CN107669649A - Solid dosage forms - Google Patents

Abstract

The present invention provides a kind of solid dosage forms for being suitable for release of bioactive substances in the oral cavity, wherein the formulation includes at least one bioactive substance and at least one matrix formers, wherein the formulation is substantially solubilized in the oral cavity.A kind of method for producing the solid dosage forms and a kind of medicine box for including the solid dosage forms are also provided.

Description

Solid dosage forms

The application be the applying date on October 11st, 2013, Application No. CN201380060281.3, it is entitled " Gu The divisional application of the application for a patent for invention of body formulation ".

Invention field

The present invention relates to the formulation for being suitable for applying to subject.Preferably, the solid dosage forms has Fast Stripping fast Rate.

Background

Tablet be it is a kind of to by oral administration come to the mankind deliver activating agent common dosage forms.For example, by sublingual viscous The medicine delivery of the oral mucosa of film allows instant medicine to be inhaled by the direct simple diffusion of jugular vein into systemic circulation Receive, so as to bypass intestines and stomach and first pass effect of hepar.The effect that epidural route generally produces rapidly and reliably occurs, and is more suitable for Expidet.

Unsatisfied needs be present to the formulation in the oral cavity with Fast Stripping speed in medical domain.To overcome Include effervescent tablet, film, chewable tablets, disintegrant and wicking agent to previous trial of solid dosage forms the problem of related.This A little formulations are especially suitable for being difficult to the patient swallowed, such as children and older personnel.In the presence of for preparing some of such formulation Technology, including be freeze-dried, be spray-dried, tablet molding and tablet press.

Freeze-drying method has been used for preparing Fast-dissolving solid forms.Depending on manufacture method, the feature of the product of acquisition exists In highly porous micro- knot of the active dose of homogenous disperse in support matrix (i.e. mannitol, glycine, lactose, gelatin etc.) Structure.This technology produce it is quick be dissolved in the water or oral cavity in product；However, the bad physical integrity of its physical arrangement Further manufacturing operation is seriously limited, such as forms blister package.In addition, Freeze Drying Technique has in terms of the formulation is manufactured High production cost, because the duration of each lyophilization cycle is very long (usual 24 to 48 hours).The complexity of industrial premises This technology of large-scale use is detrimental to develop another key factor of dissolving tablet.In addition, followed as each freeze-drying The thermal shock of the direct result of ring may physically changed microencapsulated particles outer membrane physicochemical properties.

In freeze-drying method, gelatin and other gelatin associated materials have been used for preparing the medicament in Expidet.It is bright Glue is carrier or structure-forming agent, and it is commonly used for preparing the instant version of broad range of medicine.Gelatin carries to formulation For intensity, therefore prevent dosage form breaks and burst apart.This especially problem when formulation removes from blister package.Gelatin medicine from Quickly dissolving aspect is favourable to formulation, once because formulation is placed in the oral cavity, it provides the quick dissolving of formulation.

Gelatin is a kind of by partial hydrolysis animal collagen tissue, the protein obtained such as skin, tendon, ligament and bone. However, a significant problem on mammalian source gelatin is that it has plain taste.This causes Expidet needs to make With sweetener and flavor enhancement come the taste hiding and shelter components of gelatin.Another problem on conventional mammalian source property gelatin It is that it needs to use heat to influence Gelatin.This additional step adds time and cost to manufacturing process.

On using gelatin based material as Expidet matrix another problem is that gelatin can make the viscosity of solution at any time Between increase.This can cause processing difficulties.In addition, gelatin can cause the homogenieity related to gelatin solution and sedimentation during holding Problem.Other shortcomings of gelatin formulation include being easy to bacterial growth, and some individuals detest the fact that it comes from animal origin.

The other reagents for having been used for replacing gelatin in Expidet are starch and modified starch.One on starch is asked Topic be it in mouth when there is granular sensation for patients, and patient can be caused to be discontented with.Many modified starches also result in This problem.In addition, they are expensive.

Ketamine (Ketamine) is a kind of quick-acting systemic anesthetic being only approved for intravenous injection.In recent years Come, be used as the concern of the adminicle in acute and chronic pain management under non-narcotic dosage to it has increasingly increased.Its pain Pain improved property be attributed to it is noncompetitive with reference to Hog (phencyclidine) binding site and to N- methyl- The antagonism of D-Asp (NMDA) acceptor.When being applied under sub- level of anesthesia, ketamine effectively produces analgesia, and Display that opiates saves activity, but the mechanism of behind herein is still understood insufficient.The analgesic efficacy of ketamine is right with it The suppression that the activity of the receptor-mediated pain promotion of N-methyl-D-aspartate and the brain structure to be reacted to noxious stimulus reduces Make of fully related.Therefore, its effectiveness in terms of Acute Pain is managed is concerned.Although parenteral administration ketamine Almost instant pain relief, but this approach can be unsuitable for or be easy to patient may be provided.

Ring-type Guanosine 5'-Monophosphate (cGMP) 5 type phosphodiesterase (PDE5) inhibitor is a kind of cGMP reduced in smooth muscle Degradation Level, so as to cause smooth muscle relaxation and the increased compound of blood flow.The most well known type of ring-type Guanosine 5'-Monophosphate (cGMP) 5 Phosphodiesterase (PDE5) inhibitor is 'Xiduofeng ' (sildenafil), specifically citric acid 'Xiduofeng ' or 'Xiduofeng ' is typically to take in form of tablets for about 30 minutes to 4 hours before sexual intercourse.However, very fast action delivering 'Xiduofeng ' Or other type phosphodiesterase (PDE5) inhibitor of ring-type Guanosine 5'-Monophosphate (cGMP) 5 can be favourable, particularly make at them For the therapeutic agent of pulmonary hypertension other purposes when.

Adrenaline is a kind of hormone and neurotransmitter for being used to treat many symptom, and the symptom includes：Cardiac arrest With the other Cardiac Dysthythmias for causing cardiac output to weaken or lack；Allergy；Superficial is bled；And asthma, bronchial spasm And croup.Adrenaline delivers usually through automatic injector delivery system；However, the alternative delivering system for rapid delivery System can be advantageous to be unable to safely use automatic injector person (such as children and the treatment children person for being unfamiliar with automatic injector assembly) Be not intended to use described device person.

Therefore, in the art to delivering bioactive substance to patient by oral administration, such as N- methyl Ds-asparagus fern ammonia The quick-dissolving agent of acid acceptor antagonist, adrenaline or ring-type Guanosine 5'-Monophosphate (cGMP) 5 type phosphodiesterase (PDE5) inhibitor There are needs in type, wherein the formulation quickly dissolves in the oral cavity of the patient, and wherein described formulation is without using a large amount of Mammal gelatin.

Summary of the invention

According to an aspect of the present invention, there is provided a kind of solid formulation for being suitable for release of bioactive substances in the oral cavity Type, wherein the formulation includes：

(a) at least one bioactive substance, and

(b) at least one matrix formers, wherein the formulation is substantially solubilized in the oral cavity.

Preferably, solid dosage forms is Fast-dissolving solid forms.

Preferably, bioactive substance is selected from and includes following inventory：At least one type of ring-type Guanosine 5'-Monophosphate (cGMP) 5 Phosphodiesterase (PDE5) inhibitor, the active material with reference to one or more adrenergic receptors and N- methyl Ds-asparagus fern Propylhomoserin receptor antagonist.Preferably, N-methyl-D-aspartate receptor antagonist is selected from and includes following inventory：Dextromethorphan (dextromethorphan), dextrorphan (dextrorphan) or ketamine.Preferably, with reference to one or more adrenaline The active material of energy acceptor is adrenaline (adrenaline) (adrenal hormone (epinephrine)) or adrenaline salt. Preferably, ring-type Guanosine 5'-Monophosphate (cGMP) 5 type phosphodiesterase (PDE5) inhibitor is 'Xiduofeng ' or its is pharmaceutically acceptable Salt.Preferably, 'Xiduofeng ' salt is citric acid 'Xiduofeng '.

Preferably, formulation is suitable for not leaving the residue that can be detected by patient of the formulation in the oral cavity.

Preferably, formulation fater disintegration in the oral cavity, and allow instant bioactive substance by through oral mucosa Spread and directly diffuse in the systemic blood circulatory system and absorbed.By this method, first pass effect of hepar is avoided. Preferably, formulation is suitable for directly being delivered in systemic circulation by jugular vein, so as to bypass intestines and stomach and first pass effect of hepar.

According to another aspect of the present invention, there is provided it is a kind of to produce the present invention solid dosage forms method, it include with Lower step：

(a) at least one matrix formers are combined with bioactive substance to form uniform homogeneous blend；And

(b) mixture is freeze-dried to prepare the solid dosage forms of the present invention.

Preferably, methods described is a kind of producing the method for Fast-dissolving solid forms.

Preferably, bioactive substance is selected from and includes following inventory：At least one type of ring-type Guanosine 5'-Monophosphate (cGMP) 5 Phosphodiesterase (PDE5) inhibitor, the active material with reference to one or more adrenergic receptors and N- methyl Ds-asparagus fern Propylhomoserin receptor antagonist.Preferably, N-methyl-D-aspartate receptor antagonist is selected from and includes following inventory：Dextromethorphan, Dextrorphan or ketamine.Preferably, the active material with reference to one or more adrenergic receptors is on adrenaline or kidney Parathyrine salt.Preferably, ring-type Guanosine 5'-Monophosphate (cGMP) 5 type phosphodiesterase (PDE5) inhibitor be 'Xiduofeng ' or its pharmaceutically Acceptable salt.Preferably, 'Xiduofeng ' salt is citric acid 'Xiduofeng '.

According to another aspect of the present invention, there is provided a kind of medicine box, it includes：

(a) solid dosage forms, wherein the formulation includes：

(i) at least one bioactive substance, and

(ii) at least one matrix formers, and

(b) its operation instructions

Wherein described formulation is substantially solubilized in the oral cavity.Preferably, solid dosage forms is Fast-dissolving solid forms.Preferably, Bioactive substance is selected from and includes following inventory：At least one type phosphodiesterase of ring-type Guanosine 5'-Monophosphate (cGMP) 5 (PDE5) inhibitor, the active material with reference to one or more adrenergic receptors and N-methyl-D-aspartate acceptor are short of money Anti-agent.Preferably, N-methyl-D-aspartate receptor antagonist is selected from and includes following inventory：Dextromethorphan, dextrorphan or chlorine Amine ketone.Preferably, the active material with reference to one or more adrenergic receptors is adrenaline or adrenaline salt.It is preferred that Ground, ring-type Guanosine 5'-Monophosphate (cGMP) 5 type phosphodiesterase (PDE5) inhibitor is 'Xiduofeng ' or its pharmaceutically acceptable salt. Preferably, 'Xiduofeng ' salt is citric acid 'Xiduofeng '.

According to another aspect of the present invention, there is provided be suitable for discharging at least one ring-type Guanosine 5'-Monophosphate in the oral cavity (cGMP) solid dosage forms of 5 type phosphodiesterase (PDE5) inhibitor, wherein the formulation includes：

(a) at least one type phosphodiesterase (PDE5) inhibitor of ring-type Guanosine 5'-Monophosphate (cGMP) 5；With

(b) at least one matrix formers；

Wherein described formulation is substantially solubilized in the oral cavity.Preferably, solid dosage forms is Fast-dissolving solid forms.Preferably, Ring-type Guanosine 5'-Monophosphate (cGMP) 5 type phosphodiesterase (PDE5) inhibitor is 'Xiduofeng ' or its pharmaceutically acceptable salt.It is excellent Selection of land, 'Xiduofeng ' salt are citric acid 'Xiduofeng 's.

According to another aspect of the present invention, there is provided one kind is suitable for discharging in the oral cavity with reference to one or more adrenaline The solid dosage forms of the active material of energy acceptor, wherein the formulation includes：

(a) active material of one or more adrenergic receptors is combined；With

(b) at least one matrix formers；

Wherein described formulation is substantially solubilized in the oral cavity.Preferably, solid dosage forms is Fast-dissolving solid forms.Preferably, Active material with reference to one or more adrenergic receptors is adrenaline or adrenaline salt.

According to another aspect of the present invention, there is provided one kind is suitable for discharging N-methyl-D-aspartate acceptor in the oral cavity The solid dosage forms of antagonist, wherein the formulation includes：

(a) N-methyl-D-aspartate receptor antagonist；With

(b) at least one matrix formers；

Wherein described formulation is substantially solubilized in the oral cavity.Preferably, solid dosage forms is Fast-dissolving solid forms.Preferably, N-methyl-D-aspartate receptor antagonist is selected from and includes following inventory：Dextromethorphan, dextrorphan or ketamine.

According to another aspect of the present invention, there is provided a kind of to include the solid for being suitable for release of bioactive substances in the oral cavity The wafer (wafer) of formulation.Preferably, solid dosage forms is Fast-dissolving solid forms.Preferably, bioactive substance be selected from comprising Following inventory：At least one type phosphodiesterase (PDE5) inhibitor of ring-type Guanosine 5'-Monophosphate (cGMP) 5, with reference to a kind of or more The active material and N-methyl-D-aspartate receptor antagonist of kind adrenergic receptor.Preferably, N- methyl Ds-asparagus fern Propylhomoserin receptor antagonist is selected from and includes following inventory：Dextromethorphan, dextrorphan or ketamine.Preferably, with reference to a kind of or more The active material of kind adrenergic receptor is adrenaline or adrenaline salt.Preferably, ring-type Guanosine 5'-Monophosphate (cGMP) 5 Type phosphodiesterase (PDE5) inhibitor is 'Xiduofeng ' or its pharmaceutically acceptable salt.Preferably, 'Xiduofeng ' salt is citric acid 'Xiduofeng '.Wafer can be with its operation instructions.

According to another aspect of the present invention, there is provided a kind of pharmaceutical composition of the solid dosage forms comprising the present invention.Preferably, Solid dosage forms is Fast-dissolving solid forms.

The disclosure of invention

Solid dosage forms

According to an aspect of the present invention, there is provided a kind of solid formulation for being suitable for release of bioactive substances in the oral cavity Type, wherein the formulation includes：

(a) at least one bioactive substance, and

(b) at least one matrix formers,

Wherein described formulation is substantially solubilized in the oral cavity.

Preferably, solid dosage forms is Fast-dissolving solid forms.Preferably, bioactive substance is selected from and includes following inventory： At least one type phosphodiesterase (PDE5) inhibitor of ring-type Guanosine 5'-Monophosphate (cGMP) 5, with reference to one or more adrenaline The active material and N-methyl-D-aspartate receptor antagonist of energy acceptor.

Preferably, N-methyl-D-aspartate receptor antagonist is selected from and includes following inventory：Dextromethorphan, dextrorphan Or ketamine.If antagonist is ketamine, then ketamine is preferably ketamine salt, such as ketalar.In an implementation In scheme, ketamine is the racemic mixture form in R enantiomters and S enantiomters.Preferably, ketamine is two Kind enantiomter R- (-) and S- (+) mixture.

Preferably, the bioactive substance with reference to one or more adrenergic receptors is adrenaline or adrenaline Salt.

Preferably, ring-type Guanosine 5'-Monophosphate (cGMP) 5 type phosphodiesterase (PDE5) inhibitor is 'Xiduofeng ' or its pharmacy Upper acceptable salt.Preferably, 'Xiduofeng ' salt is citric acid 'Xiduofeng '.

In one embodiment, bioactive substance is with the dry weight with solid dosage forms selected from the group consisted of The amount of meter is present：In terms of the dry weight of formulation, 0.01 to 95 weight %；0.1 to the 75 weight weight of % and 1 to 45 %.

Preferably, formulation fater disintegration in the oral cavity, and allow instant bioactive substance by through oral mucosa Spread and directly diffuse in the systemic blood circulatory system and absorbed.By this method, first pass effect of hepar is avoided. Preferably, formulation is suitable for directly being delivered in systemic circulation by jugular vein, so as to bypass intestines and stomach and first pass effect of hepar.

For " instant ", it preferably refers to that formulation is i.e. selected from the group consisted of once placing in the oral cavity It is substantially solubilized in period：It is less than 2 minutes after form of administration；Less than 1 minute；Less than 50 seconds；Less than 40 seconds；Less than 30 Second；Less than 20 seconds；Less than 15 seconds；Less than 10 seconds；Less than 7.5 seconds；Less than 5 seconds；Less than 4 seconds；Less than 3 seconds；And less than 2 seconds. Preferably, the dissolution rate of Expidet is higher than the dissolution rate of regular dosage form.

It is highly preferred that once placing in the oral cavity, " instant " solid dosage forms is i.e. in the time selected from the group consisted of It is completely dissolved in section：It is less than 2 minutes after form of administration；Less than 1 minute；Less than 50 seconds；Less than 40 seconds；Less than 30 seconds；It is small In 20 seconds；Less than 15 seconds；Less than 10 seconds；Less than 7.5 seconds；Less than 5 seconds；Less than 4 seconds；Less than 3 seconds；And less than 2 seconds.

For " substantially ", it refers to that within the selected period at least 60% Expidet dissolves in the oral cavity. Preferably, at least 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97% or 98% within the selected period Expidet dissolves in the oral cavity.Most preferably, at least 99% Expidet is molten in the oral cavity within the selected period Solution.

The present invention a highly preferred embodiment in, after administration be not present the present invention formulation can be by patient The remaining residue detected.Preferably, oral to patient, preferably after sublingual administration, formulation is completely dissolved.Therefore, by Examination person does not have an urgent demand for swallowing formulation.Specifically, pharmaceutical composition can be for example designed to for buccal or sublingual pass Send.

Activating agent

Bioactive substance includes reactive compound and the compound used for veterinary science and people, such as but is not limited to：Medicine Active matter, neutraceuticals, cosmeceutical, cosmetics, supplement sex pill, natural products, food, vitamin, nutrients, life Thing preparation, amino acid, protein, peptide, nucleotides and nucleic acid.In a preferred form, bioactive substance is suitable for orally applying With.

In a preferred embodiment of the present invention, bioactive substance is organic compound.In the height of the present invention In preferred embodiment, bioactive substance is organic, therapeutical active compound for a person to use.In another implementation of the present invention In scheme, bioactive substance is inorganic compound.When bioactive substance is medicine, it can have neutral species, alkalescence Or the acid and salt of acid or alkali.The invention is not restricted to any drug-specific classification, application type, chemical type or function point Group.

Bioactive substance is typically the improved medicament of quickly dissolving that those skilled in the art need its oral administration.It is raw Active substances can be regular activated dose or medicine.

Suitable for the present invention bioactive substance example include active matter, biological agent, amino acid, protein, peptide, Nucleotides, nucleic acid and the like, homologue and first order derivative.Bioactive substance may be selected from the medicine of a variety of known class Thing, including but be not limited to：Anti-obesity medicine, central nervous system stimulants, carotenoid, corticosteroid, elastic egg White enzyme inhibitor, antifungal agent, oncology therapy, antemetic, anodyne, cardiovascular agents, antiinflammatory (such as NSAID and COX-2 suppressions Preparation), it is pest repellant, anti-cardiac arrhythmia agent, antibiotic (including penicillin), anti-coagulants, antidepressant, antidiabetic, anti-insane Epilepsy agent, antihistaminic, rescinnamine, muscarine antagonist (antimuscarinic agent), Antimycobacterial agent, anti-superfluous life Agent, immunodepressant, antithyroid drug, antivirotic, antianxiety agent, sedative (hypnotic and tranquilizer), astringent, α-kidney Upper parathyrine energy receptor blocking pharmacon, receptor,β blocking agent, blood products and substitute, the agent of heart muscular strength, contrast media, Cough suppressant's (expectorant and mucolytic agent), diagnosticum, diagnostic imaging agent, diuretics, dopaminergic agent (anti-Parkinsonian Sick agent), styptic, immunizing agent, lipid modulators, muscle relaxant, parasympathomimetics, accessory thyroid glands calcitonin And diphosphonate, prostaglandin, radiopharmaceuticals, sex hormone (including steroids), antiabnormal reaction agent, stimulation (calcitonin) Agent and anoretics, sympathetic transmitter releasers, thyroid, vasodilator and xanthine.

The description of these classifications and an interior row material of all categories to bioactive substance is found in ' The Extra Pharmacopoeia ', the 31st edition (The Pharmaceutical Press, London, 1996) and ' Physician ' s In Desk Reference ' (the 60th edition, 2005), the document is expressly incorporated herein by reference and is this area skill Art personnel are familiar with.Activating agent is commercially available and/or can be prepared by technology as known in the art.

In addition, be adapted to bioactive substance example include however be not limited to it is following those：

·Anodyne and antiinflammatory：Aloxiprin (aloxiprin), Anranofin (auranofm), azapropazone (azapropazone), benorylate (benorylate), diflunisal (diflunisal), Etodolac (etodolac), fenbufen (fenbufen), fenoprofen calcium (fenoprofen calcim), Flurbiprofen (flurbiprofen), brufen (ibuprofen), Indomethacin (indomethacin), Ketoprofen (ketoprofen), first Clofenamic acid (meclofenamic acid), mefenamic acid (mefenamic acid), Nabumetone (nabumetone), naproxen (naproxen), olsapozine (oxaprozin), oxyphenbutazone (oxyphenbutazone), bute (phenylbutazone), piroxicam (piroxicam), sulindac (sulindac).

·Pest repellant：Albendazole (albendazole), hydroxyl naphthoic acid benzyl phenin (bephenium Hydroxynaphthoate), cambendazole (cambendazole), dichlorophen (dichlorophen), ivermectin (ivermectin), mebendazole (mebendazole), oxamniquine (oxamniquine), fen difficult to understand reach azoles (oxfendazole), oxantel pamoate (oxantel embonate), praziquantel (praziquantel), double hydroxyl naphthalenes Sour Pyrantel (pyrantel embonate), thiabendazole (thiabendazole).

·Anti- cardiac arrhythmia agent：Hydrochloric acid amiodarone (amiodarone HCl), diisopropyl pyrrole amine (disopyramide), Acetic acid flecainide (flecainide acetate), quinidine sulfate (quinidine sulphate).

·Antibacterial agent：Benethamine Penicillin (benethamine penicillin), cinoxacin (cinoxacin), salt Sour Ciprofloxacin (ciprofloxacin HCl), CLA (clarithromycin), clofazimine (clofazimine), Cloxacillin (cloxacillin), demeclocycline (demeclocycline), Doxycycline (doxycycline), erythromycin (erythromycin), 2-ethylisonicotinthionamide (ethionamide), Imipenem (imipenem), nalidixic acid (nalidixic Acid), Nifuran (nitrofurantoin), rifampin (rifampicin), spiramvcin (spiramycin), N'-phenylsulfanilamide Acyl (sulphabenzamide), sulfadoxine (sulphadoxine), sulfamerazine (sulphamerazine), sulfanilamide (SN) vinegar Acyl (sulphacetamide), sulphadiazine (sulphadiazine), sulfonamidoxazole (sulphafurazole), sulfalene Oxazole (sulphamethoxazole), sulfapryidine (sulphapyridine), tetracycline (tetracycline), trimethoxy Benzyl diaminopyrimidine (trimethoprim).

·Anti-coagulants：Bicoumarin (dicoumarol), Dipyridamole (dipyridamole), acenocoumarin (nicoumalone), phenindione (phenindione).

·Antidepressant：Amoxapine (amoxapine), ciclazindol (ciclazindol), aueural (maprotiline HCl), Mianserin Hydrochloride (mianserin HCl), psychostyl (nortriptyline HCl), trazodone hydrochloride (trazodone HCl), maleic acid trimeprimine (trimipramine maleate).

·Antidiabetic：Acetyl benzene sulfonyl ring urea (acetohexamide), chlorpropamide (chlorpropamide), glibenclamide (glibenclamide), gliclazide (gliclazide), glipizide (glipizide), tolazamide (tolazamide), orinase (tolbutamide).

·Anti-epileptics：Beclamide (beclamide), carbamazepine (carbamazepine), Clonazepam (clonazepam), ethotoin (ethotoin), methoin (methoin), mesuximide (methsuximide), methylbenzene Barbital (methylphenobarbitone), Oxcarbazepine (oxcarbazepine), paramethadione (paramethadione), phenacemide (phenacemide), phenobarbital (phenobarbitone), phenytoinum naticum (phenytoin), phensuximide (phensuximide), primidone mysoline (primidone), easypro thiazine (sulthiame), valproic acid (valproic acid)。

·Antifungal agent：Anphotericin (amphotericin), Butoconazole Nitrate (butoconazole nitrate), gram Mould azoles (clotrimazole), econazole nitrate (econazole nitrate), Fluconazole (fluconazole), Flucytosine (flucytosine), griseofulvin (griseofulvin), Itraconazole (itraconazole), ketoconazole (ketoconazole), Miconazole (miconazole), natamycin (natamycin), nystatin (nystatin), nitric acid Sulconazole (sulconazole nitrate), terbinafine HCl (terbinafine HCl), terconazole (terconazole), tioconazole (tioconazole), undecenoic acid (undecenoic acid).

·Antigout agent：Allopurinol (allopurinol), probenecid (probenecid), sulfinpyrazone (sulphinpyrazone)。

·Rescinnamine：Amlodipine (amlodipine), benidipine (benidipine), darodipine (darodipine), diltiazem hydrochloride (dilitazem HCl), diazoxiide (diazoxide), felodipine (felodipine), acetic acid guanabenz (guanabenz acetate), indoramin (indoramin), Isradipine (isradipine), loniten (minoxidil), Licardipine Hydrochloride (nicardipine HCl), nifedipine (nifedipine), Nimodipine (nimodipine), Phenoxybenzamine Hydrochloride (phenoxybenzamine HCl), hydrochloric acid piperazine azoles Piperazine (prazosin HCl), reserpine (reserpine), Terazosin Hydrochloride (terazosin HCl).

·Antimalarial agent：Amodiaquine (amodiaquine), chloroquine (chloroquine), Chlorproguanil Hydrochloride (chlorproguanil HCl), halofantrine hydrochloride (halofantrine HCl), Mefloquine Hydrochloride (mefloquine HCl), Chloroguanide hydrochloride (proguanil HCl), pyrimethamine (pyrimethamine), quinine sulfate (quinine sulphate).

·Anti-migraine agent：Dihydroetgotamine (dihydroergotamine mesylate), tartaric acid ergot Amine (ergotamine tartrate), maleic acid desernil (methysergide maleate), maleic two Sour pizotifen (pizotifen maleate), succinic acid sumatriptan (sumatriptan succinate).

·Antimuscarinic agent：Atropine (atropine), benzhexol hydrochloride (benzhexol HCl), Biperiden (biperiden), hydrochloric acid profenamine (ethopropazine HCl), scopolamine butylbromide (hyoscine butyl Bromide), hyoscyamine (hyoscyamine), mepenzolate bromide (mepenzolate bromide), brocasipal (orphenadrine), oxyphencyclimine hydrochloride (oxyphencylcimine HCl), Tropicamide (tropicamide).

·Anti- superfluous raw agent and immunodepressant：Amine Rumi spy (aminoglutethimide), amsacrine (amsacrine), Imuran (azathioprine), busulfan (busulphan), Chlorambucil (chlorambucil), cyclosporin (cyclosporin), Dacarbazine (dacarbazine), Estramustine (estramustine), Etoposide (etoposide), lomustine (lomustine), melphalan (melphalan), purinethol (mercaptopurine), first Aminopterin (methotrexate), mitomycin (mitomycin), mitotane (mitotane), mitoxantrone (mitozantrone), procarbazine hydrochloride (procarbazine HCl), TAMOXIFEN CITRATE (tamoxifen Citrate), Testolactone (testolactone).

·Antiprotozoal：Benznidazole (benznidazole), clioquinol (clioquinol), decoquinate (decoquinate), diiodohydroxyquinoline (diiodohydroxyquinoline), diloxanide furoate (diloxanide Furoate), dinitolmide (dinitolmide), furazolidone (furzolidone), flagyl (metronidazole), Nimorazole (nimorazole), nitrofurazone (nitrofurazone), Ornidazole (ornidazole), fasigyne (tinidazole)。

·Antithyroid drug：Carbimazole (carbimazole), propylthiouracil (propylthiouracil).

·Antianxiety agent, sedative, hypnotic and tranquilizer：Alprazolam (alprazolam), amobarbital (amylobarbitone), barbital (barbitone), bentazepam (bentazepam), bromazepam (bromazepam), Bromperidol (bromperidol), brotizolam (brotizolam), neonal (butobarbitone), adalin (carbromal), librium (chlordiazepoxide), chlorethiazol (chlormethiazole), chlorpromazine (chlorpromazine), clobazam (clobazam), Clotiazepam (clotiazepam), Clozapine (clozapine), Stable (diazepam), Droperidol (droperidol), valmid (ethinamate), fluanisone (flunanisone), Flunitrazepam (flunitrazepam), three chlorpromazines (fluopromazine), LU-5-110 (flupenthixol Decanoate), capric acid fluphenazine (fluphenazine decanoate), flurazepam (flurazepam), haloperole (haloperidol), Lorazepam (lorazepam), Lormetazepam (lormetazepam), medazepam (medazepam), Peaceful (meprobamate), methaqualone (methaqualone), midazolam (midazolam), intrazepam (nitrazepam), Oxazepam (oxazepam), amobarbital (pentobarbitone), fluphenazine (perphenazine), Pimozide (pimozide), prochlorperazine (prochlorperazine), Sulpiride (sulpiride), Temazepam (temazepam), thioridazine (thioridazine), triazolam (triazolam), assistant Clone (zopiclone).

·Beta blocker：Acebutolol (acebutolol), alprenolol (alprenolol), atenolol (atenolol), labetalol (labetalol), metoprolol (metoprolol), Nadolol (nadolol), oxygen alkene Lip river That (oxprenolol), the more Luo Er of product (pindolol), Propranolol (propranolol).

·Heart muscular strength agent：Amine profit ketone (amrinone), digitoxin (digitoxin), digoxin (digoxin), Enoximone (enoximone), Lanatoside C (lanatoside C), lanitop (medigoxin).

·Corticosteroid：Beclomethasone (beclomethasone), betamethasone (betamethasone), contract cloth Loose (budesonide), acetic acid cortisone (cortisone acetate), desoximetasone (desoxymethasone), fill in rice Loose (dexamethasone), acetic acid fluorine hydrogen cortisone (fludrocortisone acetate), flunisolide (flunisolide), fluocortolone (flucortolone), fluticasone propionate (fluticasone propionate), hydrogenation Cortisone (hydrocortisone), methylprednisolone (methylprednisolone), prednisolone (prednisolone), metacortandracin (prednisone), fluoxyprednisolone (triamcinolone).

·Diuretics：Acetazolamide (acetazolamide), amiloride (amiloride), bendroflumethiazide (bendrofluazide), bumetanide (bumetanide), chlorothiazide (chlorothiazide), chlorthalidone (chlorthalidone), ethacrynic acid (ethacrynic acid), FRUSEMIDE (frusemide), metolazone (metolazone), spirolactone (spironolactone), triamterene (triamterene).

·Anti-Parkinson agent：Bromocriptine methanesulfonate (bromocriptine mesylate), maleic acid ergot Ethyl urea (lysuride maleate).

·Stomach and intestine agent：Laxadin (bisacodyl), Cimetidine (cimetidine), Xisha must Sharp (cisapride), diphenoxylate hydrochloride (diphenoxylate HCl), domperidone (domperidone), famotidine (famotidine), Loperamide (loperamide), mesalazine (mesalazine), nizatidine (nizatidine), Omeprazole (omeprazole), ondansetron hydrochloride (ondansetron HCl), ranitidine hydrochloride (ranitidine HCl), SASP (sulphasalazine).

·Histamine H 1- receptor antagonists：Acrivastine (acrivastine), astemizole (astemizole), Chinese cassia tree benzene Piperazine (cinnarizine), marezine (cyclizine), anarexol (cyproheptadine HCl), dramamine (dimenhydrinate), flunarizine hydrochloride (flunarizine HCl), Loratadine (loratadine), hydrochloric acid Meike Lip river piperazine (meclozine HCl), Oxatomide (oxatomide), RMI 9918 (terfenadine), triprolidine (triprolidine)。

·Lipid modulators：Bezafibrate (bezafibrate), CLOF (clofibrate), fenofibrate (fenofibrate), Gemfibrozil Capsules (gemfibrozil), probucol (probucol).

·Local anesthetic：Neuro-muscular agent：Pyridostigmine (pyridostigmine).

·Nitrate and other angor agent：Amyl nitrate, trinitin, isosorbide dinitrate, single nitric acid Coronex, four pentaerythritol tetranitrates.

·Nutritional agents：Bata-carotene (betacarotene), vitamin A, vitamin B2, vitamin D, vitamin E, dimension life Plain K.

·Opioid analgesic agent：Codeine (codeine), dextropropoxyphene (dextropropyoxyphene), heroin (diamorphine), paracodin (dihydrocodeine), meptazinol (meptazinol), methadone (methadone), morphine base (morphine), Nalbuphine (nalbuphine), Pentazocine (pentazocine), midazolam (medazolam), fentanyl (fentanyl).

·Oral vaccine：Be designed to prevent or mitigate disease symptom vaccine, wherein following is the generation of the disease Table and non-exclusionism inventory：Influenza, tuberculosis, meningitis, hepatitis, pertussis, polio, lockjaw, diphtheria, malaria, Cholera, bleb, typhoid fever, HIV, AIDS, measles, Lyme disease (Lyme disease), traveler's diarrhea, A type, B-mode and the third type Hepatitis, tympanitis, dengue fever (Dengue Fever), rabies, parainfluenza, rubella, yellow fever, dysentery, legionaires' disease (Legionnaires Disease), tokoplasmosis, Q heat, Hemorrhagic fever (Haemorrhegic Fever), Argentinian hemorrhagic fever, Caries, Chagas' disease (Chagas Disease), the urethral infection as caused by Escherichia coli, pneumococcal disease, the cheek Adenositis and datum hole Kenya are hot (Chikungunya).

·To prevent or mitigate the vaccine of the symptom of Other diseases syndrome, wherein following is the generation of causal organism Table and non-exclusionism inventory：Vibrio species (Vibrio species), Salmonella ssp (Salmonella Species), Bordetella species (Bordetella species), Haemophilus species (Haemophilus Species), toxoplasma gondii (Toxoplasmosis gondii), cytomegalovirus category (Cytomegalovirus), clothing are former Body species (Chlamydia species), Streptococcus species (Streptococcal species), Cécile Nowak category virus (Norwalk Virus), Escherichia coli (Escherischia coli), helicobacter pylori (Helicobacter pylori), Rotavirus (Rotavirus), Neisseria gonorrhoeae (Neisseria gonorrhae), Neisseria meningitidis (Neisseria meningiditis), Adenovirus, Ai Baisitan epstein-Barr viruses (Epstein Barr Virus), Japanese brain Scorching virus (Japanese Encephalitis Virus), Pneumocystis carinii (Pneumocystis carini), pure Bleb (Herpes simplex), Clostridial species (Clostridia species), respiratory tract amalgamation virus (Respiratory Syncytial Virus), Klebsiella species (Klebsielia species), Shigella Species (Shigella species), Pseudomonas aeruginosa (Pseudomonas aeruginosa), parvovirus category (Parvovirus), campylobacter species (Campylobacter species), rickettsia species (Rickettsia species), varicella banding blister epidemic disease (Varicella zoster), Yersinia spp (Yersinia Species), ross river virus (Ross River Virus), J.C. viral (J.C.Virus), Rhodococcus equi (Rhodococcus equi), block its catarrhalis (Moraxella catarrhalis), Borrelia burgdoyferi (Borrelia ) and haemolysis Pasteurella (Pasteurella haemolytica) burgdorferi.Other instantiations include opiates, such as Fentanyl or midazolam.

·For the vaccine of the disease condition of non-infection immunity regulation：Such as surface and whole body allergy symptom, such as withered grass Hot (Hayfever), asthma, rheumatoid arthritis and carcinoma.

·The vaccine used for veterinary science：Including for those following：Global-worm illness (Coccidiosis), Newcastle (Newcastle Disease), enzootic pneumonia (Enzootic pneumonia), feline leukemia (Feline Leukaemia), atrophic rhinitis (Atrophic rhinitis), erysipelas (Erysipelas), aftosa (Foot and Mouth disease), swine fever (Swine), pneumonia and the Other diseases symptom and the other senses that influence companion animals and farm-animals Dye and autoimmune disease symptom.

·Protein, peptide and reconstituted drug：Insulin (six combinate form formulas/dimeric forms/monomeric form), glycemic element, growth Hormone (somatotropin), polypeptide or their derivative (preferred molecular weight is 1000 to 300,000), calcitonin and its conjunction Into modified form, enkephalins (enkephalin), interferon (in particular for treating α -2 interferon of common cold), LHRH (growth swashs with analog (nafarelin (nafarelin), Buserelin (buserelin), Zoladex (zolidex)), GHRH Hormone-releasing hormone), secretin, brad ykinin antagonists, GRF (the growth release factor), THF, TRH (thyroid-stimulating hormone release swash Element), ACTH analogs, IGF (IGF), CGRP (calcitonin gene related peptide), atrial natriuretic peptide, blood vessel Pitressin and analog (DDAVP, lypressin), Factor IX, G-CSF (G CFS), EPO are (red Erythropoietin).

·Sex hormone：Citric acid clomiphene (clomiphene citrate), DANAZOL (danazol), acetylene female two Alcohol (ethinyloestradiol), acetic acid medroxyprogesterone acetate (medroxyprogesterone acetate), mestranol (mestranol), methyltestosterone (methyltestosterone), norethindrone (norethisterone), methylnorethindron (norgestrel), estradiol (oestradiol), conjugated type estrogen, progesterone (progesterone), Stanozolol (stanozolol), diethylstilbestrol (stiboestrol), testosterones (testosterone), Tibolone (tibolone).

·Spermatocide：Nonoxynol 9 (nonoxynol 9).

·Stimulant：Amphetamine (amphetamine), dexamphetamine (dexamphetamine), dextrorotation sweet smell fluorine Lamine (dexfenfluramine), fenfluramine (fenfluramine), mazindol (mazindol), pemoline (pemoline)。

Although the inventive method has a general usability, the more specific examples of bioactive substance include but unlimited In：Haloperole (Dopamine D2 receptor), DL isoprenaline hydrochlorides (beta-adrenergic activator), RMI 9918 (terfenadine) (H1 antagonists), Propranolol Hydrochloride (beta-adrenergic antagonist), norpramin (desipramine hydrochloride) (antidepressant), citric acid 'Xiduofeng ', Tadalafei (tadalafil) and cut down ground That non-(vardenafil).Aid in anodyne (cyclooxygenase-2 inhibitor), fenamic acid (fenamic acid), piroxicam (piroxicam), Cox-2 inhibitor, naproxen and other anodynes can all benefit from the oral for being configured to the present invention.

Other examples of bioactive substance include but is not limited to：Alfaxalone (alfaxalone), acetyl group digoxin (acetyl digoxin), ACV analog, Alprostadil (alprostadil), Amifostine (aminofostin), Ah Ni Pa meter (anipamil), Antithrombin III, atenolol (atenolol), retrovir (azidothymidine), Bei Luo Bei Te (beclobrate), beclomethasone (beclomethasone), bleomycin (belomycin), benzocainum (benzocaine) and derivative, bata-carotene, β endorphins, beta interferon, Bezafibrate (bezafibrate), Nome is compared (binovum), Biperiden (biperiden), bromazepam (bromazepam), bromocriptine (bromocryptine), Bucindolol (bucindolol), buflomedil (bufIomedil), bupivacaine (bupivacaine), busulfan (busulfan), Cadralazine (cadralazine), camptothecine (camptothesin), canthaxanthin (canthaxanthin), card Top's profit (captopril), carbamazepine (carbamazepine), Carboprost (carboprost), Cefalexin (cefalexin), cefoxitin (cefalotin), cefadole (cefamandole), Cefazedone (cefazedone), head Spore cefuroxime (cefluoroxime), Cefmenoxime (cefinenoxime), cefoperazone (cefoperazone), CTX (cefotaxime), Cefoxitin (cefoxitin), Cefsulodin (cefsulodin), Ceftizoxime (ceftizoxime), Chlorambucil (chlorambucil), Cromoglycic acid (chromoglycinic acid), ciclonicate (ciclonicate), thiophene lattice Row ketone (ciglitazone), clonidine (clonidine), desoxycortisone (cortexolone), cortisone (corticosterone), cortisol (cortisol), cortisone (cortisone), endoxan (cyclophosphamide), cyclosporin A and other cyclosporins, cytarabine (cytarabine), desocriptine (desocryptin), Desogestrel (desogestrel), dexamethasone ester (dexamethasone ester) (such as fill in rice Loose acetic acid esters), dezocine (dezocine), stable, Diclofenac (diclofenac), DIDEOXYADENOSINE, didanosine, hair Granules glycosides (digitoxin), digoxin, dihydroergotamine (dihydroergotamine), dihydroergotoxine (dihydroergotoxin), diltiazem (diltiazem), Dopamine D2 receptor, Doxorubicin (doxorubicin), benefit Health azoles (econazole), Endralazine (endralazine), enkephalins, enalapril (enalapril), Epoprostenol (epoprostenol), estradiol, Estramustine (estramustine), Etofibrate (etofibrate), Etoposide, because Sub- ix, factor viii, Felbamate (felbamate), fragrant benzene azoles (fenbendazole), fenofibrate (fenofibrate), Fexofenadine (fexofenedine), flunarizine (flunarizin), Flurbiprofen (flurbiprofen), 5 FU 5 fluorouracil (5-fluorouracil), flurazepam (flurazepam), phosphonomycin (fosfomycin), fosmidomycin (fosmidomycin), frusemide (furosemide), Gallopamil (gallopamil), interferon, gentamicin, Ji Pei Forint (gepefrine), gliclazide (gliclazide), glipizide (glipizide), griseofulvin (griseofulvin), haptoglobin (haptoglobulin), hepatitis B vaccine, hydralazine (hydralazine), Hydrochioro (hydrochlorothiazide), hydrocortisone, brufen (ibuprofen), ibuproxam (ibuproxam), indinavir (indinavir), Indomethacin (indomethacin), iodinated aromatic x-ray contrast agent (such as iodamide), Ipratropium Bromide (ipratropium bromide), ketoconazole (ketoconazole), Ketoprofen (ketoprofen), Ketotifen (ketotifen), fumaric acid Ketotifen (ketotifen fumarate), the rotation of K- poison hair Flower glycosides (K-strophanthin), labetalol (labetalol), Lactobacillus vaccine, lidocaine (lidocaine), Lidoflazine (lidoflazin), lisuride (lisuride), maleic acid hydrogen lisuride (lisuride Hydrogen maleate), Lorazepam (lorazepam), Lovastatin (lovastatin), mefenamic acid (mefenamic Acid), melphalan (melphalan), Memantine (memantin), mesulergine (mesulergin), Metergoline (metergoline), methotrexate (MTX) (methotrexate), lanitop (methyl digoxin), methylprednisolone (methylprednisolone), flagyl, isoprinosine (metisoprenol), metipranolol (metipranolol), Metkefamide (metkephamide), metolazone (metolazone), metoprolol (metoprolol), tartaric acid Mei Tuoluo That (metoprolol tartrate), Miconazole (miconazole), miconazole nitrate (miconazole nitrate), rice Promise you (minoxidil), Misonidazole (misonidazol), molsidomine (molsidomin), Nadolol (nadolol), nafiverine (nafiverine), Nafazatrom (nafazatrom), naproxen (naproxen), natural pancreas islet Element, Nesapidil (nesapidil), nicardipine (nicardipine), nicorandil (nicorandil), nifedipine, Buddhist nun Shandong Horizon (niludipin), Nimodipine, intrazepam (nitrazepam), nitrendipine (nitrendipine), nitro happiness Set alkali (nitrocamptothesin), 9-nitrocamptothecin (9-nitrocamptothesin), Olanzapine (olanzapine), Oxazepam (oxazepam), oxprenolol (oxprenolol), oxytetracycline (oxytetracycline), penicillin (such as benzene Bright benzyl penicillin, penicillin), bute (phenylbutazone), picotamide (picotamide), the more Luo Er of product (pindolol) fragrant (piposulfan), piretanide (piretanide), piribedil (piribedil), pyrrole sieve former times, are bailed out Health, pirprofen (pirprofen), plasminogen activators, prednisolone, metacortandracin (prednisone), pregnene Alcohol ketone (pregnenolone), procarbazine (procarbacin), Procaterol (procaterol), progesterone (progesterone), proinsulin, Propafenone (propafenone), Propranolol (propanolol), Pu Luopanfeilin (propentofyllin), Propofol (propofol), Propranolol, Raloxifene (raloxifene), Rifapentine (rifapentin), Simvastatin (simvastatin), semi-synthetic insulin, Sobrerol (sobrerol), rope agate STING And its derivative, somatropin, Shi Talin (stilamine), sulfinalol hydrochloride (somastotine) (sulfinalol hydrochloride), Sulfinpyrazone (sulfinpyrazone), Suloctidil (suloctidil), suprofen (suprofen), sulprostone (sulproston), insulin synthesis, talinolol (talinolol), PTX (taxol), Thailand Rope Supreme Being (taxotere), testosterones, Bing Suan testosterones, Shi mono- Suan testosterones, totokaine (tetracane) HI, hydrochloric acid thiophene rummy Special (tiaramide HCl), tolmetin (tolmetin), tranilast (tranilast), Triquilar (triquilar), hydrochloric acid Tromantadine (tromantadine HCl), urokinase, diazepam (valium), Verapamil (verapamil), arabinose gland Glycosides (vidarabine), arabinosy ladenosine (vidarabine) sodium ascorbyl phosphate, vinblastine (vinblastine), vinburnine (vinburin), pervone (vincamine), vincristine (vincristine), eldisine (vindesine), Chang Chunxi Spit of fland (vinpocetine), vitamin A, succinic acid vitamin E and x-ray contrast agent.

In addition, it is also contemplated that the solid dosage forms of the present invention is suitable to the new chemical entity (NCE) of delivering and other active matters will It will be generated in future or becomes commercially available, and can be used as bioactive substance.

Bioactive substance can be the active material for combining one or more adrenergic receptors.Preferably, with reference to one Kind or the active materials of a variety of adrenergic receptors be adrenaline (adrenal hormone) or adrenaline salt, such as hydrogen tartrate Adrenaline or adrenalin hydrochloride.Or with reference to one or more adrenergic receptors active material can be provided as with Lower form：The analog related to adrenaline and compound, such as norepinephrine, isoprel；Or sympathomimetic god Through agent, such as tyrasamine (tyramine), ephedrine (ephedrine), pseudoephedrine (pseudoephedrine), amphetamine, willow Fourth ammonia alcohol (salbutamol) and Terbutaline (terbutaline).

Bioactive substance can be N-methyl-D-aspartate receptor antagonist.Preferably, N-methyl-D-aspartate Receptor antagonist is selected from and includes following inventory：Dextromethorphan, dextrorphan or ketamine.

Bioactive substance can be ring-type Guanosine 5'-Monophosphate (cGMP) 5 type phosphodiesterase (PDE5) inhibitor.Preferably, Ring-type Guanosine 5'-Monophosphate (cGMP) 5 type phosphodiesterase (PDE5) inhibitor is 'Xiduofeng ' or its pharmaceutically acceptable salt.It is excellent Selection of land, 'Xiduofeng ' salt are citric acid 'Xiduofeng 's.

Preferably, solid dosage forms is the form selected from the group consisted of：Wafer；Tablet；Capsule；Pill；Powder； Pill；Granule；And film.Solid dosage forms should be suitable for not leaving being detected by patient for the formulation in the oral cavity residual Excess.No matter solid dosage forms is to provide in which form；It all should fater disintegration, and allow instant bioactivity in the oral cavity Material is by spreading and directly diffusing in the systemic blood circulatory system to be absorbed through oral mucosa.Preferably, solid Formulation is Fast-dissolving solid forms.

Component

Preferably, solid dosage forms is substantially free of starch.In another embodiment of the present invention, comprising solid dosage forms Pharmaceutical composition is also substantially free of starch.Preferably, solid dosage forms is Fast-dissolving solid forms.

Precise volume of the bioactive substance in solid dosage forms is by the type depending on selected bioactive substance.However, In terms of the dry weight of formulation, active material be typically with 0.02 to 95%, preferably 0.02 to 20% or preferably 0.1 to 75%, 1 to 45% amount is present.

Bioactive substance generally can be present in solid dosage forms with the amount selected from the group consisted of：5mg；10mg； 15mg；20mg；25mg；30mg；35mg, 40mg, 45mg, 50mg, 60mg and 100mg.

Preferably, solid dosage forms of the invention also includes at least one matrix formers.

In the lyophilization system of prior art, the wall-forming ability of gelatin is attributed to, it is most commonly used as carrier or knot It is configured to agent.Gelatin is a kind of water-soluble polymer, and therefore, when being mixed with active pharmaceutical ingredient in water；Solution Viscosity can cause the solubility of soluble bad medicine in the mixture to reduce with time increase, and produce medicine in gelatin Suspension in matrix.This can cause phase separation；And it is dispersed in the possible heterogeneity of the medicine of amorphous or crystal form In matrix, this will finally influence the dissolution and absorption of final products.Therefore, gelatin is preferably not present in the solid dosage forms of the present invention In.

The validity of the solid dosage forms of the present invention is molten before being absorbed into systemic circulation dependent on bioactive substance In the fluid of the small sizes of Xie Yuru in the oral cavity.Therefore, the dissolution rate of formulation is important.One in the present invention is preferred real Apply in scheme, solid dosage forms includes super-disintegrant as at least one matrix former matter.

Concrete application can be directed to, solid formulation is selected especially for site-specific drug delivery system (as in the oral cavity) Other polymeric materials of matrix are suitably formed in type.The matrix formers of the present invention may be selected from the group consisted of：The non-food in one's mouth Newborn animal gelatin, dextrin, soybean protein, aleuronat, plantago seed protein, Arabic gum, guar gum, agaropectin, Huang Virgin rubber, polysaccharide；Alginate；Sodium carboxymethylcellulose；Carragheen；Glucan；Pectin；Sugar；Amino acid；Starch；Modified starch； Carboxymethyl cellulose；Hydroxypropyl methyl cellulose；Hydroxypropyl cellulose and methylcellulose inorganic salts；Synthetic polymer；Side chain Starch, polypeptides/proteins or polysaccharide compound.

Matrix former matter in solid dosage forms can be carbohydrate.Preferably, carbohydrate is selected from by with the following group Into group：Mannitol；Dextrose；Lactose；Galactolipin；Trehalose；And cyclodextrin.

In a highly preferred embodiment, at least one of solid dosage forms matrix formers are glycine.Glycine It is a kind of amino acid with remarkable wetting properties, and is suitable to dissolution formulation.Low amounts glycine can be used for the preparation of the present invention In to control the dissolution rate of formulation.In addition, glycine also is used as during manufacturing process or maintains formulation after encapsulation Exempt from the resist collapse agent of contraction.In one embodiment, glycine is with the 0.2 to 7.5% of formulation dry weight, more preferably from about The amount of 0.5% to about 5% is present in the formulation of the present invention.Preferably, counted with the dry weight formed of formulation, glycine be with 0.5 to 5 weight % amount is present.

In a highly preferred embodiment, at least one of solid dosage forms matrix formers are carboxymethyl celluloses Sodium.When at least one matrix formers are sodium carboxymethylcelluloses, in terms of the dry weight of solid dosage forms, polymer is with about The concentration of 0.1% to about 19% is present.In a preferred embodiment, in terms of the dry weight of formulation, sodium carboxymethylcellulose be with The amount of about 0.1% to about 15% is present.In the highly preferred embodiment of the present invention, in terms of the dry weight of solid dosage forms, carboxylic Sodium carboxymethylcellulose pyce is the amount presence with about 0.1% to about 1.0%.Preferably, counted with the dry weight formed of formulation, carboxymethyl is fine It is to exist selected from the amount of the group consisted of to tie up plain sodium：0.05% to 19%；0.1% to 15%；And 0.1% to 10%.

In another embodiment of the present invention, formulation includes amylopectin as at least one matrix formers.Side chain Starch can be by promoting preparation disintegration to increase the release of bioactivator.In terms of the dry weight of solid dosage forms, amylopectin can It is present in about 2% until being not more than under 20% concentration in formulation.Amylopectin can be with about the 2% to about 17% of formulation dry weight Amount exist.Preferably, counted with the dry weight formed of formulation, amylopectin is to exist selected from the amount of the group consisted of： 2% to 17%；And 2% to 15%.

According to another embodiment of the present invention, solid dosage forms may include matrix formers, such as mannitol.Mannitol It is a kind of component that can help to crystal structure and imparting agent type hardness tester.When mannitol is present in formulation, with formulation Dry weight meter, it exists with the concentration of about 5% to about 80%, preferably from about 10% to about 60% and most preferably from about 10% to about 50%.

Solid dosage forms can contain inorganic salts.Preferably, inorganic salts are selected from the group consisted of：Sodium phosphate；Sodium chloride；With Alumina silicate.

The solid dosage forms of the present invention can contain amino acid.Preferably, amino acid is selected from the group consisted of：Glycine； ALANINE；L-Aspartic acid；Pidolidone；L- hydroxy-prolines；ILE；L-Leu；And L-phenylalanine.

The solid dosage forms of the present invention is also preferably substantially free of starch.

Quickly dissolved from the solid dosage forms of the present invention to reach bioactive substance, diluent can be added as at least one Matrix former matter.Diluent includes microcrystalline cellulose (such as Avicel PHWith Avicel PH), lactose, shallow lake Powder and D-sorbite.These diluents can be present in formulation individually or with the form of mixtures of different ratios, and can be indivedual Ground is cumulatively about 1% to about 80%, preferably from about 2% to about 50%.

In one embodiment of the invention, solid dosage forms is formed comprising microcrystalline cellulose as at least one matrix Agent.Microcrystalline cellulose can serve as filler and adhesive in the formulation of the present invention.Microcrystalline cellulose can be pressed with minimum compacting Force tightly, and produce hard, stabilizer type, preferably Expidet.Its high surface area and high wood interior porosity are attributed to, Microcrystalline cellulose can absorb and retain a large amount of water, and this is desirable in the formulation of the present invention.When the solid of the present invention When formulation includes microcrystalline cellulose, in terms of the dry weight of formulation, it is with about 1% to about 10% and preferably from about 1% to about 8% Amount is present.

The solid dosage forms or pharmaceutical composition of the present invention is preferably substantially free of AVM hereinafter Sai Er (Avicel).

In another preferred embodiment of the present, solid dosage forms includes at least one lubricant.The formulation of the present invention may include to moisten Lubrication prescription, such as polyethylene glycol (PEG) 1000,2000,4000 and 6000, NaLS, fat or oil.Use these lubricants An advantage be to contribute to remove formulation from mould.These lubricants can be deposited individually or with the form of mixtures of different ratios In formulation, and can individually or cumulatively between 0.05% to 5%, preferably between 0.1% and 2%, preferably About 1.5%.In one embodiment, in terms of the dry weight of formulation, composition includes the polyethylene glycol between 0.05% to 5% 2000th, the polyethylene glycol 2000 between preferably 0.1% and 2%, preferably from about 1.5% polyethylene glycol 2000 or various glycol is mixed Compound.Or PEG 2000 can be replaced by PEG 1000.

In another preferred embodiment of the present, solid dosage forms includes at least one buffer reagent.Preferably, in solid dosage forms Saliva pH 7.0 to 7.8 is provided when buffer reagent dissolves in the oral cavity.The buffer reagent can improve the sublingual of weak base compound Absorb.Solid buffer reagent may be selected from including following group：It is dehydrated sodium dihydrogen phosphate, disodium hydrogen phosphate, sodium acid carbonate and carbonic acid Sodium, in terms of the weight of composition, it can be individually or with the form of mixtures of different ratios with the concentration of about 0.01% to about 10% It is present in formulation.

Or solid buffer reagent may be selected from including following inventory：Alginic acid, ascorbic acid, citric acid, malic acid, Succinic acid and tartaric acid, in terms of the weight of composition, its can individually or with the form of mixtures of different ratios with about 0.01% to About 10% concentration is present in formulation.Preferably, buffer reagent is citric acid, and in terms of the weight of solid dosage forms, it can be about 0.01% to about 10%, more preferably between 0.1% and 5%, most preferably from about 2.0% concentration presence.

For example, if the bioactive substance in solid dosage forms is 'Xiduofeng ', then the molecular structure tool of 'Xiduofeng ' There are both weak acid center and alkalescent center.This solubility of meaning 'Xiduofeng ' in water is influenceed by solution ph, and two Optimal pH (pHmax) value is 4.5 and 10.24.Therefore, absorbed to improve the transmucosal of 'Xiduofeng ', solid dosage forms can be included in mouth Saliva pH 5.0 to 6.0 solid buffer reagent is produced when being dissolved in chamber.The pH of increase 'Xiduofeng ' solution can reduce unionization The ratio of particle and ionized particles, this will cause transmucosal influx and translocation.

Preferably, buffer reagent is sodium carbonate, in terms of the weight of solid dosage forms, its can with about the 0.01% of solid dosage forms to About 10%, more preferably between 0.1% to 1%, most preferably from about 0.3% or 0.5% concentration exist.

In certain embodiments, solid dosage forms may include at least one absorption enhancer.Absorption enhancer can be polysaccharide, And positively chargeable.Preferably, absorption enhancer is beta-schardinger dextrin or its derivative.In terms of the dry weight of formulation, β-ring paste Essence or derivative can about 0.01% to about 10%, preferably between 0.2% to 2% and most preferably from about 1% concentration exist. Or at least one absorption enhancer may include trinitin (also referred to as GTN or nitroglycerin) or derivatives thereof.With agent The dry weight meter of type, trinitin or derivative can about 0.01% to about 20%, more preferably between 0.2% to 4% and Most preferably from about 2% concentration is present.

The solid dosage forms of the present invention can include flocculant to maintain bioactive substance during manufacturing process in matrix Evenly distribute.Flocculant can be glue.Glue is preferably xanthans.In terms of the dry weight of solid dosage forms, xanthans can about 0.01% Concentration to about 10%, preferably from about 0.2% to 2% and most preferably from about 1% is present.

In another preferred embodiment of the present, solid dosage forms includes at least one surfactant.To help biological active matter Matter is dissolved in the aqueous environments such as oral cavity, and surfactant can be used as wetting agent to be added in solution.Suitable surface-active Agent includes anionic detergent, such as NaLS, sulphur sodium succinate dioctyl ester and sodium sulfonate dioctyl ester.Cation can be used Detergent, and including benzalkonium chloride or benzethonium chloride.The inventory of possible nonionic detergent includes Lauromacrogol 400 (lauromacrogol 400), Myrj 52, polyoxyethylene hydrogenated castor oil 10,50 and 60, glycerine list are hard Resin acid ester, polysorbate40,60,65 and 80, sucrose fatty ester, methylcellulose and carboxymethyl cellulose.These surfaces Activating agent can be present in formulation individually or with the form of mixtures of different ratios.Preferably, surfactant helps to create Fast-dissolving solid forms.

The additive of the intake of potential enhancing bioactive substance also is present in solid dosage forms.The additive is optional Self-contained following inventory：Aliphatic acid, such as oleic acid, linolenic acid and linolenic acid.

Aesthetic property and sense of taste attraction for enhancing solid dosage forms to subject, formulation can also contain at least one as coloured Agent or the additive of flavor enhancement.Colouring agent is preferably that No. 2 indigo plants of FD＆C dyestuffs and No. 40 are red；Flavor enhancement may be selected from comprising following Inventory：Orange, peppermint, raspberry and caramel, and/or sweetener, such as Aspartame and saccharin, or two or more flavor enhancements is mixed Compound.

Therefore, in a highly preferred embodiment, the present invention provides one kind and is suitable for delivery of biologically active in the oral cavity The solid dosage forms of material, wherein the formulation includes：

(a) at least one bioactive substance, and

(b) at least one matrix formers,

Wherein described formulation is substantially solubilized in the oral cavity；Wherein described formulation includes 0.29% sodium carbonate, 0.59% carboxylic Sodium carboxymethylcellulose pyce, 1.48%PEG 2000,2.97% glycine, 5.93% microcrystalline cellulose；14.84% amylopectin, The dry weight of 29.67% lactose and 44.23% mannitol as the solid dosage forms；And it does not cause substantive detectable water Flat residue is stayed in the oral cavity of patient.Preferably, solid dosage forms is Fast-dissolving solid forms.PEG 2000 can be by PEG 1000 Replace, and have and above-mentioned oral identical advantage.

Preferably, the bioactive substance in solid dosage forms of the invention is selected from and includes following inventory：At least one ring Shape Guanosine 5'-Monophosphate (cGMP) 5 type phosphodiesterase (PDE5) inhibitor, the work with reference to one or more adrenergic receptors Property material and N-methyl-D-aspartate receptor antagonist.Preferably, N-methyl-D-aspartate receptor antagonist is selected from bag Containing following inventory：Dextromethorphan, dextrorphan or ketamine.Preferably, with reference to the work of one or more adrenergic receptors Property material is adrenaline or adrenaline salt.Preferably, the type phosphodiesterase (PDE5) of ring-type Guanosine 5'-Monophosphate (cGMP) 5 presses down Preparation is 'Xiduofeng ' or its pharmaceutically acceptable salt.Preferably, 'Xiduofeng ' salt is citric acid 'Xiduofeng '.

Carrier and excipient

As discussed above, solid dosage forms of the invention may include one or more pharmaceutically acceptable carriers.Using institute It is well known in the art to state medicament of the pharmaceutically acceptable carrier manufacture such as solid dosage forms (including Fast-dissolving solid forms). Unless acceptable carrier is incompatible with bioactive substance in any conventional pharmaceutical, otherwise covers it and be used to manufacture the present invention's Solid dosage forms.

The pharmaceutically acceptable carrier of the present invention may include one or more of following instance：

(1) surfactant and polymer, including but it is not limited to polyethylene glycol (PEG), polyvinylpyrrolidone, poly- second Enol, PVPP, polyvinylpyrrolidone-polyvinylacrylate copolymer, cellulose derivative, hydroxypropyl methyl are fine Tie up element, hydroxypropyl cellulose, carboxymethylethylcellulose, Hydroxypropyl Methylcellulose Phathalate, polyacrylate and gather Methacrylate, urea, sugar, polyalcohol and their polymer, emulsifying agent, carbohydrate gum, starch, organic acid and their salt, second Alkene pyrrolidone and vinyl acetate；And/or

(2) adhesive, such as various celluloses and PVPP, microcrystalline cellulose；And/or

(3) filler, such as lactose monohydrate, Lactis Anhydrous, mannitol, microcrystalline cellulose and various starch；And/or

(4) lubricant, such as acts on the reagent of the mobility of powder to be pressed, including cataloid, talcum, hard Resin acid, magnesium stearate, calcium stearate, silica gel；And/or

(5) sweetener, such as any natural or artificial sweetening agent, including sucrose, xylitol, saccharin sodium, cyclohexylsulfamic acid Salt, Aspartame and acesulfame potassium (accsulfame K)；And/or

(6) flavor enhancement；And/or

(7) preservative, such as potassium sorbate, methyl p-hydroxybenzoate, propylparaben, benzoic acid and it Salt, other esters (such as butyl p-hydroxybenzoate) of P-hydroxybenzoic acid, alcohol (such as ethanol or phenmethylol), phenol chemical substance are (such as Phenol) or quaternary compound (such as benzalkonium chloride)；Antioxidant, such as ascorbic acid, potassium sorbate, niter cake, Jiao Ya Sodium sulphate and sorbic acid；And/or

(8) buffer；And/or

(9) diluent, such as pharmaceutically acceptable inert filler, as microcrystalline cellulose, lactose, calcium monohydrogen phosphate, sugar and/ Or the mixture of any foregoing each thing；And/or

(10) wetting agent, such as cornstarch, farina, corn starch and modified starch, cross-linked carboxymethyl fiber Plain sodium, PVPP, Explotab and its mixture；And/or

(11) disintegrant；And/or

(12) effervescent agent, such as effervesce antithesis thing, as organic acid (such as citric acid, tartaric acid, malic acid, fumaric acid, Adipic acid, succinic acid and alginic acid and acid anhydrides and hydrochlorate) or carbonate (such as sodium carbonate, potassium carbonate, magnesium carbonate, glycine Sodium carbonate, 1B carbonate and arginine carbonate) or bicarbonate (such as sodium acid carbonate or saleratus)；

(13) absorption enhancer, such as trinitin；And/or

(14) other pharmaceutically acceptable excipient.

In another embodiment, more than one bioactive substances can be incorporated into the solid dosage forms of the present invention. In one example, if bioactive substance is adrenaline, then may achieve and provide different release characteristics-in early days from adrenal gland Element release, and the Fast-dissolving solid forms that the later stage discharges from larger average-size adrenaline.

Suitable for animal, and specifically the solid dosage forms of the invention in the mankind generally in manufacture and condition of storage It is lower must be sterile and stably.Solid dosage forms of the invention comprising bioactive substance can be configured to solid, liposome or be suitable to It is suitable for other ordered structures of the high drug concentration of oral delivery.

Actual dose intensity of the bioactive substance in the solid dosage forms of the present invention can be according to the property of bioactive substance Matter and be attributed to provide and apply bioactive substance advantage potential effect increase and change.Therefore, as used herein, " therapeutically effective amount " will refer to bioactive substance to realize the amount needed for therapeutic response in subject.Effective for the purposes Amount will depend on：Required therapeutic action；The efficiency of bioactive substance；The required duration for the treatment of；The disease treated Stage and seriousness；The weight and overall health of patient；And the judgement of prescriber.

For example, if adrenaline is the bioactive substance in the solid dosage forms of the present invention, then adrenaline Actual dose intensity according to the property of antiabnormal reaction agent/anti-allergic agent and offer can be provided and apply anti-excessively abnormal anti- Answering potential effect of the advantage of agent increases and changes.

The solid dosage forms of the present invention is to subject's oral administration.For oral administration solid dosage forms include wafer, Capsule, tablet, pill, powder, pill, film and granule.Preferably, solid dosage forms is sublingual administration.Preferably, solid formulation Type is Fast-dissolving solid forms.

It is incorporated to the excipient (as previously listed) and usual 0.1% to 95% bioactivity of any generally use Material and more preferably 0.1% to 75% material will form mean for the pharmaceutically acceptable non-toxic solid formulation of oral administration.

Although the solid dosage forms of the present invention can be with wafer, tablet, capsule；Pill；Powder；Pill；Granule；Or film Form is applied, but the oral of the present invention is also suitable for being used together with injecting type or ultrasonic sprayer, and will generally be wrapped Include the solid dosage forms being suspended in water.The formulation of the present invention may also comprise buffer and simple sugars (such as reaching protein Stabilize and regulate and control osmotic pressure).Nebulizer formulation also can contain surfactant to reduce or prevent forming aerosol by solution The compound aggregation of spatial induction caused by atomization during agent.Preferably, solid dosage forms is Fast-dissolving solid forms.

Spraying solid dosage forms preferably should not leave the residue that can be detected by patient of the formulation in the oral cavity.Spraying Instant bioactive substance in formulation should be by spreading and directly diffusing to the systemic blood circulatory system through oral mucosa In and be rapidly absorbed.

According to another aspect of the present invention, there is provided one kind is suitable for discharging in the oral cavity with reference to one or more adrenaline The solid dosage forms of the active material of energy acceptor, wherein the formulation includes：

(a) active material of one or more adrenergic receptors is combined, and

(b) at least one matrix formers,

Wherein described formulation is substantially solubilized in the oral cavity.Preferably, solid dosage forms is Fast-dissolving solid forms.Preferably, Active material with reference to one or more adrenergic receptors is adrenaline or adrenaline salt.Or adrenaline can It is provided as following form：The analog related to adrenaline and compound, such as norepinephrine, isoprel；Or Parasympathomimetic agent, such as tyrasamine, ephedrine, pseudoephedrine, amphetamine, salbutamol and Terbutaline.

In one embodiment, it is with reference to the active material (such as adrenaline) of one or more adrenergic receptors Amount in terms of the dry weight by solid dosage forms selected from the group consisted of is present：0.01 to 95%；0.1 to 75% and 1 to 45%.

In another embodiment, formulation includes：

(a) active material of 0.01 to 95 (drying) weight % combination one or more adrenergic receptor；

(b) amylopectin between 2 to 17 (drying) weight %；

(c) at least one matrix formers between 0.01 to 50 (drying) weight %；

(d) filler between 0.01 to 40 (drying) weight %；

(e) amino acid between 0.01 to 10 (drying) weight %；With

(f) diol/surfactant between 0.01 to 20 (drying) weight %

(g) carbohydrate between 0.01 to 60 (drying) weight %；

(h) the solid buffer reagent between 0.1 to 1 (drying) weight %；

(i) absorption enhancer between 0.01 to 20 (drying) weight %

In a highly preferred embodiment, the present invention provides one kind and is suitable for discharging in the oral cavity with reference to one or more The solid dosage forms of the active material (such as adrenaline) of adrenergic receptor, wherein the formulation includes：

(a) active material of one or more adrenergic receptors is combined；With

(b) at least one matrix formers,

Wherein described formulation is substantially solubilized in the oral cavity, wherein the formulation includes 0.25% sodium carbonate, 0.50% carboxylic Sodium carboxymethylcellulose pyce, 1.25%PEG 2000,2.49% glycine, 2.49% microcrystalline cellulose；12.49% amylopectin, The dry weight of 24.98% lactose, 2.00% trinitin and 37.46% mannitol as the solid dosage forms, and its The residue of substantive detectable level is not caused to stay in the oral cavity of patient.Preferably, solid dosage forms is Fast-dissolving solid forms.

In another embodiment, formulation includes the combination one or more adrenal gland of the amount selected from the group consisted of The active material (such as adrenaline) of plain energy acceptor：5mg；10mg；15mg；20mg；25mg；30mg；35mg、40mg、45mg、 50mg, 60mg and 100mg.

According to another aspect of the present invention, there is provided one kind is suitable for discharging at least one ring-type Guanosine 5'-Monophosphate in the oral cavity (cGMP) solid dosage forms of 5 type phosphodiesterase (PDE5) inhibitor, wherein the formulation includes：

(a) at least one type phosphodiesterase (PDE5) inhibitor of ring-type Guanosine 5'-Monophosphate (cGMP) 5, and

(b) at least one matrix formers,

Wherein described formulation is substantially solubilized in the oral cavity.Preferably, solid dosage forms is Fast-dissolving solid forms.Preferably, Ring-type Guanosine 5'-Monophosphate (cGMP) 5 type phosphodiesterase (PDE5) inhibitor is 'Xiduofeng ' or its pharmaceutically acceptable salt.It is excellent Selection of land, 'Xiduofeng ' salt are citric acid 'Xiduofeng 's.

In one embodiment, at least one type phosphodiesterase (PDE5) of ring-type Guanosine 5'-Monophosphate (cGMP) 5 suppresses Agent is that the amount in terms of the dry weight by solid dosage forms selected from the group consisted of is present：0.01 to 95%；0.1 to 75% and 1 to 45%.

In another embodiment, formulation includes：

(a) 0.01 to 95 (drying) weight % at least one type phosphodiesterase of ring-type Guanosine 5'-Monophosphate (cGMP) 5 (PDE5) inhibitor；

(b) amylopectin between 2 to 17 (drying) weight %；

(c) at least one matrix formers between 0.01 to 50 (drying) weight %；

(d) filler between 0.01 to 40 (drying) weight %；

(e) amino acid between 0.01 to 10 (drying) weight %；With

(f) diol/surfactant between 0.01 to 20 (drying) weight %

(g) carbohydrate between 0.01 to 60 (drying) weight %；

(h) the solid buffer reagent between 0.1 to 1 (drying) weight %；

(i) absorption enhancer between 0.01 to 20 (drying) weight %

In a highly preferred embodiment, the present invention provides one kind and is suitable for discharging at least one ring-type list in the oral cavity The solid dosage forms of guanosine 5-monophosphate (cGMP) 5 type phosphodiesterase (PDE5) inhibitor, wherein the formulation includes：

(a) at least one type phosphodiesterase (PDE5) inhibitor of ring-type Guanosine 5'-Monophosphate (cGMP) 5；With

(b) at least one matrix formers,

Wherein described formulation is substantially solubilized in the oral cavity, wherein the formulation includes 0.29% sodium carbonate, 0.59% carboxylic Sodium carboxymethylcellulose pyce, 1.48%PEG 2000,2.97% glycine, 5.93% microcrystalline cellulose；14.84% amylopectin, The dry weight of 29.67% lactose and 44.23% mannitol as the solid dosage forms, and it does not cause substantive detectable water Flat residue is stayed in the oral cavity of patient.Preferably, solid dosage forms is Fast-dissolving solid forms.

In another embodiment, formulation includes at least one ring-type monophosphate bird of the amount selected from the group consisted of Glycosides (cGMP) 5 type phosphodiesterase (PDE5) inhibitor：5mg；10mg；15mg；20mg；25mg；30mg；35mg、40mg、 45mg, 50mg, 60mg and 100mg.

According to another aspect of the present invention, there is provided one kind is suitable for discharging N-methyl-D-aspartate acceptor in the oral cavity The solid dosage forms of antagonist, wherein the formulation includes：

(a) N-methyl-D-aspartate receptor antagonist, and

(b) at least one matrix formers,

Wherein described formulation is substantially solubilized in the oral cavity.Preferably, solid dosage forms is Fast-dissolving solid forms.Preferably, N-methyl-D-aspartate receptor antagonist is selected from and includes following inventory：Dextromethorphan, dextrorphan or ketamine.

In one embodiment, N-methyl-D-aspartate receptor antagonist is with selected from the group consisted of Amount in terms of the dry weight of solid dosage forms is present：0.01 to 95%；0.1 to 75% and 1 to 45%.

In another embodiment, formulation includes：

(a) 0.01 to 95 (drying) weight % N-methyl-D-aspartate receptor antagonist；

(b) amylopectin between 2 to 17 (drying) weight %；

(c) at least one matrix formers between 0.01 to 50 (drying) weight %；

(d) filler between 0.01 to 40 (drying) weight %；

(e) amino acid between 0.01 to 10 (drying) weight %；With

(f) diol/surfactant between 0.01 to 20 (drying) weight %

(g) carbohydrate between 0.01 to 60 (drying) weight %；

(h) the solid buffer reagent between 0.1 to 1 (drying) weight %；

(i) absorption enhancer between 0.01 to 20 (drying) weight %

In a highly preferred embodiment, the present invention provides one kind and is suitable for discharging N- methyl Ds-asparagus fern in the oral cavity The solid dosage forms of propylhomoserin receptor antagonist, wherein the formulation includes：

(a) N-methyl-D-aspartate receptor antagonist；With

(b) at least one matrix formers,

Wherein described formulation is substantially solubilized in the oral cavity, wherein the formulation includes 0.25% sodium carbonate, 0.50% carboxylic Sodium carboxymethylcellulose pyce, 1.25%PEG 2000,2.49% glycine, 2.49% microcrystalline cellulose；12.49% amylopectin, The dry weight of 24.98% lactose and 37.46% mannitol as the solid dosage forms, and it does not cause substantive detectable water Flat residue is stayed in the oral cavity of patient.Preferably, solid dosage forms is Fast-dissolving solid forms.

In another embodiment, it is short of money to include the N-methyl-D-aspartate acceptor selected from the group consisted of for formulation Anti-agent：5mg；10mg；15mg；20mg；25mg；30mg；35mg, 40mg, 45mg, 50mg, 60mg and 100mg.

In another embodiment, compared to regular dosage form, solid dosage forms provide on apply and/or swallow calcination, Stimulate and/or discomfort reduces.

In another embodiment, formulation be suitable for by via oral transmucosal delivery and be delivered to systemic blood circulate In system.

According to another aspect of the present invention, there is provided a kind of to include the solid for being suitable for release of bioactive substances in the oral cavity The wafer of formulation.Preferably, solid dosage forms wafer is Fast-dissolving solid forms wafer.Preferably, bioactive substance selects Self-contained following inventory：At least one type phosphodiesterase (PDE5) inhibitor of ring-type Guanosine 5'-Monophosphate (cGMP) 5, with reference to one The active material and N-methyl-D-aspartate receptor antagonist of kind or a variety of adrenergic receptors.Preferably, N- methyl- D-Asp receptor antagonist is selected from and includes following inventory：Dextromethorphan, dextrorphan or ketamine.Preferably, ring-type list Guanosine 5-monophosphate (cGMP) 5 type phosphodiesterase (PDE5) inhibitor is 'Xiduofeng ' or its pharmaceutically acceptable salt.Preferably, former times Dove salt is citric acid 'Xiduofeng '.Preferably, the active material with reference to one or more adrenergic receptors is adrenaline Or adrenaline salt.Wafer can be with its operation instructions.

Preferably, once placing in the oral cavity, solid dosage forms wafer is i.e. in the period selected from the group consisted of It is interior substantially solubilized：After form of administration be less than 2 minutes, less than 1 minute, less than 50 seconds, less than 40 seconds, less than 30 seconds, it is small In 20 seconds, less than 15 seconds, less than 10 seconds, less than 7.5 seconds, less than 5 seconds, less than 4 seconds, less than 3 seconds, less than 2 seconds.Preferably, Gu Body formulation wafer is Fast-dissolving solid forms wafer.

It is highly preferred that once placing in the oral cavity, solid dosage forms wafer is i.e. in the time selected from the group consisted of It is completely dissolved in section：It is less than 2 minutes after form of administration；Less than 1 minute；Less than 50 seconds；Less than 40 seconds；Less than 30 seconds；It is small In 20 seconds；Less than 15 seconds；Less than 10 seconds；Less than 7.5 seconds；Less than 5 seconds；Less than 4 seconds；Less than 3 seconds；And less than 2 seconds.It is preferred that Ground, solid dosage forms wafer are Fast-dissolving solid forms wafers.

The further feature of the present invention provides the solid dosage forms wafer of the present invention, wherein the formulation is in the oral cavity substantially The residue that can be detected by subject dissolved without leaving the formulation in the oral cavity.Preferably, oral to patient, preferably After sublingual administration, solid dosage forms wafer is completely dissolved.Therefore, subject do not have swallow dry glue tablet form it is urgent highly necessary Ask, and therefore bioactive substance bypasses intestines and stomach and first pass effect of hepar, and be directly absorbed into systemic circulation blood.It is excellent Selection of land, solid dosage forms wafer are Fast-dissolving solid forms wafers.

Pharmaceutical composition

The present invention also provides a kind of pharmaceutical composition of the solid dosage forms comprising the present invention.Preferably, solid dosage forms is speed Molten solid dosage forms.

The pharmaceutical composition of the present invention can be formulated into addition with the usual amounts of conventional additives or complementary element containing State material.Composition can be in solid, liposome or be adapted for other ordered structures in the high drug concentration of oral delivery Form.Preferably, pharmaceutical composition is formulated into quickly dissolves in oral environment.

In one embodiment, composition can be formulated into strengthens substantially free of preservative, physiology or mucosa absorption Agent or propellant.In an alternate embodiment, composition can be formulated containing preservative, physiology or mucosa absorption and increase Strong agent or propellant.

Method

According to another aspect of the present invention, there is provided it is a kind of to produce the present invention solid dosage forms method, it include with Lower step：

A) at least one matrix formers are combined with bioactive substance to form mixture；And

B) mixture is freeze-dried to form the solid dosage forms.

Preferably, solid dosage forms is Fast-dissolving solid forms.

Also a kind of method for the solid dosage forms for producing the present invention is provided, it comprises the following steps：

A) at least one matrix formers are combined with combining the active material of one or more adrenergic receptors with shape Into uniform homogeneous blend；And

B) mixture is freeze-dried to form the solid dosage forms.

Preferably, solid dosage forms is Fast-dissolving solid forms.

Also a kind of method for the solid dosage forms for producing the present invention is provided, it comprises the following steps：

A) at least one matrix formers and at least one type phosphodiesterase of ring-type Guanosine 5'-Monophosphate (cGMP) 5 are combined (PDE5) inhibitor is to form uniform homogeneous blend；And

B) mixture is freeze-dried to form the solid dosage forms.

C) preferably, solid dosage forms is Fast-dissolving solid forms.

Also a kind of method for the solid dosage forms for producing the present invention is provided, it comprises the following steps：

A) at least one matrix formers are combined to mix to form homogeneous with N-methyl-D-aspartate receptor antagonist Thing；And

B) mixture is freeze-dried to form the solid dosage forms.

Preferably, solid dosage forms is Fast-dissolving solid forms.

Preferably, method provides a kind of solid dosage forms, wherein the formulation is substantially solubilized without in oral cavity in the oral cavity In leave the formulation can by subject detect residue.Preferably, solid dosage forms is Fast-dissolving solid forms.

Preferably, method of the invention produces a kind of solid dosage forms, once placing in the oral cavity, it is i.e. selected from by following It is substantially solubilized in the period of the group of composition：After administration be less than 2 minutes, less than 1 minute, less than 50 seconds, less than 40 seconds, Less than 30 seconds, less than 20 seconds, less than 15 seconds, less than 10 seconds, less than 7.5 seconds, less than 5 seconds, less than 4 seconds, less than 3 seconds, less than 2 Second.

It is highly preferred that once placing in the oral cavity, solid dosage forms is complete within the period selected from the group consisted of Fully dissolved：It is less than 2 minutes after form of administration；Less than 1 minute；Less than 50 seconds；Less than 40 seconds；Less than 30 seconds；Less than 20 seconds； Less than 15 seconds；Less than 10 seconds；Less than 7.5 seconds；Less than 5 seconds；Less than 4 seconds；Less than 3 seconds；And less than 2 seconds.

In a preferred embodiment of the present invention, the mixture comprising matrix formers and bioactive substance is measured (in terms of weight or volume) is into preformed plastics or aluminium bubble-cap mould (individual dose).Bubble-cap mould is placed to freezing 24 hours in drier, and gained Fast-dissolving solid forms then are sealed to prevent moisture absorption with aluminium or plastic foil.Preferably, Freeze Drying Technique is used to remove solvent from bubble-cap mould.Solid dosage forms, which is sealed, can prevent or reduce water into plastics or aluminium foil Divide and absorb.

Preferably, the inventive method formation is the solid dosage forms of wafer.Preferably, solid dosage forms wafer is instant solid Body formulation wafer.

In one embodiment of the invention, method can need adjust mixture pH between 3.0 and 8.0, it is excellent The pH being selected between 6.4 and 7.8.If it is required, then can be by using acid, such as hydrochloric acid, phosphoric acid or citric acid；Or Alkali compounds, pH is adjusted such as sodium hydroxide, dehydration sodium dihydrogen phosphate, disodium hydrogen phosphate, sodium acid carbonate and sodium carbonate.

In another embodiment, the step of method may include to use the solvent such as water.If water is used as solvent, then it It is preferred that removed by being freeze-dried.

Medicine box

The present invention also provides a kind of solid dosage forms including the present invention and the medicine box of its operation instructions.

In another aspect of this invention, there is provided a kind of medicine box, it includes：

A) solid dosage forms, wherein the formulation includes：

(i) at least one bioactive substance, and

(ii) at least one matrix formers, and

B) its operation instructions

Wherein described formulation is substantially solubilized in the oral cavity.Preferably, solid dosage forms is Fast-dissolving solid forms.

Preferably, bioactive substance is selected from and includes following inventory：At least one type of ring-type Guanosine 5'-Monophosphate (cGMP) 5 Phosphodiesterase (PDE5) inhibitor, the active material with reference to one or more adrenergic receptors and N- methyl Ds-asparagus fern Propylhomoserin receptor antagonist.Preferably, N-methyl-D-aspartate receptor antagonist is selected from and includes following inventory：Dextromethorphan, Dextrorphan or ketamine.Preferably, the active material with reference to one or more adrenergic receptors is on adrenaline or kidney Parathyrine salt.Preferably, ring-type Guanosine 5'-Monophosphate (cGMP) 5 type phosphodiesterase (PDE5) inhibitor be 'Xiduofeng ' or its pharmaceutically Acceptable salt.Preferably, 'Xiduofeng ' salt is citric acid 'Xiduofeng '.

Treatment method

The present invention solid dosage forms therapeutical uses include pain relief, antiphlogistic activity, migraine treatment, treating asthma and Treatment needs to apply other illnesss of the bioactive substance with high bioavilability and fast activity.

Therefore, the present invention provides a kind of method for the disease or illness for treating patient, and it comprises the following steps：To the trouble Person applies the pharmaceutical composition of the solid dosage forms comprising the present invention.Preferably, solid dosage forms is Fast-dissolving solid forms.

When needing the quick bio availability of bioactive substance, a major domain is in terms of pain is mitigated.Such as The auxiliary anodyne of cyclooxygenase-2 inhibitor (aspirin related drugs) or opiates can be prepared into the medicament of the present invention.Or Person, N-methyl-D-aspartate receptor antagonist can be used for pain relief and anesthesiology.Preferably, N-methyl-D-aspartate Receptor antagonist is selected from and includes following inventory：Dextromethorphan, dextrorphan or ketamine.N-methyl-D-aspartate acceptor is short of money Anti-agent can also be applied for the purpose for the treatment of depression, additive treatment.

Therefore, the present invention provides a kind of method for providing pain relief, and it comprises the following steps：Apply and wrap to patient Pharmaceutical composition containing the solid dosage forms of the invention containing N-methyl-D-aspartate receptor antagonist.

The present invention also provides a kind of method for being used to provide anesthesia, and it comprises the following steps：To patient apply comprising containing The pharmaceutical composition of the solid dosage forms of the invention of N-methyl-D-aspartate receptor antagonist.Preferably, N- methyl Ds-day Winter propylhomoserin receptor antagonist is selected from and includes following inventory：Dextromethorphan, dextrorphan or ketamine.

The present invention also provides a kind of method for treating depression, and it comprises the following steps：Applied to patient comprising containing N- The pharmaceutical composition of the solid dosage forms of the invention of methyl-D-aspartate receptor agonist.Preferably, N- methyl Ds-asparagus fern Propylhomoserin receptor antagonist is selected from and includes following inventory：Dextromethorphan, dextrorphan or ketamine.

The present invention also provides one kind and treats addicted method, and it comprises the following steps：Applied to patient comprising containing N- The pharmaceutical composition of the solid dosage forms of the invention of methyl-D-aspartate receptor agonist.Preferably, N- methyl Ds-asparagus fern Propylhomoserin receptor antagonist is selected from and includes following inventory：Dextromethorphan, dextrorphan or ketamine.

N-methyl-D-aspartate receptor antagonist can also be applied for the purpose for the treatment of epileptic attack.In a reality Apply in scheme, epileptic attack is caused by epilepsy.In another embodiment, epilepsy is selected from the group consisted of：Benign sieve Bright how insane sick (benign Rolandic epilepsy), frontal lobe epilepsy, infantile spasm, teenager's myoclonic epilepsy, green grass or young crops Juvenile absence epilepsy, childhood absence epilepsy (lapse), heating bath epilepsy, Lennox-Jia Situo syndromes (Lennox-Gastaut syndrome), Lan Da-Clive receive syndrome (Landau-Kleffner syndrome), De La Wei syndrome (Dravet syndrome), progressive myoclonus epilepsy, reflex epilepsy, Hans Kjeld Rasmussen Cotard (Rasmussen's syndrome), temporal epilepsy, edge epilepsy, status epilepticus, abdominal epilepsy, extensive bilateral flesh Clonic spasm, menstrual epilepsy, jacksonian seizure illness (Jacksonian seizure disorder), Lafora disease (Lafora disease) and light sensitivity epilepsy.In another embodiment, epileptic attack is selected from the group consisted of：Non- convulsion Contraction status epilepticus and convulsive epilepsy persistent state.

Therefore, the present invention provides a kind of method for treating epileptic attack, and it comprises the following steps：To patient apply comprising containing There is the pharmaceutical composition of the solid dosage forms of the invention of N-methyl-D-aspartate receptor antagonist.Preferably, N- methyl Ds- Aspartate receptor agonist is selected from and includes following inventory：Dextromethorphan, dextrorphan or ketamine.

The treatment of angiocardiopathy may also benefit from the bioactive substance in the solid dosage forms of the present invention, such as treats the heart and twists Bitterly, and specifically, molsidomine (molsidomine) can benefit from improved bioavilability.In another example, on kidney Parathyrine can be applied to treat acute cardiovascular event with solid dosage form, such as cardiac arrest or Cardiac Dysthythmia.Or knot The other active materials (such as norepinephrine) for closing one or more adrenergic receptors can be used in solid dosage forms to control Treat cardiovascular event.

Other therapeutical uses of bioactive substance in the solid dosage forms of the present invention include hair growth, sex dysfunction Or psoriasis.If the solid dosage forms of the present invention is used for the treatment of sexual dysfunction, then formulation will preferably comprise ring-type monophosphate Guanosine (cGMP) 5 type phosphodiesterase (PDE5) inhibitor.Preferably, the type phosphodiesterase of ring-type Guanosine 5'-Monophosphate (cGMP) 5 (PDE5) inhibitor is 'Xiduofeng ' or its pharmaceutically acceptable salt.Preferably, 'Xiduofeng ' salt is citric acid 'Xiduofeng '.

Therefore, the present invention provides a kind of method for the treatment of sexual dysfunction, and it comprises the following steps：Applied to patient Include the solid formulation of the invention containing at least one type phosphodiesterase (PDE5) inhibitor of ring-type Guanosine 5'-Monophosphate (cGMP) 5 The pharmaceutical composition of type.Preferably, ring-type Guanosine 5'-Monophosphate (cGMP) 5 type phosphodiesterase (PDE5) inhibitor be 'Xiduofeng ' or Its pharmaceutically acceptable salt.Preferably, 'Xiduofeng ' salt is citric acid 'Xiduofeng '.

Solid dosage forms of the invention containing ring-type Guanosine 5'-Monophosphate (cGMP) 5 type phosphodiesterase (PDE5) inhibitor Another purposes is treatment pulmonary hypertension.Preferably, ring-type Guanosine 5'-Monophosphate (cGMP) 5 type phosphodiesterase (PDE5) inhibitor is 'Xiduofeng ' or its pharmaceutically acceptable salt.Preferably, 'Xiduofeng ' salt is citric acid 'Xiduofeng '.

Therefore, the present invention provides a kind of method for treating pulmonary hypertension, and it comprises the following steps：Apply and wrap to patient Containing the solid dosage forms of the invention containing at least one type phosphodiesterase (PDE5) inhibitor of ring-type Guanosine 5'-Monophosphate (cGMP) 5 Pharmaceutical composition.Preferably, ring-type Guanosine 5'-Monophosphate (cGMP) 5 type phosphodiesterase (PDE5) inhibitor be 'Xiduofeng ' or its Pharmaceutically acceptable salt.Preferably, 'Xiduofeng ' salt is citric acid 'Xiduofeng '.

Other therapeutical uses of bioactive substance in the solid dosage forms of the present invention include allergy mitigation and allergy Treatment.The illness benefit from reference to one or more adrenergic receptors bioactive substance (such as adrenaline and its Its active material) quick absorption.

Therefore, the present invention provides a kind of method for treating allergy, and it comprises the following steps：To patient apply comprising containing There is the pharmaceutical composition of the solid dosage forms of the invention of the active material with reference to one or more adrenergic receptors.The present invention A kind of method for treating allergy is further provided for, it comprises the following steps：Applied to patient comprising containing with reference to one The pharmaceutical composition of the solid dosage forms of the invention of the active material of kind or a variety of adrenergic receptors.Preferably, with reference to one The active material of kind or a variety of adrenergic receptors is adrenaline or adrenaline salt.

Preferably, treatment method includes the solid dosage forms that the present invention is applied to patient, wherein the formulation is sublingual administration. Preferably, solid dosage forms is Fast-dissolving solid forms.

Using

The solid dosage forms of the present invention is suitable to subject's oral administration.As discussed above, formulation includes at least one biology Active material.Therefore, bioactive substance by oral transmucosal delivery to subject and was entered within the relatively short period In systemic blood system.Preferably, solid dosage forms is Fast-dissolving solid forms.

In a preferred embodiment, the effective plasma level concentration of bioactive substance is the period at most two hours It is interior, preferably at 30 minutes, 20 minutes, 15 minutes or less than 15 minutes in reach.Most preferably, effective blood of bioactive substance Starching concentration was reached within the period of 10 minutes, 9 minutes, 8 minutes, 7 minutes, 6 minutes, 5 minutes, 4 minutes, 3 minutes or 2 minutes Arrive.For example, can cause 2 to 10 minutes after administration in the solid dosage forms of the invention of sublingual fentanyl dry glue sheet form Interior detectable blood plasma fentanyl, in most cases occurred in 5 minutes.In other examples, the adrenal gland of the present invention Plain solid dosage forms can have therapeutic in 5 minutes；'Xiduofeng ' solid dosage forms is in 20 minutes, and ketamine fast dissolving solid agent Type can have therapeutic in 10 minutes.

In another embodiment, formulation provides the peak value blood selected from the group consisted of of patient's bioactive substance Starch concentration (C_max)：25ng/ml；30ng/ml；40ng/ml；50ng/ml；60ng/ml；70ng/ml；80ng/ml；90ng/ml； 100ng/ml；110ng/ml；120ng/ml；130ng/ml；140ng/ml；150ng/ml；160ng/ml；170ng/ml； 180ng/ml；190ng/ml；And 200ng/ml.

When compared with intravenous injection, low obtain can be produced in the solid dosage forms of the invention of sublingual dry glue sheet form More C_max, this can reduce the toxicity of applied bioactive substance.For example, it is clinical in I phases sublingual fentanyl wafer In experiment, the C of 100 μ g fentanyl intravenous infusions_max(5 minutes) are 1451.0pg/mL, however, 100 μ g fentanyl wafers C_maxOnly 219.3pg/mL.Similarly, in the sublingual ketamine wafer clinical test of I phases, it is transfused in 10mg ketamine intravenous C_max(30 minutes) are 128.1ng/mL, and the C of 25mg ketamine wafers_maxIt is 71.1ng/mL.

In another embodiment, solid dosage forms has the intermediate value selected from the group consisted of of bioactive substance t_max：Between 5 minutes to 90 minutes；Between 10 minutes and 75 minutes；Between 15 minutes and 60 minutes；30 minutes with Between 50 minutes；Between 40 minutes and 50 minutes；And 45 minutes.For example, the sheet of 25mg ketamines dry glue sheet form The T of the solid dosage forms of invention_maxIt can be 45 minutes.

In a highly preferred embodiment, formulation provides biological active matter within the time selected from the group consisted of The detectable plasma concentration of the first of matter：In 15 minutes；In 14 minutes；In 13 minutes；In 12 minutes；At 11 minutes It is interior；In 10 minutes；In 9 minutes；In 8 minutes；In 7 minutes；In 6 minutes；In 5 minutes；In 4 minutes；3 In minute；In 2 minutes；And in 1 minute.For example, can be after sublingual administration is carried out with the formulation of the present invention Using afterwards between 2 minutes and 10 minutes it was observed that the first detectable blood plasma fentanyl concentration.

Preferably, formulation provides the intermediate value biological utilisation selected from the group consisted of of bioactive substance in patients Degree：Between 10 and 60%；Between 20 and 40%；Between 25 and 35%；Between 28 and 30%；And 28%.Citing For, solid dosage forms can provide the intermediate value bioavilability 28% of N-methyl-D-aspartate receptor antagonist in patients, its The dosage of middle antagonist is 25mg.Solid dosage forms can also provide 29% intermediate value bioavilability of sublingual ketamine, wherein chlorine The dosage of amine ketone is 25mg.

In another embodiment, solid dosage forms provides biology after the period selected from the group consisted of to patient Effective treatment blood plasma level of active material：More than 30 minutes, 30 minutes, 25 to 30 minutes, 20 to 25 minutes, 15 to 20 points Clock, 10 to 15 minutes, 10 minutes, 9 minutes, 8 minutes, 7 minutes, 6 minutes, 5 minutes, 4 minutes, 3 minutes or 2 minutes.

The subject for receiving the solid dosage forms of the present invention can be animals or humans.When subject is the mankind, it can be into People or children, including older adult and baby.Specifically, subject can be that can not swallow or have difficulty swallowing aspect Subject.

The present invention has been surprisingly found out that addition sodium carboxymethylcellulose can improve the dissolution rate of solid dosage forms.Work as carboxymethyl The amount of sodium cellulosate in terms of the dry weight of formulation between about 0.1% and 15% when, formulation rapid release of active agent, without in oral cavity In leave residue.In addition, the use of gelatin is avoided, and therefore leaves a little or do not stayed in the oral cavity after administration Under unwanted residue.Lactose is added in the solid dosage forms of the present invention and/or mannitol is also advantageous.

Purposes

Also provide be suitable for release of bioactive substances in the oral cavity solid dosage forms be used for manufacture to treat disease or The purposes of the medicament of illness, wherein the formulation includes：

(a) at least one bioactive substance, and

(b) at least one matrix formers, wherein the formulation is substantially solubilized in the oral cavity.Preferably, solid dosage forms It is Fast-dissolving solid forms.

Preferably, bioactive substance is selected from and includes following inventory：At least one type of ring-type Guanosine 5'-Monophosphate (cGMP) 5 Phosphodiesterase (PDE5) inhibitor, the active material with reference to one or more adrenergic receptors and N- methyl Ds-asparagus fern Propylhomoserin receptor antagonist.Preferably, N-methyl-D-aspartate receptor antagonist is selected from and includes following inventory：Dextromethorphan, Dextrorphan or ketamine.Preferably, the active material with reference to one or more adrenergic receptors is adrenaline adrenal gland Element or adrenaline salt.Preferably, ring-type Guanosine 5'-Monophosphate (cGMP) 5 type phosphodiesterase (PDE5) inhibitor be 'Xiduofeng ' or Its pharmaceutically acceptable salt.Preferably, 'Xiduofeng ' salt is citric acid 'Xiduofeng '.

Preferably, disease or illness, which are selected from, includes following inventory：Pain, depression, additive, inflammation, antimigraine, heavy breathing Asthma, epilepsy, acute cardiovascular event (such as cardiac arrest or Cardiac Dysthythmia), angina pectoris, alopecia, sex dysfunction, silver bits Disease, pulmonary hypertension, allergy/allergy and offer anesthesia.

Therefore it provides the solid dosage forms for being suitable for release of bioactive substances in the oral cavity is used to manufacture to treat disease Or the purposes of the medicament of illness, wherein the formulation includes：

(a) at least one type phosphodiesterase (PDE5) inhibitor of ring-type Guanosine 5'-Monophosphate (cGMP) 5, and

(b) at least one matrix formers, wherein the formulation is substantially solubilized in the oral cavity.Preferably, solid dosage forms It is Fast-dissolving solid forms.Preferably, disease or illness, which are selected from, includes following inventory：Sex dysfunction, pulmonary hypertension.

A kind of solid dosage forms for being suitable for release of bioactive substances in the oral cavity is used to manufacture to treat disease or disease The purposes of the medicament of disease, wherein the formulation includes：

(a) N-methyl-D-aspartate receptor antagonist, and

(b) at least one matrix formers, wherein the formulation is substantially solubilized in the oral cavity.Preferably, solid dosage forms It is Fast-dissolving solid forms.Preferably, disease or illness, which are selected from, includes following inventory：Pain, depression, additive, antimigraine, Epilepsy and offer anesthesia.

A kind of solid dosage forms for being suitable for release of bioactive substances in the oral cavity is used to manufacture to treat disease or disease The purposes of the medicament of disease, wherein the formulation includes：

(a) active material of one or more adrenergic receptors is combined, and

(b) at least one matrix formers, wherein the formulation is substantially solubilized in the oral cavity.Preferably, solid dosage forms It is Fast-dissolving solid forms.Preferably, disease or illness, which are selected from, includes following inventory：Acute cardiovascular event (such as cardiac arrest Or Cardiac Dysthythmia), angina pectoris, allergy or allergy.

General provisions

Those skilled in the art will be appreciated that invention as described herein can carry out the change in addition to those being expressly recited Change and change.It should be appreciated that the present invention includes all described change and modifications.The present invention also includes individually or collectively carrying in specification And or all steps, feature, composition and the material and step that indicate or any and all combination of feature or step or spy Any two in sign or more.

The present invention is not only restricted to specific embodiment as described herein in scope, and the embodiment is only intended to example The property shown purpose.Function equivalent product, composition and method are clearly in the range of as of the invention described herein.

Invention as described herein may include one or more scopes of numerical value (such as size, concentration etc.).Number range It will be understood as one that including all numerical value in the scope, including define the numerical value of the scope and be adjacent to the scope Cause the result numerical value identical or substantially the same with the numerical value of the numerical value close to the border for defining the scope.

Herein cited all publications (including patent, patent application, journal of writings, laboratory manual, books or other File) entire disclosure be hereby incorporated herein by accordingly.Include and do not form any bibliography composition of accreditation first A part for preceding technology or the common knowledge of technical staff that the invention relates to the field.

In entire chapter this specification, unless the context requires otherwise, otherwise word " including (comprise) " or change shape Formula will be understood as one that hint includes an integer or one group of integer (such as " comprises " or " comprising "), however, It is not excluded for any other integer or any other group of integer.It must also be noted that in the disclosure, and particularly claim and/ Or in paragraph, the term of such as "comprising", which can have in United States patent law, is attributed to its implication；Such as they can refer to " comprising " etc..

Such as herein in regard to treatment method, and specifically " therapeutically effective amount " used in drug dose should refer to needing State the dosage that the specific pharmacological reaction using medicine is provided in a large amount of subjects for the treatment of.It is emphasised that under specific circumstances to " therapeutically effective amount " that particular subject is applied be not always effective in terms of disease as described herein is treated, although the dosage It is considered as " therapeutically effective amount " by those skilled in the art.It is further understood that drug dose is measured as orally under specific circumstances Dosage, or with reference to such as the levels of drugs measured in blood.

Term " suppression " is defined to the generally accepted implication for including it, and it includes forbidding, prevent, prevent and dropping Low, termination reverses progress or seriousness, and the effect to gained symptom.Therefore, the present invention takes the circumstances into consideration to include medical science and control The property treated is applied applies both with preventing and treating property.

Term " bioactive substance " is defined to refer to bioactive compound or the material comprising bioactive compound. In this definition, compound is generally viewed as referring to different chemical entities, and wherein one or more chemical formulas can be used for describing institute State material.The compound will be usual, but may not be identified in the literature by the unique class system of such as CAS numberings.One A little compounds can have more complicated and with the chemical constitution mixed.For the compound, they can only have empirical formula or It is subject to Qualitative Identification.Compound will typically pure material, but by up to the 10% of expected material, 20%, 30%, 40%, 50%, 60%th, 70%, 80%, 90% can be other impurity etc..The example of bioactive compound is, but is not limited to：Fungicide, Insecticides (tech) ＆ Herbicides (tech), seed treatment, cosmeceutical, cosmetics, supplement sex pill, natural products, vitamin, nutrients, Neutraceuticals, pharmaceutical actives, biological agent, amino acid, protein, peptide, nucleotides, nucleic acid, additive, food and food Composition with and the like, homologue and first order derivative.Material containing bioactive compound is with bioactivity Any material of the compound as a kind of its component.The example of material containing bioactive compound is, but is not limited to, Pharmaceutical preparation and product, cosmetic formulations and product, industrial preparation and product, agricultural formulations and product, food, seed, cocoa With cocoa solids, coffee, galenical, spices, other vegetable materials, mineral matter, animal product, housing and other skeleton materials Material.

Any one in term " biological active matter ", " active matter ", " active material " will all have with bioactive substance Identical meanings.

As used herein, " pharmaceutically acceptable carrier " includes physiologically compatible any and all solvent, disperseed Medium, coating agent, antibacterial agent and antifungal agent, isotonic agent and absorption delaying agent etc..Preferably, carrier is suitable to oral administration.

Brief description

The scanning electron micrograph on the surface of wafers of the Fig. 1 from lot number 071501B and 071502B.

The scanning electron micrograph on the surface of wafers of the Fig. 2 from lot number 0820A and 0820B.

The scanning electron micrograph on the surface of wafers of the Fig. 3 from lot number 0905MD.

The scanning electron micrograph of the cross section of wafers of the Fig. 4 from lot number 071501B and 071502B.

The scanning electron micrograph of the cross section of wafers of the Fig. 5 from lot number 0820A and 0820B.

The scanning electron micrograph of the cross section of wafers of the Fig. 6 from lot number 0905MD.

The powder x-ray diffraction spectrum of wafers of the Fig. 7 from lot number 071501A and 071502B.

The powder x-ray diffraction spectrum of wafers of the Fig. 8 from lot number 0820A and 0820B.

The powder x-ray diffraction spectrum of wafers of the Fig. 9 from lot number 0905MD.

Standard midazolam samples (n=3) of the Figure 10 [A] under 4.05 μ g/mL；The miaow of [B] 1 minute and 5 minutes reaches Azoles logical sequence powder dissolution sample；The midazolam powder dissolution sample of [C] at 10 minutes；[D] 15 minutes midazolam powder is molten Go out sample；And the typical HPLC chromatogram of the standard midazolam sample of [E] under 8.1 μ g/ml.

Typical HPLC chromatograms of the Figure 11 in the dissolution wafer sample S1 of 45 seconds and 1 minute.

Typical HPLC chromatograms of the Figure 12 in the dissolution wafer sample S1 of 10 minutes.

Typical HPLC chromatograms of the Figure 13 in the dissolution wafer sample S2 of 5 and 10 minutes.

Typical HPLC chromatograms of the Figure 14 in the dissolution wafer sample S2 of 30 seconds and 2 minutes.

Dissolution wafer sample S3s of the Figure 15 at 20 seconds and at 1 minute typical HPLC chromatogram.

The typical HPLC chromatogram of standard midazolam samples of the Figure 16 under 1.01 μ g/mL.

Typical HPLC chromatograms of the Figure 17 in the midazolam powder dissolution sample of 30 seconds.

Typical HPLC chromatograms of the Figure 18 in the dissolution wafer 1 of 1 minute and 5 minutes.

Typical HPLC chromatograms of the Figure 19 in the dissolution wafer 1 of 5,10 and 15 minutes.

No. 1 medicine of Figure 20 loads the typical HPLC chromatogram of test wafer sample.

Typical HPLC chromatograms of the Figure 21 in the dissolution wafer 2 of 30 seconds.

Typical HPLC chromatograms of the Figure 22 in the dissolution wafer 2 of 1 minute and 5 minutes.

Typical HPLC chromatograms of the Figure 23 in the dissolution wafer 2 of 10,15 and 30 minutes.

No. 2 medicines of Figure 24 load the typical HPLC chromatogram of test wafer sample.

Typical HPLC chromatograms of the Figure 25 in the dissolution wafer 3 of 30 seconds.

Typical HPLC chromatograms of the Figure 26 in the dissolution wafer 3 of 1 minute and 5 minutes.

Typical HPLC chromatograms of the Figure 27 in the dissolution wafer 3 of 10 and 15 minutes.

Typical HPLC chromatograms of the Figure 28 in the dissolution wafer 3 of 30,45 and 60 minutes.

No. 3 medicines of Figure 29 load the typical HPLC chromatogram of test wafer sample.

The standard HPLC calibration curves of Figure 30 midazolams (1 to 32.4 μ g/mL).

The midazolams that from wafer and midazolam powder discharges of the Figure 31 at 37 DEG C is in phosphate buffer solution (pH 6.8) cumulative concentration in.

The standard HPLC calibration curves of Figure 32 fentanyls (0.5 to 10 μ g/mL).

Dissolution collection of illustrative plates (n=4) of fentanyl wafers of the Figure 33 at 37 DEG C in phosphate buffer solution (pH 6.8).

Figure 34 A to E are in sample time 0.5, the dissolution sample 1 to 3 of the fentanyl wafer of 1,5,10,15 and 20 minutes Typical HPLC chromatogram.

Figure 35 A to J are in sample time 1, the allusion quotation of the dissolution sample 4 to 6 of the fentanyl wafer of 2,3,4,5,7 and 10 minutes Type HPLC chromatogram.

The scanning electron micrograph on the surface of Figure 36 blank Expidets.

The scanning electron micrograph on the surface of Figure 37 ketamine Expidets.

The powder x-ray diffraction spectrum of Figure 38 blank Expidets.

The powder x-ray diffraction spectrum of Figure 39 chloramines ketone powders.

The powder x-ray diffraction spectrum of Figure 40 ketamine Expidets.

Typical HPLC chromatograms of the Figure 41 in the dissolution ketamine wafer sample S2 of 1 minute.

Typical HPLC chromatograms of the Figure 42 in the dissolution ketamine wafer sample S2 of 3 minutes.

Typical HPLC chromatograms of the Figure 43 in the dissolution ketamine wafer sample S2 of 5 minutes.

Typical HPLC chromatograms of the Figure 44 in the dissolution ketamine wafer sample S2 of 7 minutes.

Typical HPLC chromatograms of the Figure 45 in the dissolution ketamine wafer sample S2 of 10 minutes.

Typical HPLC chromatograms of the Figure 46 in the dissolution ketamine wafer sample S2 of 15 minutes.

Typical HPLC chromatograms of the Figure 47 in the dissolution ketamine wafer sample S2 of 20 minutes.

Typical HPLC chromatograms of the Figure 48 in the dissolution ketamine wafer sample S2 of 30 minutes.

The standard HPLC calibration curves of Figure 49 ketalars (5 to 100 μ g/mL).

No. 1 medicine of Figure 50 loads the typical HPLC chromatogram of test ketamine wafer sample.

Stripping curve (n=3) of ketamine wafers of the Figure 51 at 37 DEG C in phosphate buffer solution (pH 6.8).

After Figure 52 gives 10mg dosage during 30 minutes intravenous infusions to 8 healthy volunteers, entirely sampling The overlapping geometrical mean of indivedual RS ketamines plasma concentrations in period.

After Figure 53 gives 10mg dosage during 30 minutes intravenous infusions to 8 healthy volunteers, at first 12 hours The overlapping geometrical mean of indivedual RS ketamines plasma concentrations of period.

Figure 54 continues indivedual RS of whole sampling time period after 25mg sublingual-dosages are given to 8 healthy volunteers The overlapping geometrical mean of ketamine plasma concentration.

Figure 55 to 8 healthy volunteers after 25mg sublingual-dosages are given, indivedual RS chloramines during first 12 hours The overlapping geometrical mean of ketone plasma concentration.

Figure 56 after 25mg sublingual-dosages are given to 8 healthy volunteers, RS ketamines it is indivedual (S=subject with Machineization is numbered) t_max。

Figure 57 during 30 minutes intravenous infusion (IV, hollow rod) to 8 healthy volunteers give 10mg dosage or After sublingual (SL, solid rod) gives 25mg, indivedual (S=subject's Randomization Number) AUC of RS ketamines_INF。

After Figure 58 gives 10mg dosage during 30 minutes intravenous infusions to 8 healthy volunteers, RS ketamines (subject's Randomization Number) clearance rate (CL) individually.

Figure 59 during 30 minutes intravenous infusion (IV, empty circles) to 8 healthy volunteers give 10mg dosage or After sublingual (SL, solid circles) give 25mg, indivedual (S=subject's Randomization Number) end-stage half-life periods of RS ketamines t_1/2。

Figure 60 to 8 healthy volunteers after 25mg RS ketamines are applied, all subjects (S=subject numbers) Bioavilability (F) % indivedual estimated values.

The mood measuring scale curve that Figure 61 IV are applied.To 30 minutes intravenous infusion 10mg ketamines of healthy volunteer Afterwards it was observed that key element " vigilant (alertness) " (key element 1), " feeling at ease (contentedness) " (key element 2) and " calmness (calmness) " average (SD) score of (key element 3).

The mood measuring scale curve of Figure 62 sublingual administrations.To healthy volunteer's sublingual administration 25mg ketamine wafers Afterwards it was observed that key element " vigilant " (key element 1), " feeling at ease " (key element 2) and " calmness " (key element 3) average (SD) score.

Li Kete (Likert) local tolerance totality scale of Figure 63 modifications

The scanning electron micrograph on the surface of Figure 64 blank Expidets.

The powder x-ray diffraction spectrum of Figure 65 blank Expidets.

The powder x-ray diffraction spectrum of Figure 66 'Xiduofeng ' powder.

The powder x-ray diffraction spectrum of Figure 67 'Xiduofeng ' Expidets.

Typical HPLC chromatograms of the Figure 68 in the dissolution 'Xiduofeng ' wafer sample S1 of 1 minute.

Typical HPLC chromatograms of the Figure 69 in the dissolution 'Xiduofeng ' wafer sample S1 of 3 minutes.

Typical HPLC chromatograms of the Figure 70 in the dissolution 'Xiduofeng ' wafer sample S1 of 5 minutes.

Typical HPLC chromatograms of the Figure 71 in the dissolution 'Xiduofeng ' wafer sample S1 of 7 minutes.

Typical HPLC chromatograms of the Figure 72 in the dissolution 'Xiduofeng ' wafer sample S1 of 10 minutes.

Typical HPLC chromatograms of the Figure 73 in the dissolution 'Xiduofeng ' wafer sample S1 of 15 minutes.

Typical HPLC chromatograms of the Figure 74 in the dissolution 'Xiduofeng ' wafer sample S1 of 20 minutes.

Typical HPLC chromatograms of the Figure 75 in the dissolution 'Xiduofeng ' wafer sample S1 of 30 minutes.

No. 1 medicine of Figure 76 loads the typical HPLC chromatogram of test 'Xiduofeng ' wafer sample.

The μ g/mL of Figure 77 'Xiduofeng 's 5 to 100) standard HPLC calibration curves.

Stripping curve (n=4) of 'Xiduofeng ' wafers of the Figure 78 at 37 DEG C in phosphate buffer solution (pH 6.8).

Figure 79 shows the table of the Demographic of the research volunteer according to embodiment 4.

Figure 80 shows the average (± SEM) plasma concentration (pg/mL) of sublingual fentanyl wafer and IV fentanyls with the time Curve figure.Illustration is the amplified curve in initial 2 hour period.

Figure 81 shows the plasma concentration data (pg/mL) of the sublingual fentanyl wafer of each volunteer with the curve of time Scheme (n=22).

Figure 82 shows the table of the average value (± 1SD) of fentanyl plasma pharmacokinetics parameter.

Figure 83 show buccal and sublingual (SL) fentanyl dosage form comparative document pharmacokinetic data (average value ± Table 1SD).

Embodiment

The present invention describes now with reference to following non-limiting example.Description to embodiment is never to this specification Previous paragraph is restrictive, and is provided to illustrate the method and composition of the present invention.

Embodiment 1

Prepared according to method and the composition illustrated such as Table 1 below in the of the invention of solid dosage forms (wafer) form Preparation：

Table 1：Fast-dissolving solid forms (wafer) are formulated

It is sufficiently mixed by using agitator in a part of purified water and adds sodium carboxymethylcellulose and amylopectin.Then Mixture is heated to 50 DEG C, is continued 10 minutes so that polymer dissolves.Once solution is cooled to room temperature, i.e., under agitation individually Polyethylene glycol 2000, glycine, sodium carbonate, microcrystalline cellulose, lactose and mannitol are added to obtain homogeneous solution.Use Brookfield Digital Viscometers (Brookfield Engineering Laboratories Inc., MA, USA) are at 25 DEG C Measure the viscosity of solution.

The mixture as obtained by pipette transfer, and correct amount then shifts into preformed blister package Into freezer unit (- 30 DEG C), last about 24 hours.After freezing, sample is freeze-dried (DYNAVAC, Australia) 24 Hour.It will prepare on the silica gel that sample is stored in drier at room temperature.

Following other dried wafer preparations are prepared by the method being explained as above.Sample 1 to 6 is substantially based on above-mentioned match somebody with somebody Side, wherein addition flavor enhancement and/or colouring agent.

Sample 1. contains flavor enhancement in addition.

Composition	Measure (g)	Weight %
			Sodium carbonate	1	0.08
Sodium carboxymethylcellulose	2	0.15
			Polyethylene glycol 2000	5	0.37
Orange flavor enhancement	10	0.74
			Glycine	10	0.74
Microcrystalline cellulose	20	1.48
			Amylopectin	50	3.71
Lactose	100	7.42
			Mannitol	150	11.13
Purified water	1000	74.18

Sample 2. contains flavor enhancement and pH adjusting agent (citric acid) in addition.

Composition	Measure (g)	Weight %
			Sodium carbonate	1	0.07
Sodium carboxymethylcellulose	2	0.15
			Citric acid	5	0.37
Polyethylene glycol 2000	5	0.37
			Mint flavor	10	0.74
Glycine	10	0.74
			Microcrystalline cellulose	20	1.48
Amylopectin	50	3.70
			Lactose	100	7.39
Mannitol	150	11.09
			Purified water	1000	73.91

Sample 3. contains flavor enhancement and colouring agent in addition

Composition	Measure (g)	Weight %
			FD＆C is red	0.1	0.01
Sodium carbonate	1	0.07
			Sodium carboxymethylcellulose	2	0.15
Polyethylene glycol 2000	5	0.37
			Grape flavor	9.9	0.74
Glycine	10	0.74
			Microcrystalline cellulose	20	1.48
Amylopectin	50	3.71
			Lactose	100	7.42
Mannitol	150	11.13
			Purified water	1000	74.18

Sample 4. contains flavor enhancement, colouring agent and absorption enhancer in addition.

Sample 5. contains colouring agent and sweetener in addition

Composition	Measure (g)	Weight %
			FD＆C is red	0.1	0.01
Sodium carbonate	1	0.07
			Sodium carboxymethylcellulose	2	0.15
Aspartame	5	0.37
			Polyethylene glycol 2000	5	0.37
Cherry flavor enhancement	9.9	0.73
			Glycine	10	0.74
Microcrystalline cellulose	20	1.48
			Amylopectin	50	3.71
Lactose	100	7.42
			Mannitol	145	10.76
Purified water	1000	74.19

Sample 6. contains colouring agent and pH adjusting agent in addition

Composition	Measure (g)	Weight %
			FD＆C is red	0.1	0.01
Sodium carbonate	1	0.07
			Sodium carboxymethylcellulose	2	0.15
Sodium acid carbonate	5	0.37
			Polyethylene glycol 2000	5	0.37
Raspberry flavor enhancement	9.9	0.73
			Glycine	10	0.74
Microcrystalline cellulose	20	1.48
			Amylopectin	50	3.71
Lactose	100	7.42
			Mannitol	145	10.76
Purified water	1000	74.19

It is next based on the formula shown in table 1 and prepares the solid dosage dry glue sheet form of various batches, and is as above explained Stating preparation, also containing midazolam (alkali) or citric acid fentanyl, (2.5mg fentanyls alkali is used for 50 wafers, and strength equivalent is 50 μ g fentanyls alkali) solid dosage dry glue sheet form as bioactive substance.Lot number and composition are listed in Table 2 below.

Table 2：Midazolam or fentanyl composition for research

Overview result

Significant difference (knot is not present between cetomacrogol 1000 or polyethylene glycol 2000 it was found that being used in dried wafer preparation Fruit does not show).

Add starch and produce hard wafer, and be less suitable for the Fast-dissolving solid forms of the present invention.

Uniformity of weight

Tested according to British Pharmacopoeia (BP) 2009 to test the uniformity of weight of instant dosage wafer form.Table will be come from 20 wafers of listed each preparation are individually weighed in 2, and average weight and relative standard deviation.From different preparations All preparations wafer all in the weight change of the receiving between 0.25 to 2%.

Hardness

Also the hardness of dosage particles listed in table 2 is tested.The mechanical strength of tablet is referred to as " hardness ".It is hard using Erweka Spend the hardness of analyzer (Germany) measure wafer.The hardness number of different preparations is in the range of 0.5 to 4.0kg.It was observed that When adding AVM hereinafter Sai Er into preparation, the hardness increase of preparation (result is not shown).

Friability

The intensity of fast dissolving solid dosage dry glue sheet form is measured, i.e., they reduce into the energy compared with fractionlet from solid matter Power.Carried out using Erweka friabilators (Germany) according to the methods of BP 2009 (friability of i.e. uncoated tablet) Test.The sample of 20 wafers of correct amount, and place in a device.Use rotational time 4 minutes under 25rpm.Move Remove and be re-weighed wafer, and calculated weight mitigates percentage.It was found that model of the weight saving of 20 wafers 8 to 20% In enclosing.Although this weight saving does not meet the standards of BP 2009 of the weight saving of compressed tablets about 1%, in BP or USP monographs In be not present wafer this class standard.

Water analysis

870Karl Fisher Titrino Plus (Metrohm Ag, Germany) analysis dry glues are used after lyophilized The moisture of piece.As a result show that the residual moisture content of different preparations changes between 1% to 5%.

Scanning electron microscopy analysis

Using selected by SEM (SEM) (Zeiss, EVO 40XVP, Oxford Instrument, UK) observation The configuration of surface of dried wafer preparation and cross section.Cross-sectional samples are prepared by using the thin slice of scalpel cutting wafer. Before an examination sample is coated with carbon.Accelerating potential is 10kV.

It is highly porous that SEM image shown in Fig. 1 to 6 illustrates that wafer is respectively provided with both surface and internal structure Matter.It is apparent that the existing forms difference between different preparations.The micro- knot for the excipient effects wafer that the instruction of these differences uses Structure.In addition, different hardness, friability, disintegration time that micro-structural may provide the wafer on being prepared from different formulations are To the explanation of stripping curve.

Powder x-ray diffraction (XRD)

X-ray diffraction experiment is carried out using the Bruker D8 Advance (Germany) with detector LynEye.Make Radiation is the CuK α of nickel filtering, and it is produced using 40kV accelerating potentials and 40mA cathode currents.In 2 θ of 7.5 to 70 degree In the range of and the scanned samples under 1 second/0.02 degree of gate time.

The physical state of material is obvious in X-ray diffraction spectra in wafer.Such as according to three kinds of the preparation of table 2 not Spectrum with preparation is shown in Fig. 7 to 9.It was observed that prepare wafer all powder collection of illustrative plates all by be located approximately at 9.58 °, 19th, the strong scattering peak at 68 ° and 20.05 ° of 2 θ is dominant, and this instruction has crystallographic property.The discovery from caused by SEM also as counting According to support (referring to Fig. 1-6).In fact, the excipient (such as glycine, lactose, mannitol and the microcrystalline cellulose that are used in preparation Element) substantially it is crystallization.It was observed that minimal physical state change in solid dispersions be present.

Disintegration and stripping analysis

Use device I (BP 2009, turn basket device) is disintegrated and dissolution test.Erweka dissolving devices (Hesenstamm, Germany) is used for two experiments.The temperature of medium is maintained at 37 ± 0.5 DEG C.

For slaking test, wafer is placed on cylinder and turned in basket, and by hydrostatic column with distillation Water is contacted to be moistened on downside.Total dissolution time of each wafer is recorded, and calculates average value.

For dissolution test, contain midazolam and be used to follow BP turns as the wafer (batch 0905MD) of model drug Both basket method and USP paddle method determine mechanism that medicine discharges from system (referring to Figure 17).Dissolution medium is that 500mL phosphate delays Solution (the close saliva fluid under 6.8 of pH value) is rushed, wherein oar rotary speed is under 75rpm.Given interval (such as 0.5, 1st, 2,3,5,10,15,20 and 30 minutes) under, replaced by 2mL solution samplings, and with isometric fresh medium to remain permanent Determine cumulative volume.Sample is filtered through 0.2 μm of Millipore filter.Pass through the medicine of HPLC measurement releases.

HPLC system is by the pumps of Waters 1525, Waters Symmetry C₁₈Post (5 μm, 150 × 4.6mm) and Waters The detectors of UV 484 form.Mobile phase is acetonitrile:10mM ammonium acetate buffers (40:60, v/v, pH 4.10), and in environment At a temperature of flow velocity be 1.2ml/min.The peak value being recorded under 220nm, and quantitative limit is about 1ng/ml.Concentration 1-32.4 μ g/ ML calibration curve (six point calibrations) is linear [the peak face of y=870714x+52057 (r=0.9998), y expression midazolam Product, and x represents the concentration of sample].

The standard HPLC calibration curves of midazolam are shown in Figure 30.Result as shown in Figure 31 proves average disintegration Time is less than 15 seconds；And dissolution research also indicates that midazolam has quick release speed.Almost 75% midazolam is 1 Dissolution in minute.Rough midazolam powder is significantly slower.This may indicate that the change of the midazolam crystal form in wafer Change, this is also apparent in X ray.X-ray spectrum points out that midazolam occurs decrystallized during freezing dry process.

The HPLC of the various samples of the preparation such as prepared according to table 1 the results analyzed are shown in Figure 11 to 29.Figure 10 A To 10E description standard midazolam samples and the HPLC of midazolam powder dissolution sample.Figure 11 to 16 is dissolution wafer sample The HPLC chromatogram of this 1 to 3 (S1, S2 and S3, BP Rotating shaker).Briefly, sample 1,2 and 3 is prepared according to table 1, and It is the triplicate sample with same recipe.Figure 17 illustrates to contain midazolam as the batch 0905MD's of model drug HPLC chromatogram.

Figure 18 to 29 reflects the HPLC chromatogram (USP paddle method) of the other three dissolution wafer sample.It is as discussed above, survey Measure the dissolution rate of the wafer containing testing drug midazolam.At 0.5 minute, 1 minute, 5 minutes, 10 minutes and 15 minutes When obtain sample.

The result of wafer 1 to 3 (batch 0905MD) is shown in Figure 18 to 29 after these time dimensions.Also in addition Three wafers (batch 0905MD) carry out medicine and load test.

The wafer of the display present invention can be completely dissolved in about 15 seconds, and not leave any residue.

Contain fentanyl to be used to follow BP Rotating shakers to determine medicine as the wafer (batch 1003FEN) of model drug From the mechanism of system release.Turn to survey under basket rotary speed in 50rpm with small size (10mL phosphate buffer solutions, pH 6.8) Determine the dissolution rate of wafer.Under given interval (such as 0.5,1,2,3,4,5,7,10 and 15 minute), sampling 0.5mL is molten Liquid, and replaced with isometric fresh medium.Pass through the medicine of HPLC measurement releases.

Mobile phase is methanol：0.4% phosphoric acid (50:50, v/v, pH 2.3), and flow velocity is 1.2ml/ at ambient temperature min.Monitor wavelength at 210 nm.Concentration 0.5-10 μ g/mL calibration curve (eight point calibrations) is linear [y=316668x+ 4675.7, (r=0.9999), y represents the peak area of fentanyl, and x represents the concentration of sample].Bioassay standard curve is shown In Figure 32.

The fentanyl wafer (batch 1003FEN) of preparation shows that weight change is ± 2.55%, and wafer is flat Equal fentanyl percentage composition is 91.32% (for homogeneity content limit, BP standards are 85 to 115%).During average disintegration Between be less than 15 seconds；And dissolution research also indicates that fentanyl has quick release speed.Almost 90% fentanyl is in 1 minute Dissolution.Stripping curve is presented in Figure 33.

Collect fentanyl wafer six dissolution samples HPLC chromatogram, and be shown in Figure 34 A to E (sample 1 to 3) and in Figure 35 A to J (sample 4 to 6).At 0.5,1,5,10,15 and 20 minute (for dissolution sample 1 to 3) and 1, 2nd, 3,4,5,7 and 10 minutes when (for dissolution sample 4 to 6) to it is each test wafer be sampled.

Expidet is the solid dispersions that medicine enters in porous matrix.After administration, the formulation is fast in the oral cavity Speed disintegration, and allow instant medicine by directly diffusing in systemic circulation to be absorbed, and avoid first pass effect.This Invention is likely to provide alternative drugs route of administration, and causes side effect rate relatively low.

Embodiment 2

It is in solid dosage forms (wafer) shape containing ketamine according to method and the composition preparation as Table 3 below illustrates The preparation of the invention of formula：

Table 3：The composition of ketamine Fast-dissolving solid forms (strength equivalent is 25mg ketamines alkali)

Composition (BP/USP)	Measure (g)	Weight %
			Sodium carbonate	1	0.07
Sodium carboxymethylcellulose	2	0.15
			Polyethylene glycol 2000	5	0.36
Glycine	1	0.07
			Microcrystalline cellulose	2	0.15
Amylopectin	50	3.64
			Ketamine	62.5	4.55
Lactose	100	7.28
			Mannitol	150	10.92
Purified water	1000	72.81

The formulation wafer containing ketamine is produced using the method for above example 1.

Following other preparations are prepared by the method for embodiment 1.Sample 1 to 6 is that (strength equivalent is based on above-mentioned formula 25mg ketamines alkali), wherein addition flavor enhancement and/or colouring agent.

Sample 1. contains flavor enhancement in addition.

Composition	Measure (g)	Weight %
			Sodium carbonate	1	0.07
Sodium carboxymethylcellulose	2	0.14
			Polyethylene glycol 2000	5	0.35
Orange flavor enhancement	10	0.71
			Glycine	10	0.71
Microcrystalline cellulose	20	1.42
			Amylopectin	50	3.54
Ketamine	62.5	4.43
			Lactose	100	7.09
Mannitol	150	10.63
			Purified water	1000	70.90

Sample 2. contains flavor enhancement and pH adjusting agent (citric acid) in addition.

Sample 3. contains flavor enhancement and colouring agent in addition

Composition	Measure (g)	Weight %
			FD＆C is red	0.1	0.01
Sodium carbonate	1	0.07
			Sodium carboxymethylcellulose	2	0.14
Polyethylene glycol 2000	5	0.35
			Grape flavor	9.9	0.70
Glycine	10	0.71
			Microcrystalline cellulose	20	1.42
Amylopectin	50	3.54
			Ketamine	62.5	4.43
Lactose	100	7.09
			Mannitol	150	10.43
Purified water	1000	70.90

Sample 4. contains flavor enhancement, colouring agent and absorption enhancer in addition

Composition	Measure (g)	Weight %
			FD＆C is blue	0.1	0.01
Sodium carbonate	1	0.07
			Sodium carboxymethylcellulose	2	0.14
Beta-schardinger dextrin	5	0.35
			Polyethylene glycol 2000	5	0.35
Grape flavor	9.9	0.70
			Glycine	10	0.71
Microcrystalline cellulose	20	1.41
			Amylopectin	50	3.53
Ketamine	62.5	4.42
			Lactose	100	7.06
Mannitol	145	10.24
			Purified water	1000	70.65

Sample 5. contains colouring agent and sweetener in addition

Composition	Measure (g)	Weight %
			FD＆C is red	0.1	0.01
Sodium carbonate	1	0.07
			Sodium carboxymethylcellulose	2	0.14
Aspartame	5	0.35
			Polyethylene glycol 2000	5	0.35
Cherry flavor enhancement	9.9	0.70
			Glycine	10	0.71
Microcrystalline cellulose	20	1.41
			Amylopectin	50	3.53
Ketamine	62.5	4.42
			Lactose	100	7.06
Mannitol	145	10.24
			Purified water	1000	70.65

Sample 6. contains colouring agent and pH adjusting agent in addition

Composition	Measure (g)	Weight %
			FD＆C is red	0.1	0.01
Sodium carbonate	1	0.07
			Sodium carboxymethylcellulose	2	0.14
Sodium acid carbonate	5	0.35
			Polyethylene glycol 2000	5	0.35
Raspberry flavor enhancement	9.9	0.70
			Glycine	10	0.71
Microcrystalline cellulose	20	1.41
			Amylopectin	50	3.53
Ketamine	62.5	4.42
			Lactose	100	7.06
Mannitol	145	10.24
			Purified water	1000	70.65

The ketamine Fast-dissolving solid forms (wafer) that the formula shown in table 3 prepares various intensity are next based on, and Prepared as illustrated in above example 1.Lot number and composition are listed in Table 4 below.

Table 4:For the Ketamine Compositions of research

In vitro study

In vitro study is the thing for describing ketamine (being equivalent to 25mg ketamines alkali) Fast-dissolving solid forms of freeze-drying Physicochemical property.

Uniformity of weight

The uniformity of weight of ketamine wafer is tested as provided in embodiment 1.By listed preparation in table 4 20 wafers individually weigh, and average weight and relative standard deviation.All preparations from different preparations Wafer is all in the weight change of 0.25 to 2% receiving.

Hardness

Also according to the hardness of the method test wafer provided in embodiment 1.The hardness number of different preparations 0.5 to In the range of 4.0kg.Batch 20110528 provides hardness 0.5 to 1.0kg, and said preparation is then used in subsequent clinical test In.Said preparation makes it possible to reach Fast Stripping speed, and allows to be easily processed.

Friability

The intensity of ketamine wafer is tested according to the method for embodiment 1.The sample of 20 ketamine wafers has 8 Weight saving percentage between to 20%.

Water analysis

The moisture of ketamine wafer is analyzed as provided in embodiment 1.As a result showing residual moisture content is About 4%.

Scanning electron microscopy analysis

The configuration of surface of dried wafer preparation sample and cross section selected by the method observation provided in embodiment 1 are provided.Figure 36 Illustrate the surface of the wafer containing ketamine with the SEM image shown in 37 and internal structure both of which have it is highly porous Matter.

Powder x-ray diffraction (XRD)

Powder x-ray diffraction experiment is carried out using the method for embodiment 1.

The physical state of material is obvious in X-ray diffraction spectra in wafer containing ketamine.Made according to table 4 The spectrum of three kinds of standby different preparations is shown in Figure 38,39 and 40.It was observed that all powder collection of illustrative plates of the wafer prepared is all It is dominant by the strong scattering peak for 2 θ for being located approximately at 9.58 °, 19,68 ° and 20.05 °, this instruction excipient AVM hereinafter Sai Er has knot Brilliant property.The discovery from data caused by SEM also as supporting.In fact, used in preparation excipient (such as glycine, lactose, Mannitol and microcrystalline cellulose) substantially it is crystallization.However, after freeze, it is all to be all changed into amorphous.

Disintegration and stripping analysis

It is disintegrated according to embodiment 1 and dissolution test.

For slaking test, showing the wafer containing ketamine of the present invention can be completely dissolved in about 15 seconds, and And do not leave any residue.

For dissolution test, the wafer containing ketamine from batch 20110528 is used to determine self-preparing agent release Levels of drugs.Turn to determine under basket rotary speed in 75rpm with large volume (200mL phosphate buffer solutions, 25mM, pH 6.8) The dissolution rate of ketamine wafer.Under given interval (such as 1,3,5,7,10,15,20 and 30 minute), sampling 1.0mL is molten Liquid, and replaced with isometric fresh medium.At ambient temperature, by using C18 posts (150x 4.6mm, 5 μm), 15%v/ V acetonitriles are in 85%50mM H₃Mobile phase (pH 3.00) in PO4,20mM triethylamine hydrochloride carries out HPLC to measure the medicine of release Thing, and flow velocity is 1.5ml/min.Monitor wavelength at 210 nm.The HPLC chromatogram of dissolving ketamine wafer is shown in figure In 41 to 48.

The μ of concentration 5 to 100 g/mL calibration curve (seven point calibrations) is linear [Y=16225X+3328.9, (R2=1), Y The peak area of ketamine is represented, and X represents the concentration of sample].Bioassay standard curve is shown in Figure 49.

The ketamine wafer (batch 20110528) of preparation shows weight change ± 2.55%, and wafer is averaged Ketamine percentage composition is 98.67% (for homogeneity content limit, BP standards are 85 to 115%).HPLC chromatogram shows It is shown in Figure 50.

Mean disintegration time (BP is disintegrated device) is less than 5 seconds；And dissolution research also indicates that ketamine has quick release Speed.Almost 95% ketamine dissolution in 1 minute.This may indicate that the change of the ketamine crystal form in wafer, This is also apparent in X ray.X-ray spectrum points out that ketamine occurs decrystallized during freezing dry process.

Stripping curve is presented in Figure 51.

Ketamine wafer is the solid dispersions that ketalar enters in porous matrix.After administration, the formulation Fater disintegration in the oral cavity, and allow instant ketamine by directly diffusing in systemic circulation to be absorbed, and keep away Exempt from first pass effect.The present invention is likely to provide alternative drugs route of administration, and causes side effect rate relatively low.

In vivo study

The purpose of In vivo study is：1) research ketamine wafer (is equivalent to 25mg ketamine alkali, lot number：In table 4 20110528) pharmacokinetic curve；2) Absolute oral for determining the ketamine wafer of single 25mg sublingual-dosages utilizes Degree；And 3) Clinical symptoms of the present invention is assessed using the Li Kete of modification and Bond (Bond) and Randt (Lader) scale And acceptability.

Ethics is checked and approved

Scheme is by imperial Adelaide human research ethics comittees (Royal Adelaide Human Research Ethics Committee) check and approve.The experimental evidence clinical test bulletin flow is to Australian treatment product management board (Australian Therapeutic Goods Administration) registers (CTN：2011/0292).

Study subject

All volunteers are being subjected to providing their written in subject's consent form before test procedure in approval Informed consent form.The subject that research includes had in 22 and 30kg/m between 19 to 41 years old²Between body quality refer to Number, history or do not show medicine or alcohol dependence or abuse be present without medicine or alcohol dependence or abuse, on clinical history and Laboratory test has normal result of study, without sublingual or cheek ulcer or disease, and on HIV, hepatitis B and the third type Hepatitis viruse test has negative result of study.

Recruited in this research and amount to the healthy male that criterion was included and excluded in 8 satisfaction researchs.

Project and design

This is single centre (imperial Adelaide hospital pain and anesthesia research clinic, Adelaide, SA 5005, the big profit of Australia It is sub-), randomization, open label, single dose, double treatments, two phases, bidirectional crossed research.Planned according to randomization, use computer The caused table of random numbers is by subject with 1:1 ratio is divided into two groups.

Volunteer receive intravenous (IV) dosage of single 10mg ketamine (be diluted to 30mL in salt solution, and after Both 30 minutes with the administration of IV infusion solutions) with the ketamines of sublingual (SL) the dry glue tablet amounts of 25mg.Equal the order for the treatment of phase Weigh and be randomized.Sublingual it is applied by the way that wafer is placed on.It is required that volunteer avoids swallowing at least 10 minutes so that logical Cross peroral route and therefore by intestinal tube and the ketamine loss reduction of hepatic metabolism (first pass effect).The ultimate survey duration is 4 weeks, including 14 days screenings and 7 days removing phases.

Continue to measure pharmacokinetics, tolerance and security in 24 hours after two kinds of delivery times.Aching Total hospital stay of pain and anesthesia research clinic is 28 hours (interim 1) and 29 hours (interim 2).

Before administration (in 5 minutes of predetermined administration time), upon administration 5,10,15,30,35 and 45 minutes and 1, 1.5th, blood sample (5mL) is obtained within 2,2.5,3,4,6,8,12 and 24 hours after IV is applied and applied with SL with quantitative chloramines Ketone concentration.The sample of 8 hours samples, hereafter all administrations after being collected in the 2 of nominal time minutes up to and including administration Sample will all be collected in the 10 of nominal time minutes afterwards.The actual blood collection time is recorded in source file.Specified above All deviations of window-external will all be recorded as Protocol Deviations.Stay in the total of the whole blood studied and obtained during the duration Amount is about 275mL.

After being collected, centrifugal blood sample 15 minutes under 4 DEG C, 2000-2500g, and extract blood plasma and put immediately Put into polypropylene memotron.Blood plasma is stored at -80 DEG C ± 10 DEG C until being transferred to bioanalysis laboratory.

Pharmacokinetic analysis

The plasma concentration of racemic ketamine is analyzed with UV detections using the HPLC methods of checking, wherein quantitative Lower limit is 2ng/mL, and deviation and inaccuracy<20%.

Standard non-compartmental analysis, which is used to obtain, removes C_max、t_maxAnd t_firstOutside pharmacokinetics variable, the C_max、t_max And t_firstIt is the observation result acquisition as the plasma concentration time curve to each subject.As report t_maxWhen using it is actual when Between.Last speed constant (λ eventually is estimated by log-linear regression_z), i.e. the slope of natural logrithm concentration to time graph, wherein λ_z=-1* slopes.Linear regression in whole latter stage uses last 3 to 6 data points, at least three point.Last t eventually_1/2It is calculated as t_1/2 =ln (2)/λ_z。

It is obtained up to last using the linear upward and downward method of logarithm and can quantify plasma concentration (AUC_last) Area under plasma concentration time curve, and use C_last/λ_z(last can quantify plasma concentration divided by λ_z) be extrapolated to it is infinite with Obtain total AUC AUC_INF.Pass through (1-AUC_tlast/AUC_INF) * 100 obtain AUC extrapolated portion (AUC_extr).With with AUC_INFClass As mode calculate gross area AUMC under first moment curve_INF, and it is 30 minutes IV infusion durations that MRT, which is obtained, AUMC_INF/AUC_INFCorrect mean residence time (MRT_i.v.).The clearance rate (CL) that IV is applied is calculated as dosage/AUC_INF, and The clearance rate of sublingual administration is calculated in the same manner.The clearance rate of non-IV approach is expressed as CL/F, i.e. clearance rate and biological utilisation The ratio of degree, because the latter is unknown.Volume of distribution V_zIt is calculated as CL/ λ_z.The MAT of sublingual administration is with two kinds of route of administration Difference between MRT is (for MRT_SL-MRT_IV) form acquisition.According to AUC_SL/AUC_IV* dosage_IV/ dosage_SL, the biology profit of ketamine Expenditure (F) is calculated as the AUC in the regulation of the post dose of IV and sublingual administration_INFRatio.

Security and tolerance

Safety evaluation include predetermined adverse events (AE) detection during 24 hours sections of administration are started certainly, from Hair property AE reports, Routine Test Lab research, 12 lead electrocardiogram (ECG) and sign of life are assessed.Before the first delivery time And carry out overall physical inspection in 24 hours after the second delivery time.

By using Likert scale before administration, dosage apply after 5,10,15,30 and 45 minutes and 1 hour assess Local tolerance.Before administration, 30 minutes and 1,1.5,2,2.5,3,4,6,8,12 and 24 small after dosage administration after being administered Shi Zhihang is assessing nation that is calm and perceiving the modification changed by using three kinds of key elements " vigilant ", " feeling at ease " and " calmness " Moral and Randt's scale.

Statistical analysis

By handling each pharmacokinetics variable statistics is summarized to calculate standard.Calculate bioavilability 90% is put Believe section (CI).

As a result

The indivedual values and general introduction statistics of volunteer's feature are reported in table 5.

Table 5：Subject Demographics

The plasma concentration of racemic (RS) ketamine

All subjects continue the overlapping of indivedual RS ketamines plasma concentrations of whole sampling time period after IV is applied Geometrical mean (g_{It is average}) be depicted in Figure 52.For clarity, individually it is shown in after administration in Figure 53 within first 12 hours.Institute There is the overlapping geometrical mean that subject continues indivedual RS ketamines plasma concentrations of whole sampling time period after SL is applied It is shown in Figure 54, and first 12 hours are shown in Figure 55.

In addition to having 4 subjects at 2-3 peak for SL approach, IV and SL plasma concentration time curves are in shape It is similar.In C_maxAfterwards, the equal two-phase of both IV and SL concentration declines, but IV trend is more prominent.

All subjects IV be administered and SL administration after first can quantitative concentrations all at 5 minutes, this instruction SL administration Quick absorption.It is administered for SL, 6 subjects were less than calmly 24 hours and 1 subject in the plasma concentration of 12 hours Measure limit.After IV administrations, all subjects had at 12 hours can quantitatively level, and 4 subjects are small 24 When have can quantify level.

After IV administrations, in all subjects in addition to 1 subject (No. 6), C_maxInfusion is appeared in terminate When, and in No. 6 subjects, observe C in the sample obtained within 5 minutes after 30 minutes infusions terminate_max。

It is administered for SL, Median Time (the i.e. t of main peak_max) it is 0.75 hour, wherein detecting within 0.25 hour after administration To earliest peak, and detect peak at the latest within 1 hour after administration.Subject 4,5,6 and 7 is bent in their Plasma concentration time There are the multiple secondary peaks observed after dosage administration during first 3 hours in line.Indivedual t_maxValue is shown in Figure 56.

The indivedual estimated values and general introduction statistics of main pharmacokinetic variable are presented in table 6.Of two kinds of route of administration Other AUC_INFValue is depicted in Figure 57.The AUC of two kinds of route of administration extrapolated portion (AUC_extr) minimum, this instruction is being estimated There is high-quality in terms of calculating AUC.For IV, AUC_extrIt is 3-7%, and for SL, it is 2-9%.

The CL of IV approach indivedual estimated values are presented in Figure 58.After SL administrations, CL is obscured by F, and therefore not Can be compared with the value obtained afterwards in IV administrations.The intermediate value CL of IV administrations is 37.7L/h.

End-stage half-life period after IV administrations are administered with SL is similar, and wherein intermediate value is 4.5 and 3.4 hours respectively. The instruction absorption of similar half-life period of IV with SL approach is quick, otherwise will dominate Plasma concentration time compared with slow-absorbing half-life period The whole latter stage of curve, and therefore show that half-life period is considerably longer than IV administrations.Indivedual values of two kinds of route of administration are provided in Figure 59 In.

Bioavilability and absorption

In most of subjects, SL wafers dissolved in 30 seconds to 1 minute.

Indivedual estimated values of bioavilability are shown in Figure 60, and individual organisms availability and MAT are (during average absorption Between) value together with general introduction statistics be provided in table 7.The bioavilability that No. 8 subjects have be significantly higher than other by Examination person 38%.In addition to highest extrapolation area 9% (for SL) and 7% (for IV) and bimodal (being administered for SL), The subject is not dramatically different compared to other subjects.The intermediate value and 90%CI [relatively low, higher] of bioavilability are 29 [27,31] %, so as to show, changeability is extremely low between subject.

Table 7：After 25mg is applied to 8 healthy volunteer SL, indivedual (subjects=Randomization Number), intermediate value, most Small and maximum RS ketamines bioavilability (F) and average absorption time (MAT).

* do not apply to

MAT represents that ketamine molecule reaches the average time that systemic circulation spent from site of administration (i.e. SL spaces). Indivedual MRT values of two kinds of route of administration are similar, and intermediate value is 3.9 hours (for IV) and 3.8 hours (for SL), so as to refer to Show quick absorption.The quick absorption of small difference (i.e. small MAT) instruction between IV and SL MRT.Due to naturally occurring changeability, There may be negative value when obtaining the difference between two similar value, as seen in some MAT values.

In a word, the PK of SL wafers is characterised by that absorption is quick and the changeability of bioavilability is relatively low.This together with The changeability of clearance rate is relatively low, and to be converted into exposed changeability together relatively low.Low changeability allows the total exposure for predicting SL wafers And the therefore accuracy increase of pharmacotoxicological effect, this may be expected to increase its effectiveness in clinical setting.

Pharmacodynamics result

Bond and Randt's mood measuring scale

Bond and Randt's scale include amounting to 16 100mm lines in either end by antonym grappling.Participant is online On their current subjective state is marked between antonym.Each line is scored as from negativity antonym to the millimeter marked. Scored according to gained, find the three kinds of measurements obtained by factor analysis.These measurements are described as representing by Bond and Randt Following key element：

Key element 1：" vigilant " (by be vigilant-hypnosis, it is wholwe-hearted-in a trance, blunt-energetic, lose one's head-brains is clear Chu, coordinating good-clumsiness, backwardness-intelligence, quick, strong-weak, interesting-be sick of, be incompetent-is proficient in the line of grappling Represent)；

Key element 2：" feeling at ease " (feel at ease-uneasiness, puzzlement-peaceful, happy-sad, hostile-friendly, introversive-sociable) with And

Key element 3：" calmness " (tranquil-excited, nervous-loose)；The score of each key element represents the promotion institute of discrete amount table State the unweighted average millimeter (maximum 100mm) of the negativity antonym of key element.

Therefore, the maximum score of key element 1 is 900；Key element 2 is 500, and key element 3 is 200.

Mood measuring scale shows that the trend for the effect of reaching is indefinite.After SL administrations, key element " vigilant " and " feeling at ease " The horizontal fluctuation before administration during whole 24 hour observation period, and " calmness " display after administration can during first hour Can be excited caused by by administration and the observation result of the local tolerance during preceding 30-60 minutes and initial drop be present It is low, it is followed by stable increase and 2.5 hours after administration recovers completely.Curve shape and SL administrations after IV administrations Curve shape is similar.The curve of average (SD) value of each key element of mood measuring scale is depicted in respectively after IV and SL administrations In Figure 61 and Figure 62.

The Li Kete local tolerance scales of modification

The Likert scale of modification is used to assess following symptom：Cheek stimulates；Calcination is felt；Bitter taste and nausea.As it is pre- Phase, the value of all values is all typically zero after IV administrations, but sporadic value 1 or 2 be present.After SL administrations, " cheek pierces Swash " value be typically zero or distribute ground 1 or 2, and the value of " burning sensations " is similar, but presence by subject 3 at 10 points The single value 3 of clock report.For " nausea ", it is identical with IV to be worth the trend of display, wherein mainly null value, but there is sporadic value 1 or 2.However, the value of " bitter taste " is different from IV；All subjects report nonzero value after administration, but peak value is in 1-9 scope Interior, wherein 1 subject each reports peak value 1 and 3, remaining subject is 5 or more than 5.Peak in 4 subjects be 5 minutes；At 10 minutes in 2 subjects；At 15 minutes in 1 subject, and 1 subject is equal at 5 minutes and 10 minutes Reported values 9.All values all had been returned to zero (Figure 63) by 1 hour.

Clinically relevant anomalous variation is not present in terms of ECG, sign of life, hematology, clinical chemistry or urinalysis or becomes Gesture.

In a word, the sublingual dried wafer preparation of ketamine is had been developed that as in acute and chronic pain management and other illnesss Potential adminicle.The intermediate value bioavilability of the embodiment is 29%, and wherein changeability is extremely low between subject, and this is advantageous to relatively Narrow treatment index medicine, such as ketamine.Low changeability also increase wafer can reappear exposure and therefore analgesic effect and The effectiveness of speech.In addition to slight and of short duration CNS type symptoms, with the sublingual dry glue sheet forms of 25mg to healthy volunteer's administration of ketamine to It is safe and well tolerable, as desired by the existing clinical experience based on ketamine.Local tolerance is remarkable, and in advance Phase, any local irritation effect was all slight, and 30-60 minute inner dissipations after administration.

Embodiment 3

It is in solid dosage forms (wafer) shape containing 'Xiduofeng ' according to method and the composition preparation as Table 8 below illustrates The preparation of the invention of formula：

Table 8：The composition of 'Xiduofeng ' Fast-dissolving solid forms (strength equivalent is 25mg 'Xiduofeng 's alkali).

Composition	Measure (g)	Weight %
			Sodium carbonate BP/USP	1	0.07
Sodium carboxymethylcellulose BP/USP	2	0.14
			Polyethylene glycol 2000 BP/USP	5	0.34
Glycine BP/USP	10	0.68
			Microcrystalline cellulose BP/USP	10	0.68
Citric acid BP/USP	10	0.68
			Amylopectin BP/USP	50	3.42
Lactose BP/USP	100	6.84
			Mannitol BP/USP	150	10.25
'Xiduofeng ' BP/USP	125	8.54
			Purified water BP/USP	1000	68.35

The formulation wafer containing 'Xiduofeng ' (25mg) is produced using the method for above example 1.

Following other preparations are prepared by the method being explained as above.Sample 1 to 6 is substantially based on above-mentioned formula, its Middle addition flavor enhancement and/or colouring agent.

Sample 1. contains flavor enhancement in addition.

Sample 2. contains flavor enhancement and pH adjusting agent (citric acid) in addition

Composition	Measure (g)	Weight %
			Sodium carbonate	1	0.07
Sodium carboxymethylcellulose	2	0.15
			Polyethylene glycol 2000	5	0.37
Citric acid	10	0.74
			Mint flavor	10	0.74
Glycine	10	0.74
			Microcrystalline cellulose	20	1.47
Amylopectin	50	3.68
			Lactose	100	6.84
Mannitol	150	10.25
			'Xiduofeng ' BP/USP	125	8.54
Purified water	1000	67.15

Sample 3. contains flavor enhancement and colouring agent in addition

Composition	Measure (g)	Weight %
			FD＆C is red	0.1	0.01
Sodium carbonate	1	0.07
			Sodium carboxymethylcellulose	2	0.15
Polyethylene glycol 2000	5	0.37
			Grape flavor	9.9	0.73
Glycine	10	0.74
			Microcrystalline cellulose	20	1.48
Amylopectin	50	3.71
			Lactose	100	6.84
Mannitol	150	10.25
			'Xiduofeng ' BP/USP	125	8.54
Purified water	1000	67.11

Sample 4. contains flavor enhancement, colouring agent and absorption enhancer in addition

Sample 5. contains colouring agent and sweetener in addition

Composition	Measure (g)	Weight %
			FD＆C is red	0.1	0.01
Sodium carbonate	1	0.07
			Sodium carboxymethylcellulose	2	0.15
Aspartame	5	0.37
			Polyethylene glycol 2000	5	0.37
Cherry flavor enhancement	9.9	0.73
			Glycine	10	0.74
Microcrystalline cellulose	20	1.48
			Amylopectin	50	3.71
Lactose	100	6.84
			Mannitol	150	10.25
'Xiduofeng ' BP/USP	125	8.54
			Purified water	1000	66.74

Sample 6. contains colouring agent and pH adjusting agent in addition

The 'Xiduofeng ' Fast-dissolving solid forms wafer that the formula shown in table 8 prepares various batches is next based on, and such as Illustrate and prepared in above example 1.Lot number and composition are listed in Table 9 below.

Table 9：For the composition of the 'Xiduofeng ' preparation of research (strength equivalent is 25mg 'Xiduofeng 's alkali)

In vitro study

Uniformity of weight

The uniformity of weight of 'Xiduofeng ' wafer is tested as provided in embodiment 1.By listed preparation in table 9 20 wafers individually weigh, and average weight and relative standard deviation.All preparations from different preparations Wafer is all in the weight change of 0.25 to 2% receiving.

Hardness

Also according to the hardness of the method test wafer provided in embodiment 1.The hardness number of different preparations 0.5 to In the range of 4.0kg.Batch 20120628 obtains wafer of the hardness under 0.5 to 1.0kg, and said preparation is used to then face In bed experiment.Said preparation makes it possible to reach Fast Stripping speed, and allows to be easily processed.

Friability

According to provided in embodiment 1 method measurement 'Xiduofeng ' wafer intensity (including they from solid matter reduce Into the ability compared with fractionlet).The sample of 20 'Xiduofeng ' wafers has the weight saving percentage between 8 to 20%.

Water analysis

The moisture of 'Xiduofeng ' wafer is analyzed as provided in embodiment 1.As a result showing residual moisture content is About 4%.

Scanning electron microscopy analysis

The configuration of surface of dried wafer preparation sample and cross section selected by the method observation provided in embodiment 1 are provided.Figure 64 And the SEM image shown in 65 shows the clear and definite morphological differences between blank wafer and 'Xiduofeng ' wafer.

Powder x-ray diffraction (XRD)

Powder x-ray diffraction experiment is carried out using the method for embodiment 1.

The physical state of material is obvious in X-ray diffraction spectra in 'Xiduofeng ' wafer.As prepared according to table 9 The spectrum of three kinds of different preparations is shown in Figure 66,67 and 68.It was observed that all powder collection of illustrative plates of the wafer prepared is all by near It is dominant like the strong scattering peak at 9.58 °, 19,68 ° and 20.05 ° of 2 θ, this instruction excipient AVM hereinafter Sai Er has crystallinity Matter.The discovery from data caused by SEM also as supporting.In fact, the excipient (such as glycine, lactose, the sweet dew that are used in preparation Sugar alcohol and microcrystalline cellulose) substantially it is crystallization.However, after freeze, it appears that all to be all changed into amorphous.

Disintegration and stripping analysis

It is disintegrated according to embodiment 1 and dissolution test.

For disintegration test, showing the wafer containing 'Xiduofeng ' of the present invention can be completely dissolved in about 15 seconds, and And do not leave any residue.

For dissolution test：

Use device I (BP 2009, turn basket device) carries out dissolution test.Erweka dissolving devices (Hesenstamm, Germany) it is used for two experiments.The temperature of medium is maintained at 37 ± 0.5 DEG C.Wafer (batch containing 'Xiduofeng ' 20120628) it is used for the levels of drugs for determining self-preparing agent release.'Xiduofeng ' wafer is determined using the method provided in embodiment 2 Dissolution rate.

The calibration curve (seven point calibrations) of the μ g/mL 'Xiduofeng 's of concentration 5 to 100 is linear [Y=32.973X-36538, (r= 0.9999), Y represents the peak area of 'Xiduofeng ', and X represents the concentration of sample].Bioassay standard curve is shown in Figure 77.

The 'Xiduofeng ' wafer (batch 20120628) of preparation shows weight change ± 2.55%, and wafer is averaged 'Xiduofeng ' percentage composition is 98.67% (for homogeneity content limit, BP standards are 85 to 115%).Mean disintegration time (BP is disintegrated device) is less than 5 seconds；And dissolution research also indicates that 'Xiduofeng ' has quick release speed.Almost 95% 'Xiduofeng ' The dissolution in 1 minute.This may indicate that the change of the 'Xiduofeng ' crystal form in wafer, and this is also apparent in X ray. X-ray spectrum points out that 'Xiduofeng ' is decrystallized during freezing dry process.

Stripping curve is presented in Figure 78.

'Xiduofeng ' wafer is the solid dispersions that hydrochloric acid 'Xiduofeng ' enters in porous matrix.After administration, the formulation Fater disintegration in the oral cavity, and allow instant 'Xiduofeng ' by directly diffusing in systemic circulation to be absorbed, and keep away Exempt from first pass effect.The present invention is likely to provide alternative drugs route of administration, and causes side effect rate relatively low.

Embodiment 4

It is in contain adrenergic solid dosage forms (dry glue according to method and the composition preparation as Table 10 below illustrates Piece) form preparation of the invention：

Table 10：The composition of adrenaline Fast-dissolving solid forms (strength equivalent is 40mg adrenaline alkali)

Composition (BP/USP)	Measure (g)	Weight %
			Sodium carbonate	1	0.07
Sodium carboxymethylcellulose	2	0.15
			Polyethylene glycol 2000	5	0.36
Glycine	1	0.07
			Microcrystalline cellulose	2	0.15
Amylopectin	50	3.64
			Adrenaline (alkali)	100	7.28
Lactose	100	7.28
			Mannitol	150	10.92
Purified water	1000	70.08

Produced using the method for above example 1 and contain adrenergic Expidet (wafer).

Following other preparations are prepared by the method being explained as above.Sample 1 to 6 is to be based on above-mentioned formula (strength equivalent It is 40mg adrenaline alkali), wherein addition flavor enhancement and/or colouring agent.

Sample 1. contains flavor enhancement in addition

Composition	Measure (g)	Weight %
			Sodium carbonate	1	0.07
Sodium carboxymethylcellulose	2	0.14
			Polyethylene glycol 2000	5	0.35
Orange flavor enhancement	10	0.71
			Glycine	10	0.71
Microcrystalline cellulose	20	1.42
			Amylopectin	50	3.54
Adrenaline (alkali)	100	7.09
			Lactose	100	7.09
Mannitol	150	10.63
			Purified water	1000	68.25

Sample 2. contains flavor enhancement and pH adjusting agent (citric acid) in addition.

Composition	Measure (g)	Weight %
			Sodium carbonate	1	0.07
Sodium carboxymethylcellulose	2	0.14
			Citric acid	5	0.35
Polyethylene glycol 2000	5	0.35
			Mint flavor	10	0.71
Glycine	10	0.71
			Microcrystalline cellulose	20	1.41
Amylopectin	50	3.53
			Adrenaline (alkali)	100	7.06
Lactose	100	7.06
			Mannitol	150	11.09
Purified water	1000	67.52

Sample 3. contains flavor enhancement and colouring agent in addition

Composition	Measure (g)	Weight %
			FD＆C is red	0.1	0.01
Sodium carbonate	1	0.07
			Sodium carboxymethylcellulose	2	0.14
Polyethylene glycol 2000	5	0.35
			Grape flavor	9.9	0.70
Glycine	10	0.71
			Microcrystalline cellulose	20	1.42
Amylopectin	50	3.54
			Adrenaline (alkali)	100	7.09
Lactose	100	7.09
			Mannitol	150	10.43
Purified water	1000	68.45

Sample 4. contains flavor enhancement, colouring agent and absorption enhancer in addition

Sample 5. contains colouring agent and sweetener in addition

Composition	Measure (g)	Weight %
			FD＆C is red	0.1	0.01
Sodium carbonate	1	0.07
			Sodium carboxymethylcellulose	2	0.14
Aspartame	5	0.35
			Polyethylene glycol 2000	5	0.35
Cherry flavor enhancement	9.9	0.70
			Glycine	10	0.71
Microcrystalline cellulose	20	1.41
			Amylopectin	50	3.53
Adrenaline (alkali)	100	7.06
			Lactose	100	7.06
Mannitol	145	10.24
			Purified water	1000	68.42

Sample 6. contains colouring agent and pH adjusting agent in addition

Composition	Measure (g)	Weight %
			FD＆C is red	0.1	0.01
Sodium carbonate	1	0.07
			Sodium carboxymethylcellulose	2	0.14
Sodium acid carbonate	5	0.35
			Polyethylene glycol 2000	5	0.35
Raspberry flavor enhancement	9.9	0.70
			Glycine	10	0.71
Microcrystalline cellulose	20	1.41
			Amylopectin	50	3.53
Adrenaline (alkali)	100	7.06
			Lactose	100	7.06
Mannitol	145	10.24
			Purified water	1000	68.37

Be next based on the formula shown in table 10 prepare various intensity hydrogen tartrate adrenaline Fast-dissolving solid forms it is (dry Film), and prepared as illustrated in above example 1.Lot number and composition are shown in Table 11.

Table 11：For the adrenaline composition of research

Embodiment 5

The I phases pharmacokinetics and bioavailability study of the sublingual fentanyl wafer carried out in healthy volunteer

Method

Study subject

Healthy volunteer is being subjected to providing written informed consent in subject's consent form before test procedure in approval Book.The subject that research includes has in 18 and 30kg/m between 19 and 32 years old²Between body-mass index, do not have There are medicine or alcohol dependence or abuse history or sign, there is normal result of study, no SL after clinical history and laboratory test (sublingual) or cheek ulcer or disease, and with the moon of human immunodeficiency virus, hepatitis B and HCV test Journal of Sex Research result.

24 are recruited in this research and meets that the volunteer of criterion is included and excluded in research.Based on TG-AUC (AUC) The significant differences of SD, 35% and 20% value give 84% power (α=0.05).

Research and design

This is single centre (Linear clinical researches Co., Ltd, Bai Si (Perth), Australia), randomization, open mark Label, single dose, double treatments, two phases, bidirectional crossed research.Planned according to randomization, will using the table of random numbers caused by computer Subject is with 1:1 ratio is divided into 2 groups.IV citric acids fentanyl or sublingual citric acid fentanyl wafer (base are given to volunteer In batch：The 1003FEN preparations of embodiment 1；It is equivalent to 100 μ g fentanyls).Each volunteer was then followed by 7 days removing phases By replacement sexual approach.

Sublingual it is applied by the way that wafer is placed on.It is required that volunteer as permanent as possible (at least continuing 10 minutes) keeps away Exempt to swallow.Night (12 hours after last time fentanyl dosage) before from the 1st day to the 2nd day orally applies for every 12 hours With naltrexone (naltrexone) piece (50mg), to block any systemic effect of fentanyl.

Before beginning one's study, special IV conduits are placed in forearm for subsequent venous blood sample.Starting dry glue Piece apply before administration before, then apply start after 2,5,10,15,20,30,45,60,120,180,360,460, 600th, blood sample (7mL) is obtained within 720,960 and 1440 minutes.It is transfused for IV, before administration, 2 and 3 points after start-up Clock and 5 minutes (infusion terminates), then since the infusion 7,10,15,20,25,30,45,60,120,180,360, 460th, blood sample is obtained within 600,720,840,960 and 1440 minutes.

After being collected, centrifugal blood sample 15 minutes under 4 DEG C, 2000 to 2500g, and extract blood plasma and put immediately Put into polypropylene memotron.Blood plasma is stored at -80 DEG C ± 10 DEG C until being transferred to bioanalysis laboratory.It is equipped with preceding Shimadzu Prominence highly effective liquid phase chromatographic systems API 4000LC-MS/MS systems (Applied Biosystems, Foster City, CA) on analyze sample extraction thing, wherein d5- fentanyls are as internal standard thing.Measure has test limit 10pg/mL.By analyze in duplicate containing 10,40 and 400pg/mL fentanyls blood plasma come determine accuracy.As a result for 10th, 40 and 400pg/mL average measurement concentration value is respectively accurate in ± 6.2%, ± 3.3% and ± 1.7%, and It is respectively accurate in 102%, 99.9% and 101.4% for 10,40 and 400pg/mL nominal concentrations.At various concentrations, The number of parallel determination is 6.

Pharmacokinetic analysis

Use 6.1 editions (Pharsight, A Certara of Phoenix WinNonlin^TMCompany,St.Louis,MO) Determine pharmacokinetic parameter.Pharmacokinetic data is C_max、t_max、AUC_0-12、AUC_0-t、AUC_0-∞、k_elAnd t_1/2.Directly from Blood plasma fentanyl concentration-time graph reads the first detectable fentanyl plasma concentration (C after SL administrations_first) and reach C_firstTime (t_first).Last elimination rate constant (k eventually_el) it is defined as best fit in the approximate log-linear elimination of end eventually phase The tropic slope.All fittings are all weighted to carry out with the unified of data.From k_elObtain end eventually and eliminate half-life period (t_1/2), And it is equal to ln 2/k_el.AUC is obtained using trapezoidal rule_0-12And AUC_0-tValue.By AUC_0-t+C_t/k_elCalculate to AUC_0-∞It is outer Push away.

Security and tolerance

Security and tolerance are assessed by monitoring sign of life (arterial pressure and heart rate) after being applied in fentanyl. Carry out overall physical inspection within 48 hours before medicament administration and after medicament administration.Enter when baseline and research are completed Row laboratory is tested and 12 lead electrocardiogram.Adverse events are assessed using direct observation, spontaneous report and nonspecific enquirement.

Statistical analysis

General introduction statistics is calculated by handling each pharmacokinetic parameter.By the biology of the SL fentanyls of each subject Availability is identified as Cmax, AUC of SL administrations_0-12、AUC_0-tAnd AUC_0-∞The ratio applied compared to IV.Using just controlling Overall bioavailability is estimated as logarithmic transformation by the linear model for subject in treatment, period, sequence and sequence C_max、AUC_0-12、AUC_0-tAnd AUC_0-∞The inverse transformation form of the difference between treatment of value.Also 90% confidential interval is calculated , and P values (CI)<0.05 is considered as statistical significance.It is all analysis all using SAS 9.2 editions (SAS Institute Inc., 2008) carry out.(Student t test) is examined to assess formula variation using student t.

As a result

By 24 patient randomizations, 12 enter SL:IV orders, and 12 enter IV:SL orders.2 volunteers are not The research of SL or IV administration groups is completed, and is removed from all analyses.Volunteer's feature is reported in Figure 79.

Pharmacokinetic results

Average blood plasma (± SEM) fentanyl concentration vs. time curve of IV and SL approach is shown in Figure 80.SL approach Individual subject's blood plasma concentration curve is shown in Figure 81.The plasma pharmacokinetics parameter C of fentanyl_max、t_max、AUC_0-12、 AUC_0-tAnd AUC_0-∞Average value (± 1SD) be shown in Figure 82.Observed after administration between 2 minutes and 10 minutes in SL Using the first detectable blood plasma fentanyl concentration (C afterwards_first)。t_firstIn the accumulation of 22 volunteers of 2,5 and 10 minutes Percentage and their average blood plasma fentanyl concentration (C_first) it is 12.5% (32.4pg/mL), 62.5% (30.7pg/ respectively ) and 100.0% (49.0pg/mL) mL.

Reach the average time (t of peak plasma concentrations after starting IV and SL and applying_max) be respectively 0.12 hour and 0.92 hour (P<0.0001) (Figure 82).Average (± SD) end-stage half-life period (t that IV and SL is applied_1/2) be 13.07 respectively ± 3.00 hours and 12.49 ± 5.24 hours (P=0.889).Average (± SD) whole last elimination rate constant that IV and SL is applied (k_el) it is 0.055 ± 0.012h respectively^-1With 0.064 ± 0.025h^-1(P=0.317).

Pass through AUC_0-12、AUC_0-tAnd AUC_0-∞The SL/IV percentages of value assess bioavilability.By AUC_0-12Estimation The mean bioavailabilities of SL fentanyls be 72.1% (CI65.3% to 79.6%), and by AUC_0-tThe SL sweet smell of estimation is too The mean bioavailability of Buddhist nun is 73.2% (CI 66.3% to 80.9%).Based on AUC_0-∞The absolute bioavailability of value is 78.9% (CI 51.1% to 121.7%).

The C of SL fentanyls_maxIt is 18.8% (CI 14.4% to 24.6%) that IV applies value, wherein reaching Cmax Average time is 0.9 hour.Applied for IV, C_maxAt the end of typically occurring in infusion, wherein after half an hour immediately after administration It is quick to reduce.Start within about 2 hours after self administration of medication, mean concentration-time graph of 2 kinds of mode of administration is similar.

Tolerance

The adverse events being had been reported that all are slightly to moderate.Wafer is dissolved in the average (± SD) time in SL capsules It is 73 ± 76 seconds.

This research is designed to the basic medicine for the instant fentanyl wafer that the I phases study to determine to develop recently for power Learn parameter.It also collects some Receptive data to product on subject.

It was found that the C of SL fentanyls (100 μ g) wafer_maxAnd t_maxValue is similar to the SL fentanyls of (Figure 83) by previous research The data of (100 μ g) tablet report.C_maxAnd t_maxValue provides the instruction to the absorption rate of medicine.Wafer is compared to SL tablets With similar C_max、t_maxWith AUC (P difference=0.573,0.331 and 0.103)；The absolute bioavailability data of SL tablets It is unavailable.Notice and SL tablets were assessed in cancer patient after 10 hours collection phases, this causes tablet and wafer to have respectively There are different t_1/2Value 6.1 and 12.5 hours (P=0.0013).

After SL administrations, by plasma concentration in 2 to 10 minutes (t_first) in can detect (in most cases exist Occur in 5 minutes) prove that fentanyl is rapidly absorbed.The C that dried wafer preparation has_firstSimilar to the C of SL tablets_first.This Reflection fentanyl is highly permeable in the enrichment blood flow of SL mucous membranes (and good vein outflow), and this is around liver " head is crossed " effect Should.SL mucous membranes (100 to 200 μm) are (40 to 80 μm) thicker than schneiderian membrane；It is anticipated that compared to the suction reported afterwards in IN administrations Speed is received, absorption rate is relatively slowly (during this investigation it turned out, the t of IN fentanyls_maxFor 4.2 to 11.4 minutes, and SL fentanyls were 54.6 minute).

The high bioavilability of fentanyl from wafer shows wafer fentanyl really by sublingual absorption, and by The possibility that part is swallowed is smaller, therefore avoids first-pass metabolism.It is not intended to distribute life to this these absorption features in studying Thing availability.Based on the more early investigative research carried out among patient after surgery, the analgesic efficacy of dried wafer preparation is seemingly Satisfactorily.

The SL fentanyls wafer produces quickly detectable blood plasma in 10 minutes of administration in healthy volunteer Fentanyl concentration, so as to indicate to treat the potentiality of explosive pain.It is 78.9% relative to the IV bioavilabilities applied.

Claims (7)

1. a kind of preparing for the fater disintegration of sublingual administration and the solid freeze-drying dry glue tablet form of dissolving in the oral cavity Purposes in medicine, it is used for the effective plasma level concentration for delivering bioactive substance, wherein the medicine provides C_maxConcentration and t_max, the C_maxThe C that equivalent intravenous injection of the concentration less than identical active material is reached_maxConcentration, the t_maxWith it is quiet Injection is suitable in arteries and veins, wherein the formulation includes：

A) at least one bioactive substance, accounts for the 0.02% to 95% of dosage form composition in terms of dry weight, and

B) matrix formers, it is included with branch existing for the 2 weight % to 17 weight % amount of the dry weight of the dosage form composition Chain starch,

Wherein described formulation dissolves in the oral cavity, the remnants that can be detected by subject without leaving the formulation in the oral cavity Thing, so as to avoid forcing the subject from swallowing the formulation；

Wherein described formulation is disintegrated and dissolved in the oral cavity in the time less than 60 seconds in the oral cavity in the time less than 15 seconds； And

Wherein described bioactive substance is selected from and includes following inventory：Opioid analgesic agent, peptide, antiinflammatory, antianxiety agent and Sedative.

2. purposes as claimed in claim 1, wherein the opioid analgesic agent, which is selected from, includes following inventory：Fentanyl, fourth Third promise coffee, naloxone, in terms of the dry weight of the composition of the formulation, it exists with 0.02-20 weight % amount.

3. purposes as claimed in claim 1, wherein the opioid analgesic agent is naltrexone, with the composition of the formulation Dry weight meter, it exists with 1-45 weight % amount.

4. purposes as claimed in claim 1, wherein the peptide or antiinflammatory are glutathione, with the composition of the formulation Dry weight meter, it exists with 1-45 weight % amount.

5. purposes as claimed in claim 1, wherein the antianxiety agent or sedative are melatonin or midazolam, with institute The dry weight meter of the composition of formulation is stated, it exists with 0.02-20 weight % amount.

6. purposes as claimed in claim 1, wherein once place in the oral cavity, the formulation is selected from consisting of It is completely dissolved in the period of group：It is less than 50 seconds after the formulation is applied；Less than 40 seconds；Less than 30 seconds；Less than 20 seconds；It is small In 15 seconds；Less than 10 seconds；Less than 7.5 seconds；Less than 5 seconds；Less than 4 seconds；Less than 3 seconds；And less than 2 seconds.

7. purposes as claimed in claim 1, wherein the formulation at most 2 hours, 30 minutes, 20 minutes or 15 minutes when Between the effective plasma level concentration of the bioactive substance is provided in section.