparation of claim 115.

117., it is characterized in that described preparation comprises about 360 milligrams of slow release delivery systems as the described slow releasing preparation of claim 115.

118., it is characterized in that described slow release delivery system comprises about 25% locust bean gum as the described slow releasing preparation of claim 115, about 25% xanthan gum, about 35% dextrose, about 10% calcium sulfate dihydrate and about 5% ethyl cellulose.

119., it is characterized in that described preparation also comprises coat as the described slow releasing preparation of claim 115.

120. a treatment suffers from the patient's of pain method, described method comprises treats effective dose such as the described slow releasing preparation of claim 115.

121. a solid dosage forms, it comprises as each described slow releasing preparation among claim 109-113 and the 115-119.

122. as the described solid dosage forms of claim 121, described dosage form comprises powder agent.

123. as the described solid dosage forms of claim 121, described dosage form comprises tablet.

124. as the described solid dosage forms of claim 121, described dosage form comprises capsule.

125. one kind prevents to issue the method that crude drug agent amount is come down in torrents in the ethanol existence, described method comprises:

May take in the medicine that alcoholic acid patient provides the anti-alcoholic acid slow releasing preparation form of effective dose when carrying out Drug therapy, described preparation comprises:

Medicine; With

Slow release delivery system, described delivery system comprise at least a hydrophilic gel, at least a homopolysaccharide glue and at least a medicinal diluent,

126., it is characterized in that described patient has the substance abuse history as the described method of claim 125.

127., it is characterized in that described substance abuse is an alcohol abuse as the described method of claim 126.

128., it is characterized in that described substance abuse is a drug dependence as the described method of claim 126.

129., it is characterized in that described anti-alcoholic acid slow releasing preparation is a solid dosage forms as the described method of claim 125.

130., it is characterized in that described hydrophilic compounds is an xanthan gum as the described method of claim 125.

131. as the described method of claim 129, it is characterized in that, in case described solid dosage forms is pulverized or powdered after contact liq can form gel-type vehicle with its mucoadhesive properties.

132. as the described method of claim 129, it is characterized in that, in case described solid dosage forms is pulverized or powdered after contact liq can form viscous solution.

133. as the described method of claim 129, described solid dosage forms is a tablet.

134., it is characterized in that described slow release delivery system also comprises at least a hydrophobic polymer as the described method of claim 125, its content is less than about 5 weight %.

135., it is characterized in that described delivery system also comprises at least a cationic crosslinked chemical compound that is selected from univalent cation, polyvalent cation or salt as the described method of claim 125.

136., it is characterized in that described medicine is antidepressants as the described method of claim 125.

137., it is characterized in that described medicine is the medicine that is used for the treatment of bipolar disorder, panic disorder, epilepsy, migraine and/or companion's attention deficit hyperactivity disorders that move more as the described method of claim 125.

138., it is characterized in that described medicine is an opioid as the described method of claim 125.

139., it is characterized in that described opioid is μ-agonist or blended μ-agonist/antagonist as the described method of claim 138.

140. such as the described method of claim 138; It is characterized in that described opioid is selected from: alfentanil; Allylprodine; Alphaprodine; Anileridine; Benzyl morphine; Bezitramide; Buprenorphine; Butorphanol; Clonitazene; Codeine; Cyclazocine; Desomorphine; Dextromoramide; Dezocine; Diampromide; Paracodin; Paramorphane; Dimenoxadol; Dimepheptanol; Dimethylthiambutene; Amidalgon; Dipipanone; Eptazocine; Ethoheptazine; Ethylmethylthiambutene; Dionin; Etonitazene; Fentanyl; Heroin; Hydrocodone; Hydromorphone; Hydroxypethidine; Isomethadone; Ketobemidone; Levallorphan; Levorphanol; Levophenacylmorphan; Lofentanil; Pethidine; Meptazinol; Metazocine; Methadone; Metopon; Morphine; Myrophine; Nalbuphine; Narceine; Nicomorphine; Norlevorphanol; Normethadone; Nalorphine; Normorphine; Norpipanone; Opium; Oxycodone; Oxymorphone; The 6-hydroxy-oxymorphone for use; Narsco; Pentazocine; Phenadoxone; Phenomorphan; Phenazocine; Phenoperidine; Piminodine; Pirinitramide; Proheptazine; Trimeperidine; Properidine; Propiram; Dextropropoxyphene; Sufentanil; C16H25NO2; Tilidine; Its stereoisomer; Its metabolin; Its ether; Its ester and derivative thereof.

141. one kind prevents to issue the method that crude drug agent amount is come down in torrents in the ethanol existence of beverage intensity, described method comprises:

Medicine; With

The slow release delivery system, described delivery system comprises at least a hydrophilic gel, at least a cationics that is selected from univalent cation, polyvalent cation or salt quantizes compound and at least a medicinal diluent, wherein, can pass through the #270 mesh screen at least about 30% hydrophilic gel that is used to prepare slow releasing preparation, absorb medicine that the back slow releasing preparation discharged less than about 70% in 2 hours with no ethanol or alcoholic beverages.

142., it is characterized in that described patient has the drug dependence medical history as the described method of claim 141.

143., it is characterized in that described substance abuse is an alcohol abuse as the described method of claim 142.

144., it is characterized in that described substance abuse is a drug dependence as the described method of claim 142.

145., it is characterized in that described anti-alcoholic acid slow releasing preparation is a solid dosage forms as the described method of claim 141.

146., it is characterized in that described hydrophilic compounds is an xanthan gum as the described method of claim 141.

147. as the described method of claim 145, it is characterized in that, in case described solid dosage forms is pulverized or powdered after contact liq can form gel-type vehicle with its mucoadhesive properties.

148. as the described method of claim 145, it is characterized in that, in case described solid dosage forms is pulverized or powdered after contact liq can form viscous solution.

149. as the described method of claim 145, described solid dosage forms is a tablet.

150., it is characterized in that described slow release delivery system also comprises at least a hydrophobic polymer as the described method of claim 141, its content is less than about 5 weight %.

151., it is characterized in that described at least a cationic crosslinked chemical compound is a sodium salt as the described method of claim 141.

152., it is characterized in that described medicine is antidepressants as the described method of claim 141.

153., it is characterized in that described medicine is the medicine that is used for the treatment of bipolar disorder, panic disorder, epilepsy, migraine and/or companion's attention deficit hyperactivity disorders that move more as the described method of claim 141.

154., it is characterized in that described medicine is an opioid as the described method of claim 141.

155., it is characterized in that described opioid is μ-agonist or blended μ-agonist/antagonist as the described method of claim 154.

156. such as the described method of claim 155; It is characterized in that described opioid is selected from: alfentanil; Allylprodine; Alphaprodine; Anileridine; Benzyl morphine; Bezitramide; Buprenorphine; Butorphanol; Clonitazene; Codeine; Cyclazocine; Desomorphine; Dextromoramide; Dezocine; Diampromide; Paracodin; Paramorphane; Dimenoxadol; Dimepheptanol; Dimethylthiambutene; Amidalgon; Dipipanone; Eptazocine; Ethoheptazine; Ethylmethylthiambutene; Dionin; Etonitazene; Fentanyl; Heroin; Hydrocodone; Hydromorphone; Hydroxypethidine; Isomethadone; Ketobemidone; Levallorphan; Levorphanol; Levophenacylmorphan; Lofentanil; Pethidine; Meptazinol; Metazocine; Methadone; Metopon; Morphine; Myrophine; Nalbuphine; Narceine; Nicomorphine; Norlevorphanol; Normethadone; Nalorphine; Normorphine; Norpipanone; Opium; Oxycodone; Oxymorphone; The 6-hydroxy-oxymorphone for use; Narsco; Pentazocine; Phenadoxone; Phenomorphan; Phenazocine; Phenoperidine; Piminodine; Pirinitramide; Proheptazine; Trimeperidine; Properidine; Propiram; Dextropropoxyphene; Sufentanil; C16H25NO2; Tilidine; Its stereoisomer; Its metabolin; Its ether; Its ester and derivative thereof.

157. a method that improves the pharmaceutical preparation safety, described method comprises:

Medicine; With

The slow release delivery system, described slow release delivery system comprises at least a hydrophilic gel, at least a homopolysaccharide glue and at least a medicinal diluent, and the raising of wherein said safety is the controlled hydrophilic gel granularity and the result of the anti-alcoholic acid sustained release property of preparation.

158., it is characterized in that described patient has the drug dependence medical history as the described method of claim 157.

159., it is characterized in that described substance abuse is an alcohol abuse as the described method of claim 158.

160., it is characterized in that described substance abuse is a drug dependence as the described method of claim 158.

161., it is characterized in that described anti-alcoholic acid slow releasing preparation is a solid dosage forms as the described method of claim 157.

162., it is characterized in that described hydrophilic compounds is an xanthan gum as the described method of claim 157.

163. as the described method of claim 161, it is characterized in that, in case described solid dosage forms is pulverized or powdered after contact liq can form gel-type vehicle with its mucoadhesive properties.

164. as the described method of claim 161, it is characterized in that, in case described solid dosage forms is pulverized or powdered after contact liq can form viscous solution.

165. as the described method of claim 160, described solid dosage forms is a tablet.

166., it is characterized in that described slow release delivery system also comprises at least a hydrophobic polymer as the described method of claim 157, its content is less than about 5 weight %.

167., it is characterized in that described delivery system also comprises at least a cationic crosslinked chemical compound that is selected from univalent cation, polyvalent cation or salt as the described method of claim 157.

168., it is characterized in that described medicine is antidepressants as the described method of claim 157.

169., it is characterized in that described medicine is the medicine that is used for the treatment of bipolar disorder, panic disorder, epilepsy, migraine and/or companion's attention deficit hyperactivity disorders that move more as the described method of claim 157.

170., it is characterized in that described medicine is an opioid as the described method of claim 157.

171., it is characterized in that described opioid is μ-agonist or blended μ-agonist/antagonist as the described method of claim 170.

172. such as the described method of claim 171; It is characterized in that described opioid is selected from: alfentanil; Allylprodine; Alphaprodine; Anileridine; Benzyl morphine; Bezitramide; Buprenorphine; Butorphanol; Clonitazene; Codeine; Cyclazocine; Desomorphine; Dextromoramide; Dezocine; Diampromide; Paracodin; Paramorphane; Dimenoxadol; Dimepheptanol; Dimethylthiambutene; Amidalgon; Dipipanone; Eptazocine; Ethoheptazine; Ethylmethylthiambutene; Dionin; Etonitazene; Fentanyl; Heroin; Hydrocodone; Hydromorphone; Hydroxypethidine; Isomethadone; Ketobemidone; Levallorphan; Levorphanol; Levophenacylmorphan; Lofentanil; Pethidine; Meptazinol; Metazocine; Methadone; Metopon; Morphine; Myrophine; Nalbuphine; Narceine; Nicomorphine; Norlevorphanol; Normethadone; Nalorphine; Normorphine; Norpipanone; Opium; Oxycodone; Oxymorphone; The 6-hydroxy-oxymorphone for use; Narsco; Pentazocine; Phenadoxone; Phenomorphan; Phenazocine; Phenoperidine; Piminodine; Pirinitramide; Proheptazine; Trimeperidine; Properidine; Propiram; Dextropropoxyphene; Sufentanil; C16H25NO2; Tilidine; Its stereoisomer; Its metabolin; Its ether; Its ester and derivative thereof.

173. a method that improves the pharmaceutical preparation safety, described method comprises:

Medicine; With

The slow release delivery system, described delivery system comprises at least a hydrophilic gel, at least a cationics that is selected from univalent cation, polyvalent cation or salt quantizes compound and at least a medicinal diluent, and the raising of wherein said safety is the controlled hydrophilic gel granularity and the result of the anti-alcoholic acid sustained release property of preparation.

174., it is characterized in that described patient has the drug dependence medical history as the described method of claim 173.

175., it is characterized in that described substance abuse is an alcohol abuse as the described method of claim 174.

176., it is characterized in that described substance abuse is a drug dependence as the described method of claim 174.

177., it is characterized in that described anti-alcoholic acid slow releasing preparation is a solid dosage forms as the described method of claim 173.

178., it is characterized in that described hydrophilic compounds is an xanthan gum as the described method of claim 173.

179. as the described method of claim 177, it is characterized in that, in case described solid dosage forms is pulverized or powdered after contact liq can form gel-type vehicle with its mucoadhesive properties.

180. as the described method of claim 177, it is characterized in that, in case described solid dosage forms is pulverized or powdered after contact liq can form viscous solution.

181. as the described method of claim 177, described solid dosage forms is a tablet.

182., it is characterized in that described slow release delivery system also comprises at least a hydrophobic polymer as the described method of claim 173, its content is less than about 5 weight %.

183., it is characterized in that described at least a cationic crosslinked chemical compound is a sodium salt as the described method of claim 173.

184., it is characterized in that described medicine is antidepressants as the described method of claim 173.

185., it is characterized in that described medicine is the medicine that is used for the treatment of bipolar disorder, panic disorder, epilepsy, migraine and/or companion's attention deficit hyperactivity disorders that move more as the described method of claim 173.

186., it is characterized in that described medicine is an opioid as the described method of claim 173.

187., it is characterized in that described opioid is μ-agonist or blended μ-agonist/antagonist as the described method of claim 186.

188. such as the described method of claim 187; It is characterized in that described opioid is selected from: alfentanil; Allylprodine; Alphaprodine; Anileridine; Benzyl morphine; Bezitramide; Buprenorphine; Butorphanol; Clonitazene; Codeine; Cyclazocine; Desomorphine; Dextromoramide; Dezocine; Diampromide; Paracodin; Paramorphane; Dimenoxadol; Dimepheptanol; Dimethylthiambutene; Amidalgon; Dipipanone; Eptazocine; Ethoheptazine; Ethylmethylthiambutene; Dionin; Etonitazene; Fentanyl; Heroin; Hydrocodone; Hydromorphone; Hydroxypethidine; Isomethadone; Ketobemidone; Levallorphan; Levorphanol; Levophenacylmorphan; Lofentanil; Pethidine; Meptazinol; Metazocine; Methadone; Metopon; Morphine; Myrophine; Nalbuphine; Narceine; Nicomorphine; Norlevorphanol; Normethadone; Nalorphine; Normorphine; Norpipanone; Opium; Oxycodone; Oxymorphone; The 6-hydroxy-oxymorphone for use; Narsco; Pentazocine; Phenadoxone; Phenomorphan; Phenazocine; Phenoperidine; Piminodine; Pirinitramide; Proheptazine; Trimeperidine; Properidine; Propiram; Dextropropoxyphene; Sufentanil; C16H25NO2; Tilidine; Its stereoisomer; Its metabolin; Its ether; Its ester and derivative thereof.