KR20150063567A - Solid dosage form - Google Patents

Abstract

There is provided a solid dosage form suitable for the release of a biologically active material in the mouth, the dosage form comprising at least one biologically active substance and at least one substrate former, said formulation being substantially soluble do. Also provided is a kit comprising a method of producing the formulation and a formulation.

Description

SOLID DOSAGE FORM < RTI ID = 0.0 >

The present invention relates to a dosage form (i. E., A formulation) suitable for administration to a subject. Preferably, the solid dosage form has a fast dissolution rate.

Tablets are conventional formulations for delivering agents to humans via oral administration. Drug delivery through the oral mucosa, for example the sublingual mucosa, allows the drug to dissolve directly into the systemic circulation through the jugular vein by simple diffusion and bypass the gastrointestinal and hepatic first-pass effects. The sublingual route produces a fast and reliable initiation of normal action and is more suitable for fast dissolving formulations.

There is an unmet need in the medical field for formulations with fast dissolution rates in the oral cavity. Previous attempts to overcome the problems associated with solid dosage forms include foaming tablets, films, chewable tablets, disintegrating tablets and wicking agents. These formulations are particularly useful for those who have difficulty swallowing, for example, children and the elderly. There are several techniques used to prepare such formulations, including freeze-drying, spray-drying, tabletting and tablet compression.

A freeze-drying process was used to prepare the fast-setting solid dosage forms. Depending on the manufacturing process, the product obtained is characterized by a highly porous microstructure of the supporting substrate (i.e., mannitol, glycine, lactose, gelatin, etc.) in which the active agent is homogeneously dispersed. This technique produces products that dissolve rapidly in water or in the mouth; However, the poor physical integrity of its physical structure seriously limits additional manufacturing operations, such as the formation of blister packs. Moreover, in the manufacture of these formulations, the freeze-drying technique is expensive to produce due to the too long duration of each freeze-drying cycle (normally 24 to 48 hours). The complexity of industrial facilities is another important factor that compromises the large-scale use of this technique for the development of fast-flowing tablets. In addition, thermal shock as a direct result of each freeze-drying cycle could physically modify the physical-chemical properties of the outer membrane of the microcapsule particles.

In the freeze-drying process, gelatin and other gelatin-related materials were used to formulate the formulation in the readily available formulations. Gelatin is a carrier or structure-forming agent, which is typically used to provide a ready-to-use form for a wide variety of drugs. Gelatin provides strength to the formulation and thus prevents cracking and degradation of the formulation. This is particularly problematic when the formulation is removed from the blister package. Gelatin is advantageous for rapidly dissolving the drug from the formulation, since once the formulation is placed in the mouth it provides a fast dissolution of the formulation.

Gelatin is a protein obtained by partial hydrolysis of animal collagenous tissues such as skin, tendons, ligaments and bones. However, one important problem with mammal-derived gelatin is that it has a monotonous taste. This requires the use of sweeteners and flavoring agents in which the ready-to-use formulations mask and hide the flavor of the gelatinous component. An additional problem with traditional mammal-derived gelatin is that it requires the use of heat to affect the gelatin solution. This additional step adds time and cost to the manufacturing process.

An additional problem with the use of gelatinous materials as the fast-formulating substrate is that gelatin can increase the viscosity of the solution over time. This can cause processing problems. In addition, gelatin can cause retention time and settling problems associated with the gelatin solution during the retention period. Another disadvantage of gelatin formulations includes that bacteria tend to grow, and some individuals dislike the fact that it is from animals.

Other preparations used to replace gelatin in the readily available formulations are starch and modified starches. One problem with starch is that when it is in the mouth the patient may have a particulate feel and cause patient complaints. Many modified starches also cause this problem. Further, they are expensive.

Ketamine is a fast acting, general anesthetic approved only for intravenous injection. Recently, there has been an increased interest in its use in unimportant doses as an adjunct in acute and chronic pain management. Its pain-modifying properties are due to its antagonistic action at the N-methyl-D-aspartate (NMDA) receptor, which binds non-competitively to the penicycidine binding site. When administered at the sub-anesthesia level, ketamine remains effective in producing impaired analgesia and also demonstrates opioid preservative activity, although the subsequent mechanism remains poorly understood. The analgesic efficacy of ketamine is highly correlated with its inhibitory action on N-methyl-D-aspartate receptor-mediated pain promotion and on the activity of brain structures in response to noxious stimuli. Therefore, its usefulness in the management of acute pain is of interest. Parenteral administration of ketamine may provide near immediate pain relief, but this route may not be appropriate or convenient for the patient.

Cyclic guanosine monophosphate (cGMP) phosphodiesterase type 5 (PDE5) inhibitors are a class of compounds that reduce cGMP degradation levels in smooth muscle smooth muscle relaxation and increased blood flow. The most well known cyclic guanosine monophosphate (cGMP) phosphodiesterase type 5 (PDE5) inhibitor is sildenafil, specifically sildenafil citrate or Viagra (TM). Sildenafil is usually taken in tablet form about 30 minutes to 4 hours before sexual intercourse. However, the delivery of a more rapid effect of sildenafil or other cyclic guanosine monophosphate (cGMP) phosphodiester 5 type (PDE5) inhibitors may be advantageous in their other applications, particularly as a treatment for pulmonary hypertension.

Adrenaline is a hormone and neurotransmitter that is used to treat a number of conditions including: cardiac arrest and other arrhythmias in which cardiac output is reduced or absent; Hypersensitivity; Epidermal hemorrhage; And asthma, bronchospasm and hyperventilation. Adrenalin is often delivered through an autologous delivery system; However, an alternative delivery system for rapid delivery may be advantageous for those who can not safely administer the self-injector (e.g., those who care for children who are unfamiliar with the self-injector device) and those who do not want to use such devices have.

Thus, oral administration can deliver the patient a biologically active substance such as an N-methyl-D-aspartate receptor antagonist, adrenaline or a cyclic guanosine monophosphate (cGMP) phosphodiester 5 type (PDE5) inhibitor There is a need for a fast-dissolving formulation wherein the formulation dissolves rapidly in the patient ' s mouth, and the formulation does not use a substantial amount of mammalian gelatin.

According to one aspect of the present invention there is provided a solid dosage form suitable for release of a biologically active material in the oral cavity,

(a) At least one biologically active substance, and

(b) At least one substrate former, wherein the formulation is substantially soluble in the oral cavity.

Preferably, the solid dosage form is a ready-to-use solid dosage form.

Preferably, the biologically active material comprises at least one cyclic guanosine monophosphate (cGMP) phosphodysterase type 5 (PDE5) inhibitor, at least one active substance that binds to an adrenergic receptor, and an N-methyl- D-aspartate receptor antagonists. Preferably, the N-methyl-D-aspartate receptor antagonist is selected from the list comprising dextromethorphan, dextrorphan or ketamine. Preferably, the active substance that binds to at least one adrenergic receptor is adrenaline (epinephrine), or an adrenergic salt. Preferably, the cyclic guanosine monophosphate (cGMP) phosphodiesterase type 5 (PDE5) inhibitor is sildenafil or a pharmaceutically acceptable salt thereof. Preferably, the sildenafil salt is sildenafil citrate.

Preferably, the formulations are adapted not to leave residues of the formulation detectable by the patient in the oral cavity.

Preferably, the formulation rapidly disintegrates in the oral cavity, rapidly dissolving the biologically active substance to be absorbed by diffusion through the oral mucosa and directly into the systemic blood circulation system. By this method, the hepatic first-pass effect is avoided. Preferably, the formulation is adapted to be delivered directly into the systemic circulation through the jugular vein and bypasses the gastrointestinal and hepatic first-pass effects.

According to another aspect of the present invention,

(a) combining at least one substrate former with a biologically active material to form a homogeneous mixture; And

(b) lyophilizing the mixture to produce a solid dosage form of the present invention.

Preferably, the method is a method for producing a ready-to-use solid dosage form.

Preferably, the biologically active material comprises at least one cyclic guanosine monophosphate (cGMP) phosphodysterase type 5 (PDE5) inhibitor, at least one adrenergic receptor binding substance, and N-methyl-D - aspartate receptor antagonist. Preferably, the N-methyl-D-aspartate receptor antagonist is selected from the list comprising dextromethorphan, dextrorphan or ketamine. Preferably, the active substance that binds to one or more of the adrenergic receptors is an adrenaline or an adrenergic salt. Preferably, the cyclic guanosine monophosphate (cGMP) phosphodiesterase type 5 (PDE5) inhibitor is sildenafil or a pharmaceutically acceptable salt thereof. Preferably, the sildenafil salt is sildenafil citrate.

According to another aspect of the present invention,

(a) a solid formulation, and

(b) a kit containing its instructions for use is provided,

The formulation

(i) at least one biologically active substance, and

(ii) at least one substrate former,

The formulation is substantially soluble in the oral cavity. Preferably, the solid dosage form is a ready-to-use solid dosage form. Preferably, the biologically active material comprises at least one cyclic guanosine monophosphate (cGMP) phosphodysterase type 5 (PDE5) inhibitor, at least one adrenergic receptor binding substance, and N-methyl-D - aspartate receptor antagonist. Preferably, the N-methyl-D-aspartate receptor antagonist is selected from the list comprising dextromethorphan, dextrorphan or ketamine. Preferably, the active substance that binds to one or more adrenergic receptors is adrenaline, or an adrenergic salt. Preferably, the cyclic guanosine monophosphate (cGMP) phosphodiesterase type 5 (PDE5) inhibitor is sildenafil or a pharmaceutically acceptable salt thereof. Preferably, the sildenafil salt is sildenafil citrate.

According to another aspect of the present invention there is provided a solid dosage form suitable for the release of at least one cyclic guanosine monophosphate (cGMP) phosphodiesterase type 5 (PDE5) inhibitor in the mouth,

(a) at least one cyclic guanosine monophosphate (cGMP) phosphodiester 5 type (PDE5) inhibitor; And

(b) at least one substrate former;

The formulation is substantially soluble in the oral cavity. Preferably, the solid dosage form is a ready-to-use solid dosage form. Preferably, the cyclic guanosine monophosphate (cGMP) phosphodiesterase type 5 (PDE5) inhibitor is sildenafil or a pharmaceutically acceptable salt thereof. Preferably, the sildenafil salt is sildenafil citrate.

According to another aspect of the present invention there is provided a solid dosage form suitable for the release of an active substance that binds to one or more adrenergic receptors in the oral cavity,

(a) an active substance that binds to one or more adrenergic receptors; And

(b) at least one substrate former;

The formulation is substantially soluble in the oral cavity. Preferably, the solid dosage form is a ready-to-use solid dosage form. Preferably, the active substance that binds to one or more of the adrenergic receptors is an adrenaline or an adrenergic salt.

According to another aspect of the present invention there is provided a solid dosage form suitable for the release of an N-methyl-D-aspartate receptor antagonist in the mouth,

(a) an N-methyl-D-aspartate receptor antagonist; And

(b) at least one substrate former;

The formulation is substantially soluble in the oral cavity. Preferably, the solid dosage form is a ready-to-use solid dosage form. Preferably, the N-methyl-D-aspartate receptor antagonist is selected from the list comprising dextromethorphan, dextrorphan or ketamine.

According to another aspect of the present invention there is provided a wafer comprising a solid dosage form suitable for release of a biologically active material in the oral cavity. Preferably, the solid dosage form is a ready-to-use solid dosage form. Preferably, the biologically active material comprises at least one cyclic guanosine monophosphate (cGMP) phosphodysterase type 5 (PDE5) inhibitor, at least one adrenergic receptor binding substance, and N-methyl-D - aspartate receptor antagonist. Preferably, the N-methyl-D-aspartate receptor antagonist is selected from the list comprising dextromethorphan, dextrorphan or ketamine. Preferably, the active substance that binds to one or more of the adrenergic receptors is an adrenaline or an adrenergic salt. Preferably, the cyclic guanosine monophosphate (cGMP) phosphodiesterase type 5 (PDE5) inhibitor is sildenafil or a pharmaceutically acceptable salt thereof. Preferably, the sildenafil salt is sildenafil citrate. The wafer may carry its instructions for use.

According to another aspect of the present invention, there is provided a pharmaceutical composition comprising the solid formulation of the present invention. Preferably, the solid dosage form is a ready-to-use solid dosage form.

Solid formulation

According to one aspect of the present invention there is provided a solid dosage form suitable for release of a biologically active material in the oral cavity,

(a) at least one biologically active substance, and

(b) at least one substrate former,

The formulation is substantially soluble in the oral cavity.

Preferably, the solid dosage form is a ready-to-use solid dosage form. Preferably, the biologically active material comprises at least one cyclic guanosine monophosphate (cGMP) phosphodysterase type 5 (PDE5) inhibitor, at least one adrenergic receptor binding substance, and N-methyl-D - aspartate receptor antagonist.

Preferably, the N-methyl-D-aspartate receptor antagonist is selected from the list comprising dextromethorphan, dextrorphan or ketamine. If the antagonist is ketamine, preferably the ketamine is a ketamine salt, such as ketamine hydrochloride. In one embodiment, the ketamine is in the form of a racemic mixture of the R-enantiomer and the S-enantiomer. Preferably, the ketamine is a mixture of two enantiomers, R - (-) and S - (+).

Preferably, the biologically active substance that binds to one or more of the adrenergic receptors is an adrenaline or an adrenergic salt.

Preferably, the cyclic guanosine monophosphate (cGMP) phosphodiesterase type 5 (PDE5) inhibitor is sildenafil or a pharmaceutically acceptable salt thereof. Preferably, the sildenafil salt is sildenafil citrate.

In one embodiment, the biologically active material is present in an amount of 0.01 to 95% by weight, based on the dry weight of the formulation; 0.1 to 75% by weight and 1 to 45% by weight of the solid formulation.

Preferably, the formulation is rapidly disintegrated in the oral cavity and rapidly dissolves the biologically active substance to be absorbed by diffusion through the oral mucosa and directly into the systemic blood circulation system. By this method, the hepatic first-pass effect is avoided. Preferably, the formulation is adapted to be delivered directly into the systemic circulation through the jugular vein and bypasses the gastrointestinal and hepatic first-pass effects.

"Conveniently" preferably means that the formulation is less than 2 minutes after administration of the formulation once it is in the oral cavity; 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; ≪ / RTI > and less than 2 seconds. Preferably, the dissolution rate of the fast-formulating formulation is higher than the dissolution rate of the conventional formulation.

More preferably, the "quick-release" solid dosage form comprises less than 2 minutes after administration of the formulation once the dosage form is in the oral cavity; 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; 3 seconds; And less than 2 seconds.

"Substantially" means that at least 60% of the ready-to-use formulation dissolves in the mouth over a selected period of time. Preferably, at least 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97% or 98% of the readily available formulations have been dissolved in the oral cavity over a selected period of time. Most preferably, at least 99% of the ready-to-use formulations have been dissolved in the oral cavity over a selected period of time.

In a most preferred embodiment of the invention there is no residue left that can be detected by the patient of the formulation of the invention after administration. Preferably, the formulation is completely dissolved in the patient after oral administration, preferably sublingually. Thus, the subject is not advised to swallow the formulation. In particular, pharmaceutical compositions can be designed for, for example, buccal or sublingual delivery.

● Activator

The biologically active material may be selected from the group consisting of active compounds and compounds for human and veterinary use, such as pharmaceutical active agents, nutraceuticals, cosmeceuticals, cosmetics, complementary medicine, natural products, , Biological materials, amino acids, proteins, peptides, nucleotides and nucleic acids. In a preferred form, the biologically active material is suitable for oral administration.

In a preferred embodiment of the present invention, the biologically active material is an organic compound. In a highly preferred embodiment of the present invention, the biologically active material is an organic, therapeutically active compound for human use. In another embodiment of the present invention, the biologically active material is an inorganic compound. When the biologically active substance is a drug, it may have a neutral species, a basic or acidic species, as well as a salt of an acid or a base. The present invention is not limited to any drug-specific classes, application types, chemical types or functional groups.

Biologically active substances are usually those that require a person skilled in the art to have improved fast dissolution for oral administration. The biologically active material may be a conventional activator or drug.

Examples of biologically active materials suitable for use in the present invention include active agents, biological materials, amino acids, proteins, peptides, nucleotides, nucleic acids and analogs, homologs and primary derivatives thereof. However, the biologically active substance may be an antiobesity agent, a central nervous system stimulant, a carotenoid, a cholesterol, an elastase inhibitor, an antifungal agent, a tumor treatment agent, a vomiting agent, an analgesic agent, a cardiovascular agent, An antihypertensive agent, an antihypertensive agent, an antihypertensive agent, an antimuscarinic agent, an anti-tuberculosis agent, an anti-neoplastic agent, an immunosuppressant, an antithyroid agent, an antiviral agent, anxiety Adrenergic receptor blockers, beta-adrenergic receptor blockers, blood products and substitutes, cardiac arrhythmics, contrast agents, cough suppressants (expectorants and mucolytics), diagnostic agents, diagnostic imaging agents , Diuretics, dopamine preparations (anti-Parkinson's agents), hemostatic agents, immunotherapeutic agents, lipid modulating agents, muscle relaxants, parasympathetic agents, parathyroid glands (Including steroids), anti-allergics, stimulants and anorectic agents, sympathetic stimulants, thyroid agents, vasodilators, and xanthines, including but not limited to calcitonin and biphosphonate, prostaglandins, nucleophilic radiopharmaceuticals, sex hormones But may be selected from a wide variety of known drug classes that are not limited to these.

Within these categories, and each of the classes of active substances are biologically the list of species described are described in [ 'The Extra Pharmacopoeia', 31st Edition (The Pharmaceutical Press, London, 1996), and 'Physician's Desk Reference' (60 th Ed , ≪ / RTI > 2005), both of which are specifically incorporated by reference to those skilled in the art. Active agents are commercially available and / or can be prepared by techniques known in the art.

Additionally, however, examples of suitable biologically active materials include, but are not limited to, those listed below:

진통제 및 항염증제: 알록시프린, 아우라노핀, 아자프로파존, 베노릴레이트, 베노릴레이트, 디플루니살, 에토돌락, 펜부펜, 페노프로펜 칼심, 플루르비프로펜, 이부프로펜, 인도메타신, 케토프로펜, 메클로페나믹산, 메페나믹산, 나부메톤, 나프록센, 옥사프로진, 옥시펜부타존, 페닐부타존, 피록시캄, 설린닥.

Analgesics and anti-inflammatory agents: Alloxifrin, auranopin, azapropazone, vinorilate, benorilate, diflunisal, etodolac, fenbufen, fenoprofen calm, fluvifropen, ibuprofen, indomethacin , Ketoprofen, meclofenamic acid, mefenamic acid, nabumetone, naproxen, oxaprozin, oxyphenbutazone, phenylbutazone, piroxycam, sulindac.

구충제: 알벤다졸, 베페니움 하이드록시나프토에이트, 캄벤다졸, 다이클로로펜, 이베르멕틴, 메벤다졸, 옥삼니퀸, 옥스펜다졸, 옥산텔 엠보네이트, 프라지퀀텔, 피란텔 엠보네이트, 티아벤다졸.

Repellent: Al cuts sol, chopping penny help hydroxy naphthoate, Kam cuts sol, dichloro pen, Yves Le Abamectin, methoxy cuts sol, oxide samni Queen, bull pen imidazole, dioxane Tel emboss carbonate, plastic support kwontel, pyran Tel Embonate, thiabendazole.

항부정맥제: 아미노다론 HCl, 다이소피라마이드, 플레카이나이드 아세테이트, 플레카이나이드 아세테이트, 퀴니딘 설페이트.

Antiarrhythmics : Aminodalon HCl, diisopiramide, phlecainide acetate, plaquinide acetate, quinidine sulfate.

항균제: 벤에타민 페니실린, 시녹사신, 시프로플록사신 HCl, 클라리트로마이신, 클로파지민, 클록사실린, 데메클로사이클린, 독시사이클린, 에리트로마이신, 에티온아마이드, 이미페넴, 날리딕스산, 니트로푸란토인, 리팜피신, 스피라마이신, 설파벤즈아마이드, 설파독신, 설파메라진, 설프아세트아마이드, 설파다이아진, 설파퓨라졸, 설프아메톡사졸, 설파피리딘, 테트라사이클린, 트라이메토프림.

Antimicrobial agents: antimicrobial agents such as benzethamine penicillin, cynoxazin, ciprofloxacin HCl, clarithromycin, clofazimine, clock factin, demeclocycline, doxycycline, erythromycin, ethionamide, imipenem, nalidixic acid, nitrofurantoin, rifampicin, Spiramycin, sulfamenzamide, sulfamethoxine, sulfamerazine, sulfacetamide, sulfadiazine, sulfaprazole, sulfamethoxazole, sulfapyridine, tetracycline, trimethoprim.

항응고제: 디쿠마린, 다이피리다몰, 니쿠말론, 페닌디온.

Anticoagulants: dicumarin, dipyridamole, nicmarone, penendione.

항응고제: 아목사핀, 시클라진돌, 마프로틸린 HCl, 미안세린 HCl, 노르트라이프틸린 HCl, 트라조돈 HCl, 트라이미프라민 말리에이트.

Anticoagulants: amoxapine, cyclazinol, mafrotiline HCl, myan serine HCl, norleaftiline HCl, trazodone HCl, traumimphicin maleate.

항당뇨병제: 아세토헥사마이드, 클로르포로파마이드, 글리벤클라마이드, 글리클라자이드, 글리피자이드, 톨라자마이드, 톨부타마이드.

Antidiabetic agents: acetohexamide, chlorophoramides, glibenclamide, glyclazide, glypizide, tolazamide, tolbutamide.

항간질약: 베클라마이드, 카바마제핀, 클로나제팜, 에토토인, 메토인, 메트숙시마이드, 메틸페노바르비톤, 옥스카르바제핀, 파라메타다이온, 펜아세마이드, 페노바르비톤, 페니토인, 펜숙시마이드,프리미돈, 설티암, 발프론산.

Antiepileptic drugs include but are not limited to beclomide, carbamazepine, clonazepam, etotone, metoin, methesuximide, methylphenobarbitone, oxcarbazepine, parametadione, phenacemide, phenobarbitone, phenytoin, Penicillin, penicillin, penicillin, penicillin, penicillin, penicillin,

항-진균제: 암포테리신, 뷰토코나졸 나이트레이트, 클로트라이마졸, 에코나졸 나이트레이트, 플루코나졸, 플루사이토신, 그리세오풀빈, 이트라코나졸, 이트라코나졸, 케토코나졸, 미코나졸, 나타마이신, 니스타틴, 설코나졸 나이트레이트, 테르비나핀 HCl, 테르코나졸, 티오코나졸, 운데센산.

Anti-fungicide: amphotericin, views Toko najol nitrate, chloride tri majol, eco najol nitrate, fluconazole, flu, cytosine, so Seo pulbin, itraconazole, itraconazole, ketoconazole, miconazole, indicate clarithromycin, your statin, snow Kona Zirconate, zirconate, terbinafine HCl, terconazole, thioconazole, undecanoic acid.

항통풍제: 알로퓨리놀, 프로베네시드, 설핀피라존.

Anti-gout agents : alopurinol, probenecid, sulfinpyrazone.

항-고혈압제: 암로디핀, 베니디핀, 다로디핀, 딜티아젬 HCl, 다이아조옥사이드, 펠로디핀, 구아나벤즈 아세테이트, 인도라민, 이스라디핀, 미녹시딜, 니카르디핀 HCl, 니페디핀, 니모디핀, 페녹시벤즈아민 HCl, 프라조신 HCl, 레세르핀, 테라조신 HCl.

Anti-hypertensives : amlodipine, vanidipine, darodipine, diltiazem HCl, diazooxide, felodipine, guanabenzoacetate, indolamine, isradipine, minoxidil, nicardipine HCl, nifedipine, Cibenzamine HCl, prazosin HCl, reserpine, terazosine HCl.

항말라리아제: 아모다이아퀸, 클로로퀸, 클로르프로구아닐 HCl, 할로판트린 HCl, 메플로퀸 HCl, 프로구아닐 HCl, 피리메타민, 퀴닌 설페이트.

Anti-malarials : Amodiaquin, chloroqueen, chlorproguanyl HCl, halofantrine HCl, mefloquine HCl, proguanil HCl, pyrimethamine, quinine sulfate.

항편두통제: 다이하이드로에르고타민 메실레이트, 에르고타민 타르트레이트, 메티세르지드 말리에이트, 피조티펜 말리에이트, 수마트립탄 숙시네이트.

Anti-migraine agents : dihydroergotamine mesylate, ergotamine tartrate, methicerezide malate, phytohippene malate, sumatriptan succinate.

항무스카린제: 아트로핀, 벤즈헥솔 HCl, 비페리덴, 에토프로파진 HCl, 히오스신 뷰틸 브로마이드, 히오스시아민, 메펜졸레이트 브로마이드, 오르펜아드린, 옥시펜사이클리민 HCl, 트로피카마이드.

Antimuscarinic agents: atropine, benzhexol HCl, bipiperidene, ethoprodine HCl, hyosine butyl bromide, hyoscyamine, mefenazolate bromide, orphenadrine, oxyphencyclimine HCl, tropicamide .

항종양제 및 면역억제제: 아미노글루테티미드, 암사크린, 아자티오프린, 부설판, 클로람부실, 사이클로스포린, 다카르바진, 에스트라무스틴, 에토포사이드, 로무스틴, 멜팔란, 머캅토퓨린, 메토트렉세이트, 미토마이신, 미토탄, 미토잔트론, 프로카바진 HCl, 타목시펜 시트레이트, 테스톨락톤.

Antitumor agents and immunosuppressive agents: aminoglutethimide, amsacrine, azathioprine, epidermis, chlorambucil, cyclosporin, Dakarbazine, estramustine, etofoside, rosmutin, melphalan, mercaptopurine, methotrexate, Mitomycin, mitotane, mitoxantrone, procavazine HCl, tamoxifen citrate, testolactone.

항-원충성간질제: 벤즈니다졸, 클리오퀴니놀, 데코퀴네이트, 다이아이오도하이드록시퀴놀린, 다이록사나이드 퓨로에이트, 디니톨마이드, 푸르졸리돈, 메트로니다졸, 니모라졸, 니트로푸라존, 오르니다졸, 티니다졸.

The present invention relates to the use of an anti-senile agent selected from the group consisting of benzindazole, clioquinol, decouquate, diiodohydroxyquinoline, dioxanadue furoate, dinitolemide, furzolydone, metronidazole, nimorazole, Ordinazole, Tinidazole.

항-갑상선제: 카르비마졸, 프로필티오유라실.

Anti-thyroid agent: carbimazole, propylthio-yracil.

불안 완화제, 진정제, 수면제 및 신경 이완제: 알프라졸람, 아밀로바르비톤, 바르비톤, 벤타제팜, 브로마제팜, 브롬페리돌, 브로티졸람, 뷰토바르비톤, 카르브로말, 클로르다이아제폭사이드, 클로르메티아졸, 클로르프로마진, 클로바잠, 클로티아제팜, 클로자핀, 다이아제팜, 드로페리돌, 에틴아메이트, 플루나니손, 플루니트라제팜, 플루오프로마진, 플루펜틱솔 데카노에이트, 플루페나진 데카노에이트, 플루라제팜, 할로페리돌, 로라제팜, 로르메타제팜, 메다제팜, 메프로바메이트, 메타콸론, 미다졸람, 니트라제팜, 옥사제팜, 펜토바르비톤, 페르페나진 피모자이드, 프로클로르페라진, 설피리드, 테마제팜, 티오리다진, 트라이아졸람, 조피클론.

Anxiolytics , antidepressants, sedatives, sedatives, and neuroleptics: alprazolam, amilobarbitone, barbitone, bentazepam, bromageprom, bromfelidol, brothiazolam, buttobarbitone, The compounds of the present invention may be selected from the group consisting of chlormethiazole, chlorpromazine, clobazam, clotiazepam, clozapine, diazepam, droperidol, etinamate, flunisin, flunitrazepam, fluoropromazine, flupenythol decanoate, Wherein the at least one compound is selected from the group consisting of atorvastatin, decanoate, plurazepam, haloperidol, lorazepam, lorometazepam, medazepam, meflobamate, metacarron, midazolam, nitrazem, oxazepam, pentobarbitone, , Sulpiride, theme zepham, thioridazine, triazolam, jovic clone.

베타-차단제: 아세뷰톨롤, 알프레놀롤, 아테놀롤, 라베탈롤, 메토프롤롤, 나돌롤, 옥스프레놀롤, 핀돌롤, 프로프라놀롤.

Beta-blockers: asbestolol, alfrenolol, atenolol, labetalol, metoprolol, nadolol, oxprenolol, pinolol, propranolol.

심장 강심제: 암리논, 디기톡신, 디곡신, 에녹시몬, 라나토사이드 C, 메디곡신.

Cardiac arrhythmia: amrinone, digethoxine, digoxin, enoximone, ranatoside C, medigosin.

코리코스테로이드 : 벨클로메타손, 베타메타손, 뷰데소나이드, 코티손 아세테이트, 데속시메타손, 덱사메타손, 플루드로코티손 아세테이트, 플루니솔라이드, 플루니솔라이드, 플루코르톨론, 플루티카손 프로피오네이트, 하이드로코티손, 메틸프레드니솔론, 프레드니솔론, 프레드니손, 트라이암시놀론.

But are not limited to, the following : coricosteroids : bellcromethosone, betamethasone, buxesone, cortisone acetate, dexamethasone, dexamethasone, fluodurocotissonate acetate, flunisolide, flunisolide, flucortolone, fluticasone propionate, Cortisone, methylprednisolone, prednisolone, prednisone, triamcinolone.

이뇨제: 아세트아졸라마이드, 아밀로라이드, 벤드로플루아자이드, 뷰메타나이드, 클로로티아자이드, 클로르탈리돈, 에타크린산, 프루세마이드, 메톨라존, 스피로놀락톤, 트라이암테렌.

Diuretics: acetazolamide, amiloride, bendrofluazide, bengenan, chlorothiazide, chlortalidone, ethacrynic acid, flucemide, metolazone, spironolactone, triamterene.

항-파킨슨제: 브로모크립틴 메실레이트, 리수라이드 말리에이트.

Anti-Parkinson's agent: bromocriptine mesylate, lysylide maleate.

위장관제: 비사코딜, 시메티딘, 시사프라이드, 디페녹실레이트 HCl, 돔페리돈, 파모티딘, 로페라마이드, 메살라진, 니자티딘, 오메프라졸, 온단세트론 HCl, 라니티딘 HCl, 설파살라진.

Gastrointestinal agents: bisacodyl, cimetidine, sisaferide, diphenoxylate HCl, domperidone, famotidine, loperamide, mesalazine, nizatidine, omeprazole, ondansetron HCl, lanitidine HCl, sulfasalazine.

히스타민 H1 -수용체 길항물질: 아크리바스틴, 아스테미졸, 신나리진, 사이클리진, 사이프로헵타딘 HCl, 다이멘하이드리네이트, 플루나리진 HCl, 로라타딘, 메클로진 HCl, 옥사토마이드, 테르페나딘, 트라이프롤리딘.

Histamine H1 -receptor antagonists: acrivastine, astemizole, cinarginine, cyclizine, cyproheptadine HCl, dimenhydrinate, flunarizine HCl, loratadine, mechlorine HCl, oxathomide, Terfenadine, troprolidine.

지질 조절제: 베자피브레이트, 클로피브레이트, 페노피브레이트, 겜피브로질, 프로뷰콜.

Lipid modifiers: bezafibrate, clofibrate, fenofibrate, gemfibrozil, propobucol.

국소 마취제: 신경-근육 제제: 피리도스티그민.

Local anesthetics: Neuro-muscle preparations: Pyridostigmine.

질산염 및 기타 항- 협심증제 : 아밀 아질산염, 글라이세릴 트라이나이트레이트, 아질산아이소소르바이드, 일질산아이소소르바이드, 4질산펜타에리트리톨.

Nitrate and other anti- angina agents : amyl nitrite, glyceryl trinitrate, isosorbide nitrite, isosorbide mononitrate, pentaerythritol nitrate.

영양제: 베타카로텐, 비타민 A, 비타민 B2, 비타민 D, 비타민 E, 비타민 K.

Nutrition: Beta-carotene, vitamin A, vitamin B2, vitamin D, vitamin E, vitamin K.

오피오이드 진통제: 코데인, 덱스트로프로피옥시펜, 다이아몰핀, 다이하이드로코데인, 멥타지놀, 메타돈, 몰핀, 날뷰핀, 펜타조신, 메다졸람, 펜타닐.

Opioid analgesics: codeine, dextropropyoxyphene, diamorphine, dihydrocodeine, 멥 tazinol, methadone, morphine, nalbutyne, pentazocine, medazolam, fentanyl.

경구 백신: 다음이 대표적이지만 배타적인 열거는 아닌 질환의 증상을 예방 또는 감소시키도록 설계된 백신: 인플루엔자, 결핵, 뇌막염, 간염, 백일해, 소아마비, 파상풍, 디프테리아, 말라리아, 콜레라, 포진, 장티푸스, HIV, AIDS, 홍역, 라임병, 여행자 설사, A, B 및 C형 간염, 중이염, 뎅기열, 광견병, 파라인플루엔자, 루벨라, 황열, 이질, 냉방병, 톡소플라스모시스, Q-열, 출혈열, 아르헨티나 출혈열, 카리에스, 샤가스병, 이콜라이(E. coli)에 의해 야기되는 요로감염증, 폐렴구균, 볼거리 및 치쿤구니야(Chikungunya).

Oral Vaccines: Vaccines designed to prevent or reduce the symptoms of a disease that are not representative but exclusively include: influenza, tuberculosis, meningitis, hepatitis, pertussis, polio, tetanus, diphtheria, malaria, cholera, herpes, typhoid, HIV, AIDS, measles, Lyme disease, traveler's diarrhea, hepatitis A, B and C, otitis media, dengue fever, rabies, parainfluenza, rubella, yellow fever, dysentery, Urinary tract infections caused by E. coli, S. pneumoniae, mumps, and Chikungunya.

다음이 대표적이지만 원인이 되는 유기체의 배타적인 열거는 아닌 다른 질환 증후군의 증상을 예방 또는 감소시키는 백신: 비브리오(Vibrio) 종, 살모넬라(Salmonella) 종, 보르데텔라(Bordetella) 종, 헤모필루스(Haemophilus) 종, 톡소플라스모시스 곤디(Toxoplasmosis gondii), 사이토메갈로바이러스(Cytomegalovirus), 클라미디아(Chlamydia) 종, 스트렙토코커스(Streptococcal) 종, 노르워크 바이러스(Norwalk Virus), 에스케리키아 콜라이(Escherischia coli), 헬리코박터 파일로리(Helicobacter pylori), 로타바이러스(Rotavirus), 임균(Neisseria gonorrhae), 네이세리아 메닝기디티스(Neisseria meningiditis), 아데노바이러스(Adenovirus), 엡스타인 바르 바이러스(Epstein Barr Virus), 일본 뇌염 바이러스(Japanese Encephalitis Virus), 뉴모시스티스 카리니(Pneumocystis carini), 단순포진, 클로스트리디아(Clostridia) 종, 호흡기 세포융합 바이러스, 클렙시엘리아(Klebsielia) 종, 쉬겔라(Shigella) 종, 슈도모나스 아에루기노사(Pseudomonas aeruginosa), 파르보바이러스(Parvovirus), 캄필로박터( Campylobacter) 종, 리케차(Rickettsia) 종, 수두, 예르시니아(Yersinia) 종, 로스강 바이러스(Ross River Virus), J. C. 바이러스, 로도코커스 에퀴(Rhodococcus equi), 모락셀라 카타랄리스(Moraxella catarrhalis), 보렐리아 부르그도르페리(Borrelia burgdorferi) 및 파스퇴렐라 헤몰리티카(Pasteurella haemolytica). 추가 구체적 예는 펜타닐 또는 미다졸람과 같은 오피오이드를 포함한다.

Vibrio, Salmonella, Bordetella, Haemophilus, which prevent or reduce the symptoms of other disease syndromes, but not exclusively, of the following organisms , A virus, a virus, a Toxoplasmosis gondii, a Cytomegalovirus, a Chlamydia species, a Streptococcal species, a Norwalk Virus, an Escherischia coli, a Helicobacter pylori virus, The virus is useful for the treatment of Helicobacter pylori, Rotavirus, Neisseria gonorrhae, Neisseria meningitidis, Adenovirus, Epstein Barr Virus, Japanese Encephalitis Virus ), Pneumocystis carini, Herpes simplex, Clostridia species, Respiratory cell fusion Virus, Klebsielia sp., Shigella sp., Pseudomonas aeruginosa, Parvovirus, Campylobacter sp., Rickettsia sp., Chicken pox, The strain Yersinia, the Ross River Virus, the JC virus, Rhodococcus equi, Moraxella catarrhalis, Borrelia burgdorferi, Pasteurella haemolytica. Additional specific examples include opioids such as fentanyl or midazolam.

비감염성 면역-조절 질환 병태와 관련된 백신: 예컨대 국소 및 전신성 알레르기성 병태, 예컨대 고초열, 천식, 류마티스 관절염 및 암종.

Vaccines associated with non-infectious immune-mediated disease states: e.g., local and systemic allergic conditions such as psoriasis, asthma, rheumatoid arthritis and carcinoma.

수의적 용도를 위한 백신: 콕시듐증, 뉴캐슬병, 유행성 폐렴, 고양이 백혈병, 위축성비염, 단독, 구제역, 돼지, 뉴모니아 및 반려 동물 및 농장 동물에 영향을 미치는 기타 질환 병태 및 기타 감염 및 자가면역 질환 병태에 관한 것을 포함함.

Vaccines for mulitple use: Conditions such as coccidiosis, Newcastle disease, pneumonia, feline leukemia, atrophic rhinitis, solitary, foot-and-mouth disease, swine, pneumonia and other diseases affecting companion animals and farm animals and other infectious and autoimmune disease conditions .

단백질, 펩타이드 및 재조합체 약물: 인슐린(헥사머/다이머/모노머 형태), 글루카곤, 성장 호르몬(소마토트로핀), 폴리펩타이드 또는 이들의 유도체, (바람직하게는 분자량이 1000 내지 300,000임), 칼시토닌 및 이들의 합성 변형, 엔케팔린, 인터페론(특히 통상적인 감기 치료용의 알파-2 인터페론), LHRH 및 유사체(나파렐린, 부세렐린, 졸리덱스), GHRH(성장 호르몬 방출 호르몬), 세크레틴, 브래디킨 길항물질, GRF(성장 방출 인자), THF, TRH(갑상선 자극 호르몬, 갑상선 자극 호르몬 방출 호르몬), ACTH 유사체, IGF(인슐린 유사 성장 인자), CGRP(칼시토닌 유전자 관련 펩타이드), 심방성 나트륨 배설 촉진인자(atrial natriurectic) 펩타이드, 바소프레신 및 유사체(DDAVP, 리프레신), 인자VIII, G-CSF(과립구-집락자극인자), EPO(에리트로포이에틴).

Proteins, peptides and recombinant drugs: insulin (hexamer / dimer / monomer form), glucagon, growth hormone (somatotrophin), polypeptides or derivatives thereof (preferably having a molecular weight of 1000 to 300,000), calcitonin And synthetic derivatives thereof, enkephalin, interferon (especially alpha-2 interferon for conventional cold therapy), LHRH and analogs (napalelin, boserelin, Jolyndex), GHRH (growth hormone releasing hormone), secretin, (Thyroid stimulating hormone releasing hormone), ACTH analog, IGF (insulin like growth factor), CGRP (calcitonin gene related peptide), atrial sodium excretion promoting factor atrial natriurectic peptide, vasopressin and analogs (DDAVP, lymphocyte), factor VIII, G-CSF (granulocyte-colony stimulating factor), EPO (erythropoietin).

성 호르몬: 클로미펜 시트레이트, 다나졸, 에티닐로에스트라다이올, 메드록시프로게스테론 아세테이트, 메스트라놀, 메틸테스토스테론, 노르에티스테론, 노르게스트렐, 에스트라다이올, 접합된 에스트로겐, 프로게스테론, 스타노졸롤, 스티보에스트롤, 테스토스테론, 티볼론.

Sex hormones such as clomiphene citrate, danazol, ethinyloestradiol, medroxyprogesterone acetate, mestranol, methyl testosterone, norethersterone, norgestrel, estradiol, conjugated estrogens, progesterone, Boestrol, testosterone, and tibolone.

살정자제: 노녹시놀 9.

Spermatozoic: nonoxynol 9.

자극제: 암페타민, 덱삼페타민, 덱스펜플루라민, 펜플루라민, 마진돌, 페몰린.

Stimulants: amphetamine, dexamphetamine, dexfenfluramine, fenfluramine, marginal stones, pemoline.

Despite the general applicability of the method of the present invention, more specific examples of biologically active substances are: haloperidol (dopamine antagonist), DL isoproterenol hydrochloride (? -Adrenergic agonist), terfenadine (H1-antagonist But are not limited to, corticosteroids, corticosteroids, substances), propranolol hydrochloride ([beta] -adrenaline antagonist), desipramine hydrochloride (antidepressant), sildenafil citrate, tadalafil and bar- An additional analgesic (cyclooxygenase inhibitor), phenamic acid, piroxycam, Cox-2 inhibitor, naproxen, and others may all be advantageously formulated into oral formulations of the invention.

Additional examples of biologically active substances include, but are not limited to, alphacarone, acetyldigosin, acyclovir analogs, alpoadhildil, aminopostatin, anispamil, antithrombin III, atenolol, azatrimidine, But are not limited to, metasone, belomycin, benzocaine and derivatives, beta carotene, beta endorphin, beta interferon, bezafibrate, vinobom, biperidene, bromage palm, bromocriptine, adrenalol, , Ceftriaxone, ceftriaxone, cephinoxine, cephinoxaline, cepharanthin, cepharanthin, cepharanthin, cepharanthin, A corticosteroid, a cortisone, a cortisone, a cortisone, a cortisone, a cortisone, a cortisone, a cortisone, a cortisone, a cortisone, a cortisone, a cortisone, Pharmade, Cyclos Dexamethasone, dexamethasone, such as acetate, dezocine, diazepam, diclofenac, dideoxyadenosine, dideoxyinosine, digethoxine, digoxin, dihydroergone But are not limited to, thymine, dihydroergotoxin, diltiazem, dopamine antagonist, doxorubicin, econazole, endralazine, enkephalin, enalapril, epoprostenol, estradiol, estramustine, etopibrate, The factor ix, the factor viii, the felbamate, the fenbamide, the phenobarzol, the phenobarbate, the peptophenadine, the flunarizine, the flurbiprofen, the 5-fluorouracil, the flourazepam, the phosphomycin, the fosmidomycin, Gemcitabine, glycopeptide, glycoprotein, germoglobinin, hepatitis B vaccine, hydralala , Iodinated aromatic x-ray contrast agents such as iodamide, ipratropium bromide, ketoconazole, ketoprofen, ketotifene, ketoprofen, ketoprofen, Lactobacillus, Lactobacillus, Lidocaine, Lidoflavin, Lysuride, Lysridohydrogene Maleate, Lorazepam, Lovastatin, Mefenamic acid, Melphalan, Memantine, Lactobacillus, Lactobacillus, Lactobacillus, But are not limited to, methylanthraquine, methergolin, methergoline, methotrexate, methyldigosin, methylprednisolone, metronidazole, methisoprenol, methifranolol, methepamamide, methazolone, methoprolol, methoprolol tartrate, myconazole, Naproxen, naprazat, naproxen, natural insulin, nepadil, nicardipine, < RTI ID = 0.0 & Oxytetracycline, penicillin, oxytetracycline, oxytetracycline, oxytetracycline, oxytetracycline, oxytetracycline, oxytetracycline, norfloxacin, Such as, for example, penicillin G venetamine, penicillin O, phenylbutazone, picotamide, pindolol, povosulfan, piretanide, pyridyldil, piroxycam, pyroprofen, plasminogenesis activator, prednisolone, prednisone, Wherein the at least one compound is selected from the group consisting of atorvastatin, atorvastatin, atorvastatin, atorvastatin, atorvastatin, atorvastatin, atorvastatin, atorvastatin, atorvastatin, A derivative thereof, a derivative thereof, somatropin, stilamine, sulfinol hydrochloride, sulfin pyrazone, suloxylidyl, suroprofen, sulprostone, synthetic insulin, tallinolol, taxol, , Testosterone propionate, testosterone undecanoate, tetracan HI, tiaramide HCI, tolmetin, tranilast, triquila, tromantadine HCl, urokinase, valium, verapamil, vidarabine, sodium vidarabine phosphate, But are not limited to, vinblastine, vinblueine, vincamine, vincristine, vindesine, vinpocetine, vitamin A, vitamin E succinate and x-ray contrast agents.

In addition, the solid formulations of the present invention will either be made commercially available or will be made available as a biologically active material, either in the form of new chemical entities (NCE) and other active agents suitable for delivery .

The biologically active substance may be an active substance that binds to one or more adrenergic receptors. Preferably, the active substance that binds to the at least one adrenergic receptor is adrenaline (epinephrine), or an adrenaline salt, such as adrenaline acid tartrate or adrenaline hydrochloride. Alternatively, the active substance that binds to one or more adrenergic receptors may be an adrenaline, such as norepinephrine, analogs and compounds related to isoprenaline; Or in the form of sympathetic stimulants such as tyramine, ephedrine, pseudoephedrine, amphetamine, salbutamol, and terbutaline.

The biologically active material may be an N-methyl-D-aspartate receptor antagonist. Preferably, the N-methyl-D-aspartate receptor antagonist is selected from the list comprising dextromethorphan, dextrorphan or ketamine.

The biologically active material may be a cyclic guanosine monophosphate (cGMP) phosphodiesterase type 5 (PDE5) inhibitor. Preferably, the cyclic guanosine monophosphate (cGMP) phosphodiesterase type 5 (PDE5) inhibitor is sildenafil or a pharmaceutically acceptable salt thereof. Preferably, the sildenafil salt is sildenafil citrate.

Preferably, the solid dosage form comprises a wafer; refine; capsule; pill; powder; Pellets; Granules; And a film. The solid dosage form should be suitable for not leaving residue of the formulation detectable by the patient in the mouth. Any form in which solid formulations are provided; It must quickly disintegrate in the mouth and rapidly dissolve the biologically active material to be absorbed through diffusion through the oral mucosa and directly into the systemic blood circulation system. Preferably, the solid dosage form is a ready-to-use solid dosage form.

구성성분

Constituent

Preferably, the solid dosage form is substantially free of starch. In a further embodiment of the invention, the pharmaceutical composition comprising the solid formulation is also substantially free of starch. Preferably, the solid dosage form is a ready-to-use solid dosage form.

The exact amount of biologically active material in a solid dosage form will depend upon the type of biologically active material selected. However, the active substance is usually provided in an amount of 0.02 to 95%, preferably 0.02 to 20%, or preferably 0.1 to 75%, and 1 to 45% by dry weight of the formulation.

Biologically active substances are generally 5 mg; 10 mg; 15 mg; 20 mg; 25 mg; 30 mg; 35 mg, 40 mg, 45 mg, 50 mg, 60 mg and 100 mg.

Preferably, the solid dosage form of the present invention also comprises at least one substrate former.

In the prior art lyophilized systems, gelatin is the most commonly used carrier or builder due to its wall-forming ability. Gelatin is a water soluble polymer and thus, when mixed with active pharmaceutical ingredients in water; The increased viscosity of the solution over time can cause a decrease in the solubility of the poorly water-soluble drug in the mixture, resulting in the suspension of the drug in the gelatin matrix. This may cause phase separation to occur; In the amorphous or crystalline form, the drug may not be homogeneously dispersed in the matrix, which will ultimately affect the dissolution and absorption of the final product. Thus, preferably, gelatin is not provided as a solid dosage form of the present invention.

The effectiveness of the solid dosage form of the present invention depends on the biologically active material that is dissolved in the body fluid before absorption into the systemic circulation as in the oral cavity. Therefore, the dissolution rate of the formulation is important. In a preferred embodiment of the invention, the solid dosage form comprises a defrosting agent as at least one substrate forming substance.

Other polymeric materials suitable for forming a substrate may be selected for specific applications, such as in the oral cavity, particularly as solid formulations for site-specific drug delivery systems. The matrix forming agent of the present invention may be selected from non-mammalian gelatin, dextrin, soy protein, wheat protein, cilium seed protein, acacia gum, guar gum, agar gum, zanthin gum, polysaccharide; Alginate; Carboxymethylcellulose sodium; Carnitine; dextrin; pectin; Party; amino acid; Starch; Modified starch; Carboxymethylcellulose; Hydroxypropylmethylcellulose; Hydroxypropylcellulose and methylcellulose inorganic salts; Synthetic polymers; Amylopectin, polypeptide / protein or polysaccharide complexes.

The substrate forming material in the solid dosage form may be a carbohydrate. Preferably, the carbohydrate is mannitol; Dextrose; Lactose; Galactose; Trehalose; And cyclodextrins.

In a highly preferred embodiment, the at least one substrate former in the solid dosage form is glycine. Glycine is an amino acid with good wetting properties and is suitable for fast-drying formulations. Low amounts of glycine can be used in the formulations of the invention to control the rate of dissolution of the formulation. Furthermore, glycine can also be used as an anti-collapse agent, which keeps the formulation from contracting during or after the manufacturing process. In one embodiment, glycine is provided in the formulations of the present invention in an amount of from 0.2 to 7.5%, more preferably from about 0.5% to about 5% dry weight of the formulation. Preferably, the glycine is provided in an amount of 0.5 to 5% by weight, based on the dry weight of the composition of the formulation.

In a highly preferred embodiment, the at least one substrate former in the solid dosage form is carboxymethylcellulose sodium. When at least one of the substrate formers is sodium carboxymethylcellulose, the polymer is provided in a concentration of from about 0.1% to about 19% by dry weight of the solid dosage form. In a preferred embodiment, sodium carboxymethylcellulose is provided in an amount from about 0.1% to about 15% by dry weight of the formulation. In a highly preferred embodiment of the present invention, sodium carboxymethylcellulose is provided in an amount of about 0.1% to about 1.0% by dry weight of the solid dosage form. Preferably, sodium carboxymethylcellulose is present in an amount ranging from 0.05% to 19%; 0.1% to 15%; And 0.1% to 10% by weight of the composition.

In another embodiment of the invention, the formulation comprises amylopectin as at least one substrate former. Amylopectin can increase the release of biologically active agents by promoting formulation collapse. Amylopectin may be provided in formulations at a concentration of about 2% to 20% by dry weight of the solid dosage form. Amylopectin may be provided in an amount from about 2% to about 17% dry weight of the formulation. Preferably, the amylopectin is between 2% and 17%; And 2% to 15% by weight of the composition.

According to another embodiment of the present invention, the solid dosage form may comprise a matrix forming agent such as mannitol. Mannitol is a component that helps the nodular structure and imparts the hardness of the formulation. When mannitol is provided in a formulation, it is present in a concentration of from about 5% to about 80%, preferably from about 10% to about 60%, and most preferably from about 10% to about 50% by dry weight of the formulation.

Solid formulations may contain inorganic salts. Preferably, the inorganic salt is selected from the group consisting of sodium phosphate, sodium chloride and aluminum silicate.

The solid dosage forms of the present invention may contain amino acids. Preferably, the amino acid is glycine; L-alanine; L-aspartic acid; L-glutamic acid; L-hydroxyproline; L-isoleucine; L-leucine; And L-phenylalanine.

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

In order to achieve rapid dissolution of the biologically active material from the solid dosage forms of the present invention, the diluent may be added as at least one substrate forming material. Diluents include microcrystalline cellulose (e.g., Avicel PH 101 (R) and Avicel PH 102 (R)), lactose, starch and sorbitol. These diluents may be provided in the formulations, either alone or as a mixture of different proportions, and may be individually or cumulatively from about 1% to about 80%, preferably from about 2% to about 50%.

In one embodiment of the invention, the solid dosage form comprises microcrystalline cellulose as at least one substrate former. Microcrystalline cellulose may act as a filler and binder in the formulation of the present invention. Microcrystalline cellulose has the ability to compress to the minimum compression pressure and results in a hard, stable formulation, preferably spontaneously. Because of its large surface area and high internal porosity, microcrystalline cellulose can absorb and retain large amounts of water, which is desirable for the formulation of the present invention. When the solid formulation of the present invention comprises microcrystalline cellulose, it is provided in an amount of about 1% to about 10%, and preferably about 1% to about 8%, by dry weight of the formulation.

The solid dosage form or pharmaceutical composition of the present invention may preferably be substantially free of avicel.

In another preferred embodiment, the solid dosage form comprises at least one lubricant. The formulations of the present invention may include lubricants such as polyethylene glycol (PEG) 1000, 2000, 4000 and 6000, sodium lauryl sulfate, fats or oils. One advantage of using these lubricants is that they assist in the removal of formulations from the mold. These lubricants may be provided in formulations as a mixture of different ratios, either singly or in combination, and may be individually or incrementally from about 0.05% to about 5%, preferably from about 0.1% to 2%, preferably about 1.5% have. In one embodiment, the composition comprises 0.05% to 5% polyethylene glycol 2000, preferably 0.1% to 2% polyethylene glycol 2000, preferably as a dry weight of the formulation, or as a mixture of various glycols, 1.5% polyethylene glycol 2000. Alternatively, PEG 2000 can be replaced by PEG 1000.

In another preferred embodiment, the solid dosage form comprises at least one buffering reagent. Preferably, the buffering reagent in the solid dosage form provides saliva at pH 7.0 to 7.8 when dissolved in the mouth. Such buffering agents can improve the sublingual absorption of weakly basic compounds. The solid buffering reagent may comprise at least one compound selected from the group consisting of sodium dihydrogenphosphate, sodium hydrogenphosphate, sodium bicarbonate, and sodium carbonate, which may be provided in a formulation, alone or in a different ratio, at a concentration of from about 0.01% Lt; / RTI >

Alternatively, the solid buffering reagent may include alginic acid, ascorbic acid, citric acid, malic acid, succinic acid, and tartaric acid, which may be provided in the formulations at different ratios at a concentration of from about 0.01% to about 10% Lt; / RTI > Preferably, the buffering reagent is citric acid which may be provided at a concentration of from about 0.01% to about 10%, more preferably from 0.1% to 5%, and most preferably about 2.0% by weight of the solid formulation.

For example, if the biologically active material in the solid dosage form is sildenafil, the molecular structure of sildenafil has both a weak acid center and a weak acid center. This is because the solubility of sildenafil in water is affected by the solution pH value and the two optimum pH values (pHmax) are 4.5 and 10.24. Thus, to improve the transmucosal absorption of sildenafil, the solid dosage form may comprise a solid buffering reagent that when salvaged in the mouth produces saliva at a pH of from 5.0 to 6.0. Increasing the pH of a solution of sildenafil can reduce the ratio of nonionized to ionized particles, which will result in enhanced transmucosal absorption.

Preferably, the buffering reagent is present at a concentration of about 0.01% to about 10%, more preferably 0.1% to 1%, most preferably about 0.3% or 0.5% by weight of the solid dosage form It is sodium carbonate, which can be provided.

Solid formulations may, in certain embodiments, comprise at least one absorption enhancer. The absorption enhancer may be a polysaccharide and may be positively charged. Preferably, the absorption enhancer is? -Cyclodextrin or a derivative thereof. The? -cyclodextrin or derivative may be provided in an amount of from about 0.01% to about 10%, preferably from 0.2% to 2%, and most preferably about 1% by dry weight of the formulation. Alternatively, the at least one absorption enhancer may comprise glyceryl trinitrate (also known as GTN or nitroglycerine) or derivatives thereof. The glyceryl trinitrate or derivative may be provided in a concentration of from about 0.01% to about 20%, more preferably from 0.2% to 4%, and most preferably about 2% by dry weight of the formulation.

The solid dosage forms of the present invention may include a precipitant to maintain uniform consumption of the biologically active material in the matrix during the manufacturing process. The precipitant may be a gum. It is the preferred black xanthan gum. The xanthan gum may be provided at a dry weight of the solid formulation of from about 0.01% to about 10%, preferably from about 0.2% to 2%, and most preferably about 1%.

In another preferred embodiment, the solid dosage form comprises at least one surfactant. To aid dissolution of a biologically active substance into an aqueous environment, such as the mouth, a surfactant may be added to the solution as a wetting agent. Suitable surfactants include anionic detergents such as sodium lauryl sulfate, sodium dioctyl sulfosuccinate, and sodium dioctyl sulfonate. Cationic detergents are used, which may include sodium in benzalkonium chloride or benzene chloride. A list of possible non-ionic detergents includes LauroMegro Goalt 400, Polyoxyl 40 Stearate, Polyoxyethylene hydrogenated castor oil 10,50 and 60, Glycerol monostearate, Polysorbate 40,60,65 and 80, Sucrose fatty acid esters, methylcellulose, and carboxymethylcellulose. These surfactants may be provided in formulations either alone or as a mixture of different ratios. Preferably, the surfactant assists in making the ready-to-use solid dosage form.

Additives that potentially enhance absorption of the biologically active material may also be provided in the solid dosage form. Such additives may be selected from the list comprising fatty acids such as oleic acid, linoleic acid and linolenic acid.

To enhance the aesthetic and tasteful appeal of the solid dosage form to a subject, the formulation may also contain at least one additive, such as a coloring or flavoring agent. The colorant may preferably be FD & C dye Blue No. 2 and Red 40; Flavoring agents may be selected from orange, mint, raspberry and caramel, and / or sweeteners such as aspartame and saccharin or mixtures of two or more flavors.

Thus, in a highly preferred embodiment, the present invention provides a solid dosage form suitable for release of a biologically active substance in the oral cavity,

(a) at least one biologically active substance and

(b) at least one substrate former,

The formulation is substantially dissolved in the oral cavity; The formulation contained 0.29% sodium carbonate, 0.59% carboxymethylcellulose sodium, 1.48% PEG 2000, 2.97% glycine, 5.93% microcrystalline cellulose as the dry weight of the solid formulation; 14.84% amylopectin, 29.67% lactose and 44.23% mannitol; Does not result in a substantially detectable level of residue remaining throughout the patient ' s mouth. Preferably, the solid dosage form is a ready-to-use solid dosage form. PEG 2000 could be replaced by PEG 1000, which has the same advantages as the oral formulation described above.

Preferably, the biologically active material in the solid dosage form of the invention comprises at least one cyclic guanosine monophosphate (cGMP) phosphodiesterase type 5 (PDE5) inhibitor, at least one active substance that binds to an adrenergic receptor, And N-methyl-D-aspartate receptor antagonists. Preferably, the N-methyl-D-aspartate receptor antagonist is selected from the list comprising dextromethorphan, dextrorphan or ketamine. Preferably, the active substance that binds to one or more of the adrenergic receptors is an adrenaline or an adrenergic salt. Preferably, the cyclic guanosine monophosphate (cGMP) phosphodiesterase type 5 (PDE5) inhibitor is sildenafil or a pharmaceutically acceptable salt thereof. Preferably, the sildenafil salt is sildenafil citrate.

담체 및 부형제

Carrier and excipient

As discussed above, the solid formulations of the present invention may comprise one or more pharmaceutically acceptable carriers. The use of such pharmaceutically acceptable carriers for the manufacture of a medicament, such as a solid dosage form, comprising the fastidious solid dosage form is well known in the art. Except for any conventional pharmaceutically acceptable carrier, its use in the manufacture of solid dosage forms according to the present invention is contemplated.

Pharmaceutically acceptable carriers according to the present invention may include one or more of the following examples:

(1) a polymeric material such as polyethylene glycol (PEG), polyvinylpyrrolidone, polyvinyl alcohol, crospovidone, polyvinylpyrrolidone-polyvinyl acrylate copolymer, cellulose derivative, hydroxypropyl methylcellulose, , Carboxymethylethylcellulose, hydroxypropylmethylcellulose phthalate, polyacrylates and polymethacrylates, ureas, sugars, polyols and polymers thereof, emulsifiers, sugar gums, starches, organic acids and their salts, vinyls Surfactants and polymers including, but not limited to, pyrrolidone and vinyl acetate; And / or

(2) binders such as various celluloses and crosslinked polyvinylpyrrolidones, microcrystalline cellulose; And / or

(3) fillers such as lactose monohydrate, lactose anhydride, mannitol, microcrystalline cellulose and various starches; And / or

(4) agents that act on the fluidity of the powder to be extruded, including lubricants such as colloidal silicon dioxide, talc, stearic acid, magnesium stearate, calcium stearate, silica gel; And / or

(5) any natural or artificial sweetener including sweeteners such as sucrose, xylitol, sodium saccharin, cyclamate, asphaltene and acesulfame K; And / or

(6) a flavoring agent; And / or

(7) Preservatives such as potassium sorbate, methylparaben, propylparaben, benzoic acid and its salts, other esters of parahydroxybenzoic acid such as butylparaben, alcohols such as ethyl or benzyl alcohol, phenolic chemicals such as phenol ) Or a quaternary compound (e.g., benzalkonium chloride); Antioxidants such as ascorbic acid, potassium sorbate, sodium hydrogen sulfate sodium metabisulfite and sorbic acid; And / or

(8) Buffering agents; And / or

(9) a diluent such as a pharmaceutically acceptable inert filler such as microcrystalline cellulose, lactose, dibasic calcium phosphate, saccharide and / or any mixture of the foregoing; And / or

(10) wetting agents such as corn starch, potato starch, maize starch, and modified starch, croscarmellose sodium, crospovidone, sodium starch glycolate and mixtures thereof; And / or

(11) disintegrating; And / or

(12) Foaming agents such as foaming agents such as effervescent couple such as organic acids such as citric acid, tartaric acid, malonic acid, fumaric acid, adipic acid, succinic acid and alginic acid and anhydrides and acid salts, For example, sodium carbonate, potassium carbonate, magnesium carbonate, sodium glycine carbonate, L-lysine carbonate and alkaline carbonates) or bicarbonates (for example sodium bicarbonate or potassium bicarbonate);

(13) absorption enhancers such as glyceryl trinitrate; And / or

(14) Other pharmaceutically acceptable excipients.

In other embodiments, more than one biologically active material may be combined into a solid dosage form of the present invention. In one example, if the biologically active material is adrenaline, a readily available solid formulation can be achieved that provides different release characteristics-release from adrenaline initially, and subsequent release from larger average-sized adrenaline.

Solid formulations of the present invention suitable for use in animals and especially humans are typically sterile and must be stable under the conditions of manufacture and storage. Solid formulations of the invention comprising biologically active materials can be formulated as solid, liposomes or other ordered structures suitable for high drug concentrations suitable for oral delivery.

The actual dosage strength of the biologically active material in the solid dosage form of the present invention may vary depending on the nature of the biologically active material as well as the potential increased efficacy due to the benefit of providing and administering the biologically active material. Thus, a "therapeutically effective amount " as used herein will refer to the amount of biologically active material required to achieve a therapeutic response in a subject. An amount effective for such use will depend on the intended therapeutic effect; The efficacy of biologically active substances; The duration for the purpose of treatment; The stage and severity of the disease being treated; Weight and general health status of the patient; And the judgment of the attending physician.

For example, if adrenaline is a biologically active substance in the solid dosage forms of the present invention, the actual dosage strength of adrenaline may be a potential < RTI ID = 0.0 > anti-allergic / anti- Lt; / RTI >

The solid dosage forms of the invention are administered orally to the subject. Solid dosage forms for oral administration include wafers, capsules, tablets, pills, powders, pellets, films, and granules. Preferably, the solid dosage form is administered sublingually. Preferably, the solid dosage form is a ready-to-use solid dosage form.

The inclusion of any normally used excipients such as those listed above and generally 0.1% to 95% of the biologically active material, and more preferably 0.1% to 75% of the material, is pharmaceutically acceptable for oral administration Lt; RTI ID = 0.0 > non-toxic solid < / RTI >

The solid dosage forms of the present invention may be used in wafers, tablets, capsules; pill; powder; Pellets; Granules; Or film, the oral formulations of the present invention will also include solid formulations that are suitable for use with a nebulizer as one of the injections or supersonic waves, and typically suspended in water. The formulations of the present invention may also include buffers and simple sugars (for example, for protein stabilization and control of osmotic pressure). The nebulizer formulation may also contain a surfactant to reduce or prevent surface-induced aggregation of the compound caused by atomization of the solution in forming the aerosol. Preferably, the solid dosage form is a ready-to-use solid dosage form.

Nebulized solid formulations should preferably not leave residues of the formulation detectable by the patient in the mouth. Rapidly dissolving biologically active materials in nebulized formulations must be rapidly absorbed through the oral mucosa and into the systemic blood circulation system by diffusion.

According to another aspect of the present invention there is provided a solid dosage form suitable for the release of an active substance that binds to one or more adrenergic receptors in the oral cavity,

(a) an active substance that binds to one or more adrenergic receptors, and

(b) at least one substrate former,

The formulation is substantially soluble in the oral cavity. Preferably, the solid dosage form is a ready-to-use solid dosage form. Preferably, the active substance that binds to one or more of the adrenergic receptors is an adrenaline or an adrenergic salt. Alternatively, the adrenaline may be adrenergic, such as norepinephrine, isoprenaline; Or sympathetic stimulants such as tyramine, ephedrine, pseudoephedrine, amphetamine, salbutamol, and terbutaline.

In one embodiment, the active substance binding to one or more adrenergic receptors, such as adrenaline, is present in an amount of 0.01 to 95%; 0.1 to 75% and 1 to 45% by weight of the solid formulation.

In another embodiment,

(a) 0.01 to 95 (dry) wt.% active substance binding to one or more adrenergic receptors;

(b) amylopectin 2 to 17% (dry) wt%;

(c) at least one substrate former 0.01 to 50) (dry) wt%;

(d) filler 0.01 to 40 (dry) wt%;

(e) 0.01 to 10 (dry) weight% amino acid; And

(f) Glycol / surfactant 0.01 to 20 (dry) weight%

(g) Carbohydrate 0.01 to 60 (dry) wt%;

(h) 0.1 to 1 (dry) weight% solid buffering reagent;

(i) 0.01 to 20 (dry) weight% of an absorption enhancer.

In a highly preferred embodiment, the invention provides a solid dosage form suitable for the release of an active substance, such as adrenaline, binding to one or more adrenergic receptors in the oral cavity,

(a) an active substance that binds to one or more adrenergic receptors; And

(b) at least one substrate former,

The formulation is substantially dissolved in the mouth, the formulation comprising 0.25% sodium carbonate, 0.50% carboxymethylcellulose sodium, 1.25% PEG 2000, 2.49% glycine, 2.49% microcrystalline cellulose as the dry weight of the solid formulation; 12.49% amylopectin, 24.98% lactose, 2.00% glyceryl trinitrate, and 37.46% mannitol, which do not result in a substantially detectable level of residue remaining throughout the patient's mouth. Preferably, the solid dosage form is a ready-to-use solid dosage form.

In another embodiment, the formulation comprises 5 mg; 10 mg; 15 mg; 20 mg; 25 mg; 30 mg; Such as adrenaline, which binds to at least one adrenergic receptor selected from the group consisting of 35 mg, 40 mg, 45 mg, 50 mg, 60 mg and 100 mg.

According to another aspect of the present invention there is provided a solid dosage form suitable for the release of at least one cyclic guanosine monophosphate (cGMP) phosphodiesterase type 5 (PDE5) inhibitor in the mouth,

(a) at least one cyclic guanosine monophosphate (cGMP) phosphodiesterase type 5 (PDE5) inhibitor, and

(b) at least one substrate former,

The formulation is substantially soluble in the oral cavity. Preferably, the solid dosage form is a ready-to-use solid dosage form. Preferably, the cyclic guanosine monophosphate (cGMP) phosphodiesterase type 5 (PDE5) inhibitor is sildenafil or a pharmaceutically acceptable salt thereof. Preferably, the sildenafil salt is sildenafil citrate.

In one embodiment, the at least one cyclic guanosine monophosphate (cGMP) phosphodiesterase type 5 (PDE5) inhibitor is present in an amount of 0.01 to 95%; 0.1 to 75% and 1 to 45% by weight of the solid formulation.

In another embodiment,

(a) at least one cyclic guanosine monophosphate (cGMP) 0.01 to 95 (dry)% by weight of phosphodiester 5 type (PDE5) inhibitor;

(b) amylopectin 2 to 17% (dry) wt%;

(c) at least one substrate former 0.01 to 50) (dry) wt%;

(d) filler 0.01 to 40 (dry) wt%;

(e) 0.01 to 10 (dry) weight% amino acid; And

(f) Glycol / surfactant 0.01 to 20 (dry) weight%

(g) Carbohydrate 0.01 to 60 (dry) wt%;

(h) 0.1 to 1 (dry) weight% solid buffering reagent;

(i) 0.01 to 20 (dry) weight% of an absorption enhancer.

In a highly preferred embodiment, the present invention provides a solid dosage form suitable for the release of at least one cyclic guanosine monophosphate (cGMP) phosphodiesterase type 5 (PDE5) inhibitor in the oral cavity,

(a) at least one cyclic guanosine monophosphate (cGMP) phosphodiester 5 type (PDE5) inhibitor; And

(b) at least one substrate former,

The formulation is substantially dissolved in the mouth, the formulation comprising 0.29% sodium carbonate, 0.59% carboxymethylcellulose sodium, 1.48% PEG 2000, 2.97% glycine, 5.93% microcrystalline cellulose as dry weight of the solid formulation; 14.84% amylopectin, 29.67% lactose, and 44.23% mannitol, which do not result in a substantially detectable level of residue remaining throughout the patient's mouth. Preferably, the solid dosage form is a ready-to-use solid dosage form.

In another embodiment, the formulation comprises 5 mg; 10 mg; 15 mg; 20 mg; 25 mg; 30 mg; (CGMP) phosphodiesterase type 5 (PDE5) inhibitor selected from the group consisting of L-carnitine, L-carnitine, L-carnitine, .

According to another aspect of the present invention there is provided a solid dosage form suitable for the release of an N-methyl-D-aspartate receptor antagonist in the mouth,

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

(b) at least one substrate former,

The formulation is substantially soluble in the oral cavity. Preferably, the solid dosage form is a ready-to-use solid dosage form. Preferably, the N-methyl-D-aspartate receptor antagonist is selected from the list comprising dextromethorphan, dextrorphan or ketamine.

In one embodiment, the N-methyl-D-aspartate receptor antagonist is 0.01 to 95%; 0.1 to 75% and 1 to 45% by weight of the solid formulation.

In another embodiment,

(a) 0.01 to 95 (dry) wt% N-methyl-D-aspartate receptor antagonist;

(b) amylopectin 2 to 17% (dry) wt%;

(c) at least one substrate former 0.01 to 50) (dry) wt%;

(d) filler 0.01 to 40 (dry) wt%;

(e) 0.01 to 10 (dry) weight% amino acid; And

(f) Glycol / surfactant 0.01 to 20 (dry) weight%

(g) Carbohydrate 0.01 to 60 (dry) wt%;

(h) 0.1 to 1 (dry) weight% solid buffering reagent;

(i) 0.01 to 20 (dry) weight% of an absorption enhancer.

In a highly preferred embodiment, the present invention provides a solid dosage form suitable for the release of an N-methyl-D-aspartate receptor antagonist in the mouth,

(a) an N-methyl-D-aspartate receptor antagonist; And

(b) at least one substrate former,

The formulation is substantially dissolved in the mouth, the formulation comprising 0.25% sodium carbonate, 0.50% carboxymethylcellulose sodium, 1.25% PEG 2000, 2.49% glycine, 2.49% microcrystalline cellulose as the dry weight of the solid formulation; 12.49% amylopectin, 24.98% lactose, and 37.46% mannitol, which do not result in a substantially detectable level of residue remaining throughout the patient's mouth. Preferably, the solid dosage form is a ready-to-use solid dosage form.

In another embodiment, the formulation comprises 5 mg; 10 mg; 15 mg; 20 mg; 25 mg; 30 mg; D-aspartate receptor antagonist selected from the group consisting of 35 mg, 40 mg, 45 mg, 50 mg, 60 mg and 100 mg.

In another embodiment, solid formulations provide reduced burning sensation, irritation and / or discomfort during administration and / or swallowing compared to traditional formulations.

In another embodiment, the formulation is suitable for delivery through the oral mucosa and into the systemic blood circulation system.

According to another aspect of the present invention, there is provided a wafer comprising a solid formulation suitable for release of a biologically active material in the oral cavity. Preferably, the solid formulation wafers are ready-to-use solid formulation wafers. Preferably, the biologically active material comprises at least one cyclic guanosine monophosphate (cGMP) phosphodysterase type 5 (PDE5) inhibitor, at least one active substance that binds to an adrenergic receptor, and an N-methyl- D-aspartate receptor antagonists. Preferably, the N-methyl-D-aspartate receptor antagonist is selected from the list comprising dextromethorphan, dextrorphan or ketamine. Preferably, the cyclic guanosine monophosphate (cGMP) phosphodiesterase type 5 (PDE5) inhibitor is sildenafil or a pharmaceutically acceptable salt thereof. Preferably, the sildenafil salt is sildenafil citrate. Preferably, the active substance that binds to one or more of the adrenergic receptors is an adrenaline or an adrenergic salt. The wafer may carry its instructions for use.

Preferably, the solid formulation wafers, once placed in the oral cavity, will 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 seconds. Preferably, the solid formulation wafers are ready-to-use solid formulation wafers.

More preferably, the solid formulation wafers, once placed in the mouth, are less than 2 minutes after administration of the formulation; 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. Preferably, the solid formulation wafers are ready-to-use solid formulation wafers.

A further aspect of the present invention provides a solid formulation wafer according to the invention wherein the formulation is substantially soluble in the oral cavity without leaving a residue of the formulation detectable by the object in the mouth. Preferably, the solid formulation wafers are completely dissolved in the patient after oral administration, preferably sublingually. Thus, the subject is not required to swallow the wafer formulation, and thus the biologically active material bypasses the gastrointestinal and hepatic first-pass effects and is absorbed directly into the systemic circulating blood. Preferably, the solid formulation wafers are ready-to-use solid formulation wafers.

Pharmaceutical composition

The present invention also provides pharmaceutical compositions comprising the solid dosage forms of the present invention. Preferably, the solid dosage form is a ready-to-use solid dosage form.

The pharmaceutical compositions of the present invention may be formulated to contain conventional additives or supplemental ingredients in conventional amounts of these materials. The composition may be in the form of solid, liposomes or other ordered structures suitable for high drug concentrations suitable for oral delivery. Preferably, the pharmaceutical composition is formulated to dissolve rapidly in an oral environment.

The composition may, in one embodiment, be formulated to be substantially free of preservative, physiological or mucosal absorption enhancer or propellant. The compositions may, in an alternative embodiment, be formulated to contain a preservative, a physiological or mucosal absorption enhancer or a propellant.

Way

According to a further aspect of the present invention,

a) combining at least one substrate former with a biologically active material to form a mixture; And

and b) lyophilizing the mixture to form a solid dosage form.

Preferably, the solid dosage form is a ready-to-use solid dosage form.

In addition:

a) combining at least one substrate former with an active agent that binds to at least one adrenergic receptor to form a homogeneous mixture; And

b) freeze-drying the mixture to form a solid dosage form.

Preferably, the solid dosage form is a ready-to-use solid dosage form.

In addition:

a) combining at least one substrate former with at least one cyclic guanosine monophosphate (cGMP) phosphodiesterase type 5 (PDE5) inhibitor to form a homogeneous mixture; And

b) freeze-drying the mixture to form a solid dosage form.

c) Preferably, the solid dosage form is a ready-to-use solid dosage form.

Also provided is a method of producing a solid dosage form of the invention comprising the steps of:

a) combining at least one substrate former with an N-methyl-D-aspartate receptor antagonist to form a homogeneous mixture; And

b) lyophilizing the mixture to form a solid dosage form.

Preferably, the solid dosage form is a ready-to-use solid dosage form.

Preferably, the method provides an oral solid dosage form wherein the formulation is substantially soluble in the oral cavity without leaving a residue of the formulation detectable by the subject in the mouth. Preferably, the solid dosage form is a ready-to-use solid dosage form.

Preferably, the method according to the present invention is administered after the administration, once in the oral cavity, 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 5 seconds, less than 4 seconds, less than 3 seconds, less than 2 seconds.

More preferably, the solid dosage form, after administration of the formulation, is less than 2 minutes once placed in the oral cavity; 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; 3 seconds; And less than 2 seconds.

In a preferred embodiment of the invention, the mixture comprising the matrix forming agent and the biologically active substance is measured (by weight or volume) into a preformed plastic or aluminum blister mold (individual volume). The blister mold is placed in a freeze dryer for 24 hours, and the resulting ready-to-use solid formulation is then sealed with an aluminum or plastic foil to prevent moisture absorption. Preferably, the freeze drying technique is used to remove the solvent from the blister mold. Sealing a solid dosage form into a plastic or aluminum foil prevents or reduces moisture absorption.

Preferably, the method of the invention forms a solid dosage form that is a wafer. Preferably, the solid formulation wafers are ready-to-use solid formulation wafers.

In one embodiment of the invention, the process may require the pH of the mixture to be adjusted to a pH in the range of 3.0 to 8.0, preferably 6.4 to 7.8. If necessary, the pH can be adjusted with an acid such as hydrochloric acid, phosphoric acid or citric acid; Or by using basic compounds such as sodium hydroxide, sodium dihydrogenphosphate, sodium hydrogenphosphate, sodium hydrogen carbonate and sodium carbonate.

In another embodiment, the method may comprise using a solvent such as water. If water is used as the solvent, it may be desirable to be removed by freeze drying.

Kit

The present invention also provides a kit comprising the solid formulation of the present invention and instructions for its use.

In a further aspect of the invention,

a) a solid formulation, and

b) a kit containing its instructions for use is provided,

The formulation comprises:

(i) at least one biologically active substance, and

(ii) at least one substrate former,

The formulation is substantially soluble in the oral cavity. Preferably, the solid dosage form is a ready-to-use solid dosage form.

Preferably, the biologically active material comprises at least one cyclic guanosine monophosphate (cGMP) phosphodysterase type 5 (PDE5) inhibitor, at least one adrenergic receptor binding substance, and N-methyl-D - aspartate receptor antagonist. Preferably, the N-methyl-D-aspartate receptor antagonist is selected from the list comprising dextromethorphan, dextrorphan or ketamine. Preferably, the active substance that binds to one or more of the adrenergic receptors is an adrenaline or an adrenergic salt. Preferably, the cyclic guanosine monophosphate (cGMP) phosphodiesterase type 5 (PDE5) inhibitor is sildenafil or a pharmaceutically acceptable salt thereof. Preferably, the sildenafil salt is sildenafil citrate.

Treatment method

Therapeutic uses of the solid dosage forms of the invention include the treatment of pain relief, anti-inflammatory activity, migraine treatment, asthma treatment and other disorders requiring biologically active substances to be administered using high bioavailability and rapid activity .

The invention provides a method of treating a disease or disorder in a patient comprising administering to the patient a pharmaceutical composition comprising a solid dosage form of the invention. Preferably, the solid dosage form is a ready-to-use solid dosage form.

One of the main areas when rapid bioavailability of biologically active materials is needed is relief of pain. Ancillary analgesics such as cyclo-oxygenase inhibitors (aspirin-related drugs) or opioids may be prepared as medicaments according to the present invention. Alternatively, N-methyl-D-aspartate receptor antagonists can be used for pain relief and anesthesia. Preferably, the N-methyl-D-aspartate receptor antagonist is selected from the list comprising dextromethorphan, dextrorphan or ketamine. N-methyl-D-aspartate receptor antagonists may be administered for the purpose of depression treatment, addiction treatment.

Accordingly, the present invention provides a method for providing pain relief comprising the step of administering to a patient a pharmaceutical composition comprising a solid dosage form of the invention comprising an N-methyl-D-aspartate receptor antagonist.

The present invention provides a method for providing anesthesia comprising administering to a patient a pharmaceutical composition comprising a solid dosage form of the invention comprising an N-methyl-D-aspartate receptor antagonist. Preferably, the N-methyl-D-aspartate receptor antagonist is selected from the list comprising dextromethorphan, dextrorphan or ketamine.

The present invention also provides a method of treating depression, comprising the step of administering to a patient a pharmaceutical composition comprising a solid dosage form of the invention comprising an N-methyl-D-aspartate receptor antagonist. Preferably, the N-methyl-D-aspartate receptor antagonist is selected from the list comprising dextromethorphan, dextrorphan or ketamine.

The present invention also provides a method of treating addiction comprising administering to a patient a pharmaceutical composition comprising a solid dosage form of the invention comprising an N-methyl-D-aspartate receptor antagonist. Preferably, the N-methyl-D-aspartate receptor antagonist is selected from the list comprising dextromethorphan, dextrorphan or ketamine.

N-methyl-D-aspartate receptor antagonists may also be administered for the purpose of treating interstitial seizures. In one embodiment, epileptic seizures are caused by epilepsy. In a further embodiment, the epilepsy is selected from the group consisting of benign Rolandic epilepsy, frontal lobe epilepsy, infantile spasms, juvenile myelosuppressive epilepsy, juvenile dysentery epilepsy, epileptic seizure epilepsy (peak no-lepse), high temperature epilepsy, Lennox- Syndrome, Dravet syndrome, progressive myofascial epilepsy, reflex epilepsy, Rasmussen syndrome, temporal lobe epilepsy, limbic epilepsy, epileptic seizure, abdominal epilepsy, , And photosensitive epilepsy. In a further embodiment, the epileptic seizure is selected from the group consisting of non-convulsive epilepsy persistence and spastic epilepsy persistence.

Accordingly, the present invention provides a method of treating an epileptic seizure comprising administering to a patient a pharmaceutical composition comprising a solid formulation of the invention comprising an N-methyl-D-aspartate receptor antagonist. Preferably, the N-methyl-D-aspartate receptor antagonist is selected from the list comprising dextromethorphan, dextrorphan or ketamine.

The treatment of cardiovascular diseases, such as the treatment of angina, may also benefit from the biologically active substances in the solid dosage forms according to the invention, and in particular, the molocidins may benefit from improved bioavailability. In another example, adrenaline may be administered as a solid dosage form for the treatment of acute cardiovascular events such as cardiac arrest or arrhythmia. Alternatively, other active agents that bind to one or more adrenergic receptors such as noradrenaline may be used as solid formulations for the treatment of cardiovascular events.

Other therapeutic uses for biologically active substances in solid dosage forms according to the present invention include the treatment of hair loss, sexual dysfunction or psoriasis. If the solid formulation of the present invention is used to treat sexual dysfunction, the formulation preferably contains a cyclic guanosine monophosphate (cGMP) phosphodiesterase type 5 (PDE5) inhibitor. Preferably, the cyclic guanosine monophosphate (cGMP) phosphodiesterase type 5 (PDE5) inhibitor is sildenafil or a pharmaceutically acceptable salt thereof. Preferably, the sildenafil salt is sildenafil citrate.

Accordingly, the present invention comprises a method of treating a patient comprising administering to a patient a pharmaceutical composition comprising a solid formulation of the invention comprising at least one cyclic guanosine monophosphate (cGMP) phosphodiesterase type 5 (PDE5) inhibitor , And methods for treating sexual dysfunction. Preferably, the cyclic guanosine monophosphate (cGMP) phosphodiesterase type 5 (PDE5) inhibitor is sildenafil or a pharmaceutically acceptable salt thereof. Preferably, the sildenafil salt is sildenafil citrate.

A further use for the solid dosage form of the invention comprising cyclophosphate (cGMP) phosphodiester 5 type (PDE5) inhibitors is the treatment of pulmonary hypertension. Preferably, the cyclic guanosine monophosphate (cGMP) phosphodiesterase type 5 (PDE5) inhibitor is sildenafil or a pharmaceutically acceptable salt thereof. Preferably, the sildenafil salt is sildenafil citrate.

Accordingly, the present invention comprises a method of treating a patient comprising administering to a patient a pharmaceutical composition comprising a solid formulation of the invention comprising at least one cyclic guanosine monophosphate (cGMP) phosphodiesterase type 5 (PDE5) inhibitor , And methods of treating pulmonary hypertension. Preferably, the cyclic guanosine monophosphate (cGMP) phosphodiesterase type 5 (PDE5) inhibitor is sildenafil or a pharmaceutically acceptable salt thereof. Preferably, the sildenafil salt is sildenafil citrate.

Additional therapeutic uses for biologically active substances in solid formulations according to the present invention include allergy relief and hypersensitivity treatment. Such disorders benefit from rapid absorption of biologically active substances such as adrenaline and other active substances that bind to one or more adrenergic receptors.

Accordingly, the present invention provides a method of treating hypersensitivity comprising administering to a patient a pharmaceutical composition comprising a solid formulation of the invention comprising an active substance that binds to one or more adrenergic receptors. The present invention further provides a method of treating an allergic reaction comprising administering to a patient a pharmaceutical composition comprising a solid formulation of the invention comprising an active substance that binds to one or more adrenergic receptors. Preferably, the active substance that binds to one or more of the adrenergic receptors is an adrenaline or an adrenergic salt.

Preferably, the method of treatment comprises administering to the patient a solid dosage form of the invention, wherein the dosage form is administered sublingually. Preferably, the solid dosage form is a ready-to-use solid dosage form.

투여

administration

The solid dosage forms of the present invention are suitable for oral administration to a subject. As discussed above, the formulations comprise at least one biologically active material. Thus, the biologically active material is delivered to the subject through the oral mucosa and into the systemic circulation within a relatively short period of time. Preferably, the solid dosage form is a ready-to-use solid dosage form.

In a preferred embodiment, the effective plasma concentration of the biologically active substance is reached within a period of less than 2 hours, preferably within 30 minutes, 20 minutes, 15 minutes or 15 minutes. Most preferably, the effective plasma concentration of the biologically active substance is reached within a period of 10 minutes, 9 minutes, 8 minutes, 7 minutes, 6 minutes, 5 minutes, 4 minutes, 3 minutes or 2 minutes. For example, the solid dosage forms of the invention in the form of sublingual fentanyl wafers may result in detectable plasma fentanyl occurring within 2 to 10 minutes after administration, most often within 5 minutes. In another example, adrenaline may be therapeutic within 5 minutes of the solid formulation of the present invention; The sildenafil solid dosage form is within 20 minutes, and the ketamine-soluble solid dosage form can be therapeutic within 10 minutes.

In another embodiment, the formulation comprises 25 ng / ml; 30 ng / ml; 40 ng / ml; 50 ng / ml; 60ng / ml; 70 ng / ml; 80 ng / ml; 90ng / ml; 100 ng / ml; 110 ng / ml; 120 ng / ml; 130 ng / ml; 140 ng / ml; 150 ng / ml; 160 ng / ml; 170 ng / ml; 180 ng / ml; 190 ng / ml; And biologically selected from the group consisting of 200ng / ㎖ provides the patient with a maximum plasma concentration (C _max) of the active substance.

In comparison to intravenous injection, the solid dosage forms of the invention in the form of sublingual wafers can produce much lower C _max , which can reduce the toxicity of the biologically active material being administered. For example, in an I-phase sublingual fentanyl wafer clinical trial, the C _max of the 100 μg fentanyl intravenous infusion (5 min) was 1451.0 pg / ml, but the C _max of the 100 μg fentanyl wafer was only 219.3 pg / ml. Similarly, in a Phase I subcutaneous ketamine wafer clinical trial, the _Cmax of 10 mg ketamine intravenous infusion (30 min) was 128.1 ng / ml while the _Cmax of 25 mg ketamine wafers was 71.1 ng / ml.

In another embodiment, the solid dosage form comprises 5 minutes to 90 minutes; 10 minutes to 75 minutes; 15 to 60 minutes; 30 minutes to 50 minutes; 40 to 50 minutes; And 45 min. &_Lt; / RTI > For example, the T _max of a 25 mg ketamine wafer of the solid formulation of the present invention can be 45 minutes.

In a highly preferred embodiment, the formulation is administered within 15 minutes; Within 14 minutes; Within 13 minutes; Within 12 minutes; Within 11 minutes; Within 10 minutes; Within 9 minutes; Within 8 minutes; Within 7 minutes; Within 6 minutes; Within 5 minutes; Within 4 minutes; Within 3 minutes; Within 2 minutes; And within one minute, the first detectable plasma concentration of the biologically active material. For example, after sublingual administration with the formulations of the present invention, the first detectable plasma concentration can be observed from 2 minutes to 10 minutes after administration.

Preferably, the formulation comprises 10 to 60%; 20 to 40%; 25 to 35%; 28 to 30%; ≪ / RTI > and 28% of the biologically active material in the patient. For example, solid dosage forms may provide median bioavailability of N-methyl-D-aspartate receptor antagonists in 28% of patients, with the antagonistic dose being 25 mg. Solid formulations can also provide a median bioavailability of 29% of sublingual ketamine, with an antagonistic dose of 25 mg.

In other embodiments, the solid dosage forms may contain more than 30 minutes, 30 minutes, 25 to 30 minutes, 20 to 25 minutes, 15 to 20 minutes, 10 to 15 minutes, 10 minutes, 9 minutes, 8 minutes, 7 minutes, 5 minutes, 4 minutes, 3 minutes, or more than 2 minutes. ≪ / RTI >

The subject receiving the solid dosage form of the present invention may be an animal or a human. When the subject is a human, the subject may be an adult or a child, including an elderly and an infant. In particular, the subject may be a subject that is unable to swallow or difficult to swallow.

It has surprisingly been found that the addition of carboxymethylcellulose sodium improves the dissolution rate of the solid dosage form. When the amount of carboxymethylcellulose sodium is 0.1% to 15% by dry weight of the formulation, the formulation rapidly releases the active agent without leaving residue in the mouth. In addition, the use of gelatin was avoided, so that little or no unwanted residue remained in the mouth after administration. The addition of lactose and / or mannitol is also advantageous in the solid dosage forms of the present invention.

Usage

Also provided is the use of a solid dosage form suitable for the release of a biologically active substance in the oral cavity, wherein the formulation in the manufacture of a medicament for treating a disease or disorder,

(a) at least one biologically active substance, and

(b) at least one substrate former, wherein the formulation is substantially soluble in the oral cavity.

Preferably, the solid dosage form is a ready-to-use solid dosage form.

Preferably, the biologically active material comprises at least one cyclic guanosine monophosphate (cGMP) phosphodysterase type 5 (PDE5) inhibitor, at least one adrenergic receptor binding substance, and N-methyl-D - aspartate receptor antagonist. Preferably, the N-methyl-D-aspartate receptor antagonist is selected from the list comprising dextromethorphan, dextrorphan or ketamine. Preferably, the active substance that binds to at least one adrenergic receptor is adrenaline (epinephrine), or an adrenergic salt. Preferably, the cyclic guanosine monophosphate (cGMP) phosphodiesterase type 5 (PDE5) inhibitor is sildenafil or a pharmaceutically acceptable salt thereof. Preferably, the sildenafil salt is sildenafil citrate.

Preferably the disease or disorder is selected from the group consisting of pain, depression, poisoning, inflammation, migraine, asthma, epilepsy, acute cardiovascular events such as cardiac arrest or arrhythmia, angina pectoris, hair loss, sexual dysfunction, psoriasis, pulmonary hypertension, And the like.

Accordingly, there is provided the use of a solid dosage form suitable for the release of a biologically active substance in the oral cavity, and in the manufacture of a medicament for the treatment of a disease or disorder,

(a) At least one cyclic guanosine monophosphate (cGMP) phosphodiesterase type 5 (PDE5) inhibitor, and

(b) At least one substrate former, wherein the formulation is substantially soluble in the oral cavity.

Preferably, the solid dosage form is a ready-to-use solid dosage form. Preferably the disease or disorder is selected from the list comprising sexual dysfunction, pulmonary hypertension.

For use as a solid dosage form suitable for the release of a biologically active substance in the oral cavity, the formulation in the manufacture of a medicament for the treatment of a disease or disorder,

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

(b) at least one substrate former, wherein the formulation dissolves sublingually in the oral cavity.

Preferably, the solid dosage form is a ready-to-use solid dosage form. Preferably the disease or disorder is selected from the list comprising the provision of pain, depression, poisoning, migraine, epilepsy and anesthesia.

For use as a solid dosage form suitable for the release of a biologically active substance in the oral cavity, the formulation in the manufacture of a medicament for the treatment of a disease or disorder,

(a) an active substance that binds to one or more adrenergic receptors, and

(b) at least one substrate former, wherein the formulation is substantially soluble in the oral cavity.

Preferably, the solid dosage form is a ready-to-use solid dosage form. Preferably the disease or disorder is selected from the list comprising acute cardiovascular events such as cardiac arrest or arrhythmia, angina, allergies or hypersensitivity.

Normal

Those skilled in the art will recognize that the invention described herein is susceptible to variations and modifications other than those specifically described. It is to be understood that the invention includes all such variations and modifications. The present invention also includes all steps, features, compositions and materials, and any and all combinations or any two or more steps or features, individually or collectively referred to or indicated herein.

The present invention is not intended to be limited by the scope of the specific embodiments described herein, but is for the purpose of illustration only. Functionally equivalent products, compositions and methods are within the scope of the invention as described herein.

The invention described herein may include one or more ranges of values (e.g., size, concentration, etc.). Numerical ranges will be understood to include all values within a range that encompasses numerical values that range, and numerical values that are close to ranges that result in the same or substantially the same result as the numerical values immediately adjacent the numerical values.

The entire disclosure of all publications (patents, patent applications, articles, experimental manuals, textbooks or other documents) cited herein are incorporated herein by reference. The inclusion does not constitute an admission that any reference is made to the prior art or is part of the normal general knowledge of the work in the context of the invention.

It will be understood that throughout the present specification, unless the context requires otherwise, the word "comprises" or variations such as "comprises" or "comprising" will be understood to imply inclusion of the stated integer or group of integers, Or a group of integers. Also in this disclosure, it should be noted that in the claims and / or paragraphs, terms such as " comprising, "" including, "" including," For example, they may mean "including," "including," "including," and the like.

A "therapeutically effective amount " as used herein with respect to the method of treatment and at a particular dosage level will refer to the appropriate dosage which provides the specific pharmaceutical response to which the drug is administered in a significant number of subjects in need of such treatment . A "therapeutically effective amount" administered to a particular subject in a particular example is emphasized to be not always effective in treating the disorders described herein, even though such dosage is regarded by the skilled artisan as "therapeutically effective amount & It is to be further understood that the dosage of the drug is measured with reference to the drug level as measured in oral dosage in the specific example or in the blood.

The term "inhibiting" is defined as including its generally accepted meaning, including progress or severity, and inhibiting, preventing, inhibiting and reducing, stopping or reversing such an effect on the resulting symptoms. As such, the present invention encompasses both medical and prophylactic administration, where appropriate.

The term "biologically active material" is defined to mean a biologically active compound, or a material comprising a biologically active compound. In this definition, a compound is generally taken to mean a separate chemical entity in which the chemical formula or chemical formulas may be used to describe the material. However, such compounds generally do not necessarily have to be identified in the literature by a unique class system such as a CAS number. Some compounds can be more complex and have mixed chemical structures. For such compounds, they may have only empirical formulas or may be quantitatively identified. Compounds may generally be pure materials, although up to 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90% of the material is expected to be other impurities and the like. However, examples of biologically active compounds are fungicides, insecticides, herbicides, seed treatment, cosmetic products, cosmetics, complementary medicine, natural products, vitamins, nutrients, health foods, pharmaceutical active agents, biological substances, amino acids, proteins, peptides, But are not limited to, nucleotides, nucleic acids, additives, food and food ingredients and analogs, homologs and primary derivatives thereof. A substance containing a biologically active compound is any substance having a biologically active compound as one of its components. However, examples of materials containing biologically active compounds include pharmaceutical formulations and products, cosmetic formulations and products, industrial formulations and products, agricultural formulations and products, foods, seeds, cocoa and cocoa solids, coffee, herbs, spices, Other plant materials, minerals, animal products, shells, and other scaffold materials.

Any term, "biologically active "," active ", "active material" will have the same meaning as a biologically active material.

"Pharmaceutically acceptable carrier" as used herein includes any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents which are physiologically compatible. Preferably, the carrier is suitable for oral administration.

Brief Description of Drawings

BRIEF DESCRIPTION OF THE DRAWINGS Figure 1 is a scanning electron micrograph of the surface of a wafer of batch (batch) number 071501B and 071502B.

Figure 2 is a scanning electron micrograph of the surface of a wafer from batch numbers 0820A and 0820B.

3 is a scanning electron micrograph of the surface of the wafer from batch number 0905 MD;

4 is a scanning electron micrograph of a cross section of a wafer from batch numbers 071501B and 071502B;

5 is a scanning electron micrograph of a cross section of a wafer from batch numbers 0820A and 0820B.

6 is a scanning electron micrograph of a cross section of a wafer from batch number 0905 MD;

7 shows a powder X-ray diffraction spectrum of a cross section of a wafer from batch numbers 071501A and 071502B;

8 is a graphical illustration of a powder X-ray diffraction spectrum of a cross-section of a wafer from batch numbers 0820A and 0820B;

9 is a diagram showing a powder X-ray diffraction spectrum of a wafer from batch number 0905 MD;

Figure 10 shows a typical HPLC chromatogram (n = 3) of a standard midazolam sample at [a] 4.05 g / ml; [b] Midazolam powder dissolution sample at 1 minute and 5 minutes; [c] 10 minutes dissolution sample of the microcrystalline powder; [d] Midazolam powder dissolution sample 15 min; And [e] a standard midazolam sample at 8.1 [mu] g / ml.

Figure 11 shows a typical HPLC chromatogram of dissolved wafer sample S1 at 45 seconds and 1 minute.

Figure 12 shows a typical HPLC chromatogram of dissolved wafer sample S1 at 10 minutes.

Figure 13 shows a typical HPLC chromatogram of dissolved wafer sample S2 at 5 and 10 minutes.

Figure 14 shows a typical HPLC chromatogram of dissolved wafer sample S2 at 30 seconds and 2 minutes.

Figure 15 shows a typical HPLC chromatogram of dissolved wafer sample S3 at 20 seconds and 1 minute.

Figure 16 shows a typical HPLC chromatogram of a standard midazolam sample at 1.01 [mu] g / ml.

Figure 17 shows a typical HPLC chromatogram of a dissolution sample of a microcrystalline powder at 30 seconds.

Figure 18 shows a typical HPLC chromatogram of dissolution wafer 1 at 1 and 5 minutes.

Figure 19 shows a typical HPLC chromatogram of dissolution wafer 1 at 5, 10 and 15 minutes.

20 shows a typical HPLC chromatogram of a drug loading test wafer sample No. 1;

Figure 21 shows a typical HPLC chromatogram of dissolution wafer 2 in 30 seconds.

Figure 22 shows a typical HPLC chromatogram of dissolution wafer 2 at 1 and 5 minutes.

Figure 23 shows a typical HPLC chromatogram of dissolution wafer 2 at 10, 15 and 30 minutes.

24 shows a typical HPLC chromatogram of a drug loading test wafer sample 2;

Figure 25 shows a typical HPLC chromatogram of dissolution wafer 3 in 30 seconds.

Figure 26 shows a typical HPLC chromatogram of dissolution wafer 3 at 1 and 5 minutes.

Figure 27 shows a typical HPLC chromatogram of dissolution wafer 3 at 10 and 15 minutes.

28 shows a typical HPLC chromatogram of dissolution wafer 3 at 30, 45 and 60 minutes.

Figure 29 shows a typical HPLC chromatogram of drug loading test wafer sample 3;

Figure 30 shows a standard HPLC calibration curve of midazolam (1 to 32.4 g / ml).

31 shows the cumulative concentration of the midazolam released from the wafer and the midazolam powder in the phosphate buffer solution (pH 6.8) at 37 < 0 > C.

Figure 32 shows a standard HPLC calibration curve of fentanyl (0.5-10 mu g / ml).

33 is a drawing (n = 4) showing the dissolution profile of a fentanyl wafer in a phosphate buffer solution (pH 6.8) at 37 ° C.

Figures 34A-34E illustrate typical HPLC chromatograms of dissolving Samples 1-3 of a fentanyl wafer at sampling times of 0.5, 1, 5, 10, 15, and 20 minutes.

Figures 35a-35j illustrate typical HPLC chromatograms of dissolution Samples 4-6 of a fentanyl wafer at 1, 2, 3, 4, 5, 7, and 10 minutes sampling time.

36 is a scanning electron micrograph of a blank ready-to-use formulation;

FIG. 37 is a scanning electron microscope photograph of the surface of the ketamine-soluble preparation. FIG.

Figure 38 shows a powder X-ray diffraction spectrum of a ready-to-blank dosage form.

39 shows a powder X-ray diffraction spectrum of a ketamine powder;

40 is a powder X-ray diffraction spectrum of a ketamine-soluble preparation.

Figure 41 shows a typical HPLC chromatogram of dissolved ketamine wafer sample S2 at 1 minute.

Figure 42 shows a typical HPLC chromatogram of dissolved ketamine wafer sample S2 at 3 minutes.

Figure 43 shows a typical HPLC chromatogram of dissolved ketamine wafer sample S2 at 5 minutes.

Figure 44 shows a typical HPLC chromatogram of dissolved ketamine wafer sample S2 at 7 minutes.

Figure 45 shows a typical HPLC chromatogram of dissolved ketamine wafer sample S2 at 10 minutes.

Figure 46 shows a typical HPLC chromatogram of dissolved ketamine wafer sample S2 at 15 minutes.

Figure 47 shows a typical HPLC chromatogram of dissolved ketamine wafer sample S2 at 20 minutes.

Figure 48 shows a typical HPLC chromatogram of dissolved ketamine wafer sample S2 at 30 minutes.

Figure 49 shows a standard HPLC calibration curve of ketamine hydrochloride (5-100 ug / ml).

Figure 50 shows a typical HPLC chromatogram of a drug loading test ketamine wafer sample No. 1;

51 shows the dissolution profiles of ketamine wafers in a phosphate buffer solution (pH 6.8) at 37 ° C (n = 3).

52 illustrates geometric means by overlapping of individual RS ketamine plasma concentrations over the entire sampling period after a given 10 mg dose for 30 minutes intravenous infusion to 8 healthy volunteers.

53 shows geometric means by overlapping of individual RS ketamine plasma concentrations for the first 12 hours after a given 10 mg dose for 30 minutes intravenous infusion to 8 healthy volunteers.

54 shows geometric means by overlapping of individual RS ketamine plasma concentrations over the entire sampling period after 25 mg of sulphate capacity to 8 healthy volunteers;

Figure 55 shows geometric means by overlapping of individual RS ketamine plasma concentrations for the first 12 hours after a 25 mg sublingual dose to 8 healthy volunteers.

Figure 56 shows individual (S = random number of subjects) t _max for RS ketamine after 25 mg sublingual dose to 8 healthy volunteers.

Figure 57 shows the results of an individual (S = random number of subjects) for RS ketamine after 10 mg dose or 25 mg (SL, filled rod) given for 8 minutes to a healthy volunteer for 30 minutes intravenous infusion (IV, AUC _INF .

Figure 58 shows the clearance (CL) of individual (S = randomized number of subjects) for RS ketamine after a 10 mg dose given for 30 minutes intravenous infusion (IV, empty rod) to 8 healthy volunteers.

Figure 59 shows the effect of each individual (S = random number of subjects) on RS ketamine after 10 mg dose or 25 mg (SL, filled circles) given for 8 minutes to a healthy volunteer for 30 minutes intravenous infusion (IV, view showing the final half-life of t ^_1/2.

Figure 60 shows the individual estimates for all subjects (S = number of subjects) of bioavailability (F)% after administration of 25 mg RS ketamine to 8 healthy volunteers.

61 shows a mood-rating scale for IV administration. The mean (SD) scores for the factors "Boundary" (factor 1), "Satisfaction" (factor 2) and "Serenity" (factor 3) were observed in healthy volunteers after 30 minutes intravenous infusion of 10 mg ketamine.

62 shows a mood scaling scale for sublingual administration; The mean (SD) scores for the factor "boundaries" (factor 1), "satisfaction" (factor 2) and "calmness" (factor 3) were observed in healthy volunteers after sublingual administration of 25 mg ketamine wafers.

FIG. 63 shows the total modified likert scale of the local tolerance; FIG.

64 shows a scanning electron microscope photograph of the surface of a ready-to-blank dosage form.

65 shows a powder X-ray diffraction spectrum of a blank-form soluble formulation;

FIG. 66 is a powder X-ray diffraction spectrum of sildenafil powder. FIG.

67 is a diagram showing a powder X-ray diffraction spectrum of a sildenafil-usable formulation;

Figure 68 shows a typical HPLC chromatogram of dissolved sildenafil wafer sample Sl at 1 minute.

Figure 69 shows a typical HPLC chromatogram of dissolved sildenafil wafer sample Sl at 3 minutes.

Figure 70 shows a typical HPLC chromatogram of dissolved sildenafil wafer sample Sl at 5 minutes.

Figure 71 shows a typical HPLC chromatogram of dissolved sildenafil wafer sample Sl at 7 minutes.

Figure 72 shows a typical HPLC chromatogram of dissolved sildenafil wafer sample Sl at 10 minutes.

Figure 73 shows a typical HPLC chromatogram of dissolved sildenafil wafer sample S1 at 15 minutes.

Figure 74 shows a typical HPLC chromatogram of dissolved sildenafil wafer sample Sl at 20 minutes.

Figure 75 shows a typical HPLC chromatogram of dissolved sildenafil wafer sample Sl at 30 minutes.

76 shows a typical HPLC chromatogram of drug loading test test sildenafil wafer sample No. 1;

Figure 77 shows a standard HPLC calibration curve of sildenafil 5-100 [mu] g / ml).

78 shows the dissolution profile of a sildenafil wafer in phosphate buffer solution (pH 6.8) at 37 ° C (n = 4);

79 is a table showing demographic characteristics of a research applicant according to the fourth embodiment;

80 is a graph showing the mean (± SEM) plasma concentration (pg / ml) over time for sublingual fentanyl water and IV fentanyl; The inset is an extension profile for the initial two hour period.

FIG. 81 is a graph (n = 22) showing plasma concentration data (pg / ml) profiles over time for sublingual fentanyl wafers for each applicant.

82 is a table showing a mean value (+/- 1 SD) of fentanyl plasma pharmacokinetic parameters;

Figure 83 shows a table showing comparative pharmacokinetic data (mean +/- 1 SD) for buccal and sublingual (SL) fentanyl formulations.

Example

The present invention will now be described with reference to the following non-limiting examples. The description of the embodiments is not intended to be limiting in any way to the preceding paragraphs of this specification, but is provided for illustration of the methods and compositions of the present invention.

Example 1

Formulations of the present invention in the form of solid dosage forms (wafers) were prepared according to the methods and ingredients as set forth in Table 1 below:

Quickness  Solid formulation (wafer) formulation ingredient Amount (g) weight% Sodium carbonate BP / USP 10 0.075 Carboxymethylcellulose sodium BP / USP 20 0.149 Polyethylene glycol 2000 BP / USP 50 0.374 Glycine BP / USP 100 0.747 Microcrystalline cellulose BP / USP 200 1.495 Amylopectin BP / USP 500 3.737 Lactose BP / USP 1000 7.474 Mannitol BP / USP 1500 11.211 Purified water BP / USP 10000 74.738

Carboxymethylcellulose sodium and amylopectin were added to some purified water by thorough mixing using a stirrer. The mixture was then heated to 50 DEG C for 10 minutes to dissolve the polymer. Once the solution was cooled to room temperature, polyethylene glycol 2000, glycine, sodium carbonate, microcrystalline cellulose, lactose and mannitol were added individually with stirring to obtain a homogeneous solution. The viscosity of the solution was measured at 25 占 폚 using a Brookfield Digital Viscometer (Brookfield Engineering Laboratories Inc., Massachusetts, USA).

The resulting mixture was transferred to a pipette, precisely weighed into a preformed blister pack and transferred into a refrigerator (-30 ° C) for approximately 24 hours. After freezing, the samples were freeze-dried for 24 hours (DYNAVAC, Australia). The preparation samples were stored in a desiccator through silica gel at room temperature.

The following additional wafer formulations were prepared as described above. Essentially Samples 1 to 6 were based on the formulation described above, and flavors and / or colorants were added.

Subsequently, various batches in the form of solid dose wafers were prepared on the basis of the formulations shown in Table 1, and were also prepared as biologically active substances using either midazolam (base) or fentanyl citrate (2.5 mg fentanyl base on 50 wafers, ≪ / RTI > strength equivalent to that of < RTI ID = 0.0 > The effluents and components are listed in Table 2.

The midazolam or fentanyl composition used for the study Batch 071501B Batch 071502B Batch
0820A Batch 0820B Batch
0905MD Batch
1003FEN ingredient Amount (g) Amount (g) Amount (g) Amount (g) Amount (g) Amount (g) Amylopectin 1.0 1.0 1.0 0.00 1.0 0.5 Mannitol 3.0 3.0 3.0 3.0 3.0 1.5 Lactose 2.0 2.0 2.0 2.0 2.0 1.0 Glycine 0.2 0.2 0.5 0.3 0.2 0.1 PEG 2000 0.1 0.1 0.1 0.1 0.1 0.05 Carboxymethylcellulose sodium 0.04 0.04 0.04 0.04 0.04 0.02 Sodium carbonate 0 0.02 0 0 0.02 0.01 Starch 1.0 0 0 0 0 0 Avicel 0.2 0.2 0.00 0.2 0.2 0.1 Active pharmaceutical ingredient 0 0 0 0 0.255 Midazolam (base) 0.004 Fentanyl citrate (2.5 mg fentanyl base) Purified water 40 40 40 40 40 20

General observation

There was no significant difference in the use of polyethylene glycol 1000 or polyethylene glycol 2000 in wafer formulations (results not shown).

The addition of starch resulted in a hard wafer and was less suitable for fast solubility solid formulations of the present invention.

Weight uniformity

The uniformity of fast dose weight wafer form weight was tested according to the British Pharmacopoeia (BP) 2009 test. Twenty wafers from each of the formulations listed in Table 2 were weighed individually and then the average weight and relative standard were calculated. All manufactured wafers from different formulations were within an allowable weight variation of 0.25 to 2%.

Hardness

The hardness of the dosage formulations listed in Table 2 was also tested. The mechanical strength of the tablet is referred to as "hardness ". The hardness of the wafers was determined using an Erkeka hardness tester (Germany). The hardness values from the different formulations range from 0.5 to 4.0 kg. It was observed that the hardness of the formulation increased when the avicel was added to the formulation (results not shown).

Heterogeneity

Fast soluble solid dosage We measured the strength of the wafer form, i.e. their ability to be reduced from solid material to smaller operations. The test was performed according to the BP 2009 method (i.e., the washability of the uncoated tablet), using a Rochexis tester (Germany). A sample of 20 wafers was precisely weighed and then placed in the apparatus. A rotation time of 4 minutes at 25 rpm was used. The wafers were removed and reweighed, and then the percent weight loss was calculated. 20 wafers were in the range of 8 to 20%. There was no such standard for wafers in one of the BP or USP papers, although this weight loss did not comply with the BP 2009 standard of about 1% weight loss for compressed tablets.

Moisture analysis

The water content of 870 Karl Fisher Titrino Plus (Metrohm Ag, Germany) wafers was analyzed. The results indicate that the residual moisture content differs from 1% to 5% for the different formulations.

Scanning electron microscope analysis

The surface morphology and cross-sections of the selected wafer formulations were observed using a scanning electron microscope (SEM) (Zeiss, EVO 40 XVP, Oxford Instrument, England). A transverse sample was prepared by cutting a thin slice of the wafer using a scalpel. The sample was coated with carbon prior to testing. The acceleration voltage was 10 kV.

The SEM image shown in Figures 1 to 6 shows the highly porous nature of the wafer for both the surface and the internal structure. Obviously, there was a difference in shape between different formulations. These differences indicated that the excipients used affected the microstructure of the wafers. In addition, the microstructure can provide a description of dissolution profiles of wafers made from different hardnesses, haze, disintegration time, and even different formulations.

Powder X-ray diffraction (XRD)

X-ray diffraction experiments were performed using a Bruker D8 Advance (Germany) using a detector LynEye. The radiation used was nickel filtration CuKa produced using an accelerating voltage of 40 kV and a cathode current of 40 mA. The sample was scanned over a 2 [theta] range of 7.5 to 70 degrees and the counting time was 1 second / 0.02 degrees.

The physical state of the material in the wafer was evident in the X-ray diffraction spectrum. The spectra of three different formulations as made according to Table 2 are shown in Figures 7-9. All powder patterns of the prepared wafers were observed to dominate strong scattering peaks located approximately at 2-theta of 9.58 °, 19, 68 ° and 20.05 ° indicating crystalline properties. This discovery was also supported by the data generated from the SEM (see Figures 1 to 6). In fact, the excipients used in the formulation, such as glycine, lactose, mannitol and microcrystalline cellulose, are naturally crystalline. It was observed that there was minimal physical state change in the solid dispersion.

Decay and dissolution analysis

Disintegration and dissolution tests were performed using Device I (BP 2009, Basket device). A Löker dissolution unit (Hesenstamm, Germany) was used for both tests. The temperature of the medium was maintained at 37 ± 0.5 ° C.

For the collapse test, the wafer was placed in a cylindrical basket and wetted the bottom by contacting it with distilled water in a cylindrical container. The total dissolution time of each wafer was noted, and the average value was calculated.

For the dissolution test, a drug release mechanism from the system according to both the BP basket and the USP paddle method was determined using a wafer containing midazolam (model B 0905 MD) as model drug (see FIG. 17). The dissolution medium was a 500 ml phosphate buffer solution (pH value approached saliva at 6.8) and the paddle rotation rate was 75 rpm. At a given interval (e.g., 0.5, 1, 2, 3, 5 10 15, 20 and 30 minutes), 2 ml of the solution was sampled and replaced with the same volume of fresh medium to maintain a constant total volume. The sample was filtered through a 0.2 占 퐉 Millipore filter. The released drug was measured by HPLC.

The HPLC system consisted of a Waters 1525 pump, a Waters Symmetry C ₁₈ column (5 占 퐉, 150 占 4.6 mm), and a Waters UV 484 detector. The mobile phase was acetonitrile: 10 mM ammonium acetate buffer (40:60, v / v, pH 4.10) and the flow rate was 1.2 ml / min at ambient temperature. The peak was recorded at 220 nm and the quantification limit was approximately 1 ng / ml. The calibration curve for concentration 1 to 32.4 g / ml (6 point calibration) was linear [y = 870714x + 52057 (r = 0.9998), y represents the peak area of midazolam and x represents the concentration of the sample ].

A standard HPLC calibration curve for midazolam is shown in Fig. The results as shown in Figure 31 were that the average decay time was less than 15 seconds; The dissolution study also showed a rapid rate of release of midazolam, demonstrating that nearly 75% of the midazolam dissolved within 1 minute. The semidazolam powder was considerably slower. This could indicate a change in the morphology of the midazolam crystal in the wafer, which was also evident at the X-ray. X-ray showed amorphization of midazolam during the freeze-drying process.

The results of HPLC analysis on various samples of formulations as made according to Table 1 are shown in Figs. 11-29. Figures 10a-10e illustrate HPLC of a standard midazolam sample, and a midazolam powder dissolution sample. 11 to 16 are HPLC chromatograms of dissolved wafer samples 1 to 3 (S1, S2 and S3, BP basket method). Briefly, Samples 1, 2 and 3 were prepared according to Table 1, which is three samples of the same formulation. Figure 17 shows HPLC chromatograms of batch 0905 MD containing midazolam as a model drug.

Figures 18-29 reflect HPLC chromatograms of three other dissolved wafer samples (USP paddle method). As discussed above, the dissolution rate of wafers containing the test drug midazolam was measured. Samples were taken at 0.5 minute, 1 minute, 5 minutes, 10 minutes to 15 minutes.

Results of wafers 1 to 3 (batch 0905 MD) are shown in Figs. 18 to 29 along these times. Drug loading tests were also performed on the other three wafers (batch 0905 MD).

The wafers of the present invention were found to be completely soluble in about 15 seconds, leaving no residue behind.

The mechanism of drug release from the system after the BP basket method was determined using a wafer containing fentanyl as a model drug (Batch 1003FEN). The rate of dissolution of the wafers was determined in small volumes (10 ml phosphate buffer solution, pH 6.8) using the basket rotation speed at 50 rpm. At a given interval (for example, 0.5, 1, 2, 3, 4, 5, 7, 10 and 15 minutes), 0.5 ml of the solution was sampled and replaced with the same volume of fresh medium. The released drug was measured by HPLC.

The mobile phase was methanol: 0.4% phosphoric acid (50:50, v / v, pH 2.3) and the flow rate was 1.2 ml / min at ambient temperature. The monitoring wavelength was at 210 nm. (Y = 316668x + 4675.7, (r = 0.9999), where y represents the peak area of the fentanyl and x represents the concentration of the sample), the calibration curve (8 point calibration) . The analysis standard curve is shown in Fig.

The manufactured fentanyl wafer (Batch 1003FEN) exhibited a weight deviation of ± 2.55%, and the average percentage of the fentanyl content of the wafer was 91.32% (BP standard for the uniformity content is limited to 85 to 115%). The average decay time was less than 15 seconds; Dissolution studies also showed fast release rates of fentanyl. Nearly 90% of the fentanyl dissolved in 1 minute. The dissolution profile is shown in Fig.

HPLC chromatograms of the six dissolution samples of the fentanyl wafer were collected and are shown in Figures 34A-34E (Samples 1-3) and Figures 35A-35J. (Samples 4-6). Sampling of each test wafer was performed at 0.5, 1, 5, 10, 15 and 20 minutes time for dissolving Samples 1 to 3 and 1, 2, 3, 4, 5, 7 And 10 min.

A readily available formulation is a solid dispersion of a drug into a porous matrix. After administration, this formulation rapidly disintegrates in the oral cavity, rapidly dissolves the drug to be adsorbed by diffusion into the systemic circulation, and avoids the first-pass effect. The present invention is likely to provide an alternative drug administration route and results in lower rates of side effects.

Example 2

The formulations of the present invention in the form of solid dosage forms (wafers) containing ketamine were prepared according to the methods and components as set forth in Table 3 below:

Composition of soluble solid dosage form of ketamine
(Equivalent to 25 mg ketamine base) Component (BP / USP) Amount (g) weight% Sodium carbonate One 0.07 Carboxymethylcellulose sodium 2 0.15 Polyethylene Glycol 2000 5 0.36 Glycine One 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

Formulated wafers containing ketamine were produced using the method of Example 1 above.

The following additional formulations were prepared by the method of Example 1. Samples 1 to 6 were based on the formulation described above (strength equivalent to a 25 mg ketamine base) with the addition of flavoring and / or coloring agents.

Various strengths of ketamine-soluble solid formulations (wafers) were then prepared based on the formulations shown in Table 3 and prepared as described in Example 1 above. Batch numbers and ingredients are listed in Table 4.

Ketamine composition used for the study Batch 20110323K
(Equivalent to 25 mg ketamine base) Batch 20110528
(Equivalent to 25 mg ketamine base) Batch 20110820
(Equivalent to 50 mg ketamine base) ingredient Amount (g) Amount (g) Amount (g) Amylopectin 1.0 1.0 1.2 Mannitol 3.0 3.0 2.9 Lactose 2.0 2.0 1.9 Glycine 0.2 0.2 0.3 Polyethylene Glycol 2000 0.1 0.1 0.1 Carboxymethylcellulose sodium 0.04 0.04 0.04 Sodium carbonate 0.02 0.02 0.05 Avicel 0.2 0.2 0.2 Active pharmaceutical ingredient 1.250 ketamine (base) 1.250 ketamine (base) 2.50 ketamine (base) Purified water 40 40 40

시험관내 연구

In vitro study

In vitro studies have demonstrated physicochemical properties of soluble solid formulations in freeze-dried ketamine (equivalent to 25 mg ketamine base).

Weight uniformity

The uniformity of the weight of the ketamine wafers was tested as provided in Example 1. The 20 wafers from the formulations listed in Table 4 were individually weighed and then the average weight and relative standard deviation were calculated. All manufactured wafers from the different formulations were within an acceptable weight deviation of 0.25 to 2%.

Hardness

The hardness of the wafers was also tested according to the method provided in Example 1. The hardness values from the different formulations ranged from 0.5 to 4.0 kg. Batch 20110528 provided a hardness of 0.5 to 1.0 kg, and this formulation was then used in subsequent clinical trials. This formulation allows a fast dissolution rate and allows for easy manipulation.

Heterogeneity

The strength of the ketamine wafers was tested according to the method of Example 1. A sample of 20 ketamine wafers had a weight loss percentage of 8 to 20%.

Moisture analysis

The moisture content of the ketamine wafers was analyzed as provided in Example 1. The results indicated that the residual moisture content was about 4%.

Scanning electron microscope analysis

The surface morphology and cross-sections of the selected wafer formulation samples were observed using the method provided in Example 1. [ The SEM image shown in Figures 36 and 37 shows the highly porous nature of the ketamine-containing wafers for both the surface and internal structures.

Powder X-ray diffraction (XRD)

Powder X-ray diffraction experiments were performed using the method of Example 1.

The physical state of the material in the ketamine-containing wafers was clear in the X-ray diffraction spectrum. The spectra of three different formulations prepared according to Table 4 are shown in Figures 38, 39 and 40. [ All powder patterns of the wafers produced showed dominant strong scattering peaks located at 2-theta of 9.58 DEG, 19 DEG, 68 DEG and 20.05 DEG, indicating the crystalline properties of the excipient Avicel. This discovery was also supported by data generated from SEM. In fact, the excipients used in the formulation, such as glycine, lactose, mannitol and microcrystalline cellulose, are naturally crystalline. However, it became amorphous after freeze-drying.

Decay and dissolution analysis

Disintegration and dissolution tests were carried out according to Example 1.

For the disintegration test, the ketamine-containing wafers of the present invention could be completely dissolved in about 15 seconds, after which no residue remained.

For dissolution tests, wafers from batches containing ketamine were used to determine drug release levels from the formulations. The dissolution rate of ketamine wafers was determined in large volumes (200 ml phosphate buffer solution, 25 mM, pH 6.8) and the basket rotation rate was 75 rpm. At a given interval (e. G., 1, 3, 5, 7, 10, 15, 20 and 30 minutes), 1.0 ml of the solution was sampled and replaced with the same volume of fresh medium. By the emitted substance on HPLC using a mobile phase C18 column (150 x 4.6㎜, 5㎛), 85% of _{50mM H 3 PO 4 15% v} / v acetonitrile, 20mM triethylamine HCl (pH 3.00) in the And the flow rate was 1.5 ml / min at ambient temperature. The monitoring wavelength was at 210 nm. HPLC chromatograms of the dissolved ketamine wafers are shown in Figures 41-48.

(Y = 16225X + 3328.9, (R2 = 1), Y represents the peak area of the ketamine, and X represents the sample concentration), the calibration curve (7 point calibration) for the concentration of 5 to 100 占 퐂 / . The analysis standard curve is shown in Fig.

The prepared ketamine wafers (Batch 20110528) exhibited a weight deviation of +/- 2.55% and the average ketamine content of the wafers was 98.67% (limiting the BP standard for uniformity content to 85 to 115%). The HPLC chromatogram is shown in Fig.

The mean decay time (BP decay device) was less than 5 seconds; Dissolution studies also showed a rapid release rate of ketamine. Nearly 95% of the ketamine dissolved in 1 minute. This could indicate a change in the ketamine crystal morphology of the wafer, which was also evident at the X-ray. The X-ray spectrum showed amorphization of the ketamine during the freeze-drying process.

A dissolution profile is provided in FIG.

The ketamine wafer is a solid dispersion of ketamine hydrochloride in a porous matrix. After administration, this formulation quickly disintegrates in the mouth, rapidly dissolving the ketamine to be adsorbed by diffusion into the systemic circulation, and avoiding the first-pass effect. The present invention is likely to provide an alternative drug administration route and results in lower rates of side effects.

생체내 연구

In vivo study

The objectives of in vivo studies were 1) to study the pharmacokinetic profile of ketamine wafers (equivalent to 25 mg of ketamine base, batch number: 20110528 in Table 4); 2) determining the absolute bioavailability of a single 25 mg sublingual dose of ketamine wafers; And 3) to evaluate the clinical features and tolerability of the present invention using modified Leak and Bond and Lader scales.

Ethical approval

The protocol was approved by the Royal Adelaide Human Research Ethics Committee. This test was registered by the Australian Therapeutic Products Administration under the Notification of Clinical Trial (CTN: 2011/0292).

Research subject

All applicants agreed in writing to the approved subject consent before receiving the test procedure. The subjects included in the study were 19 to 41 years of age and had a body mass index of 22 to 30 kg / m 2 and showed no drug or alcohol dependence or history of misuse, or did not show any drug or alcohol dependency or misuse, There was a normal finding for the test, no sublingual or buccal ulceration or disease, and no evidence of a negative for the HIV, B and C hepatitis virus tests.

A total of eight healthy males who met the inclusion and exclusion criteria were enrolled in this study.

Research Planning and Design

This was a randomized, open-label, single dose, two-treatment, two-period, two-way crossover study at a single center (Royal Adelaide Hospice Pain and Anesthesiology Clinic, Adelaide, Australia 5005 South Australia) Following randomization, the subjects were divided into two groups with a 1: 1 ratio using a random number computer-generated table.

Volunteers received both a single 10-mg intravenous (IV) dose of ketamine (diluted to 30 mL in saline and administered as IV infusion over 30 minutes) and a 25 mg sublingual (SL) wafer dose of ketamine. The order of treatment periods was balanced and randomized. The wafers were administered by placing them under the tongue. They asked the volunteer to avoid swallowing for at least 10 minutes and minimized the loss of ketamine through the oral route, thus intestinal and hepatic metabolism (first pass effect). The total duration of the study was four weeks, including a 14-day screening period and a 7-day washout period.

Both pharmacokinetic, tolerability and safety measures were performed for 24 hours after dosing. The total length of stay in the pain and anesthesia study clinics was 28 hours for period 1 and 29 hours for period 2.

At 5, 10, 15, 30, 35 and 45 minutes after dosing and at 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12 and 24 hours after dosing Blood samples (5 ml) for quantification of ketamine concentration were taken after both IV and SL administration. Samples of up to 8 hours (including 8 hours) after dosing were collected within 2 minutes of nominal time, after which all samples were collected within 10 minutes of nominal time. The actual blood collection time was recorded in the original document. All deviations out of the specified window were recorded as protocol deviations. The total amount of blood taken over the duration of the study was approximately 275 ml.

After collection, the blood samples were immediately centrifuged at 4 ° C, 2000 to 2500 g for 15 minutes, then the plasma was extracted and placed in a polypropylene storage tube. Plasma was stored at -80 ° C ± 10 ° C until transferred to the Biological Analytical Laboratories.

Pharmacokinetic analysis

Plasma concentration analysis of racemic ketamine was performed using a suitable HPLC method with UV detection, with a lower limit of quantification of 2 ng / ml and a bias and inaccuracy of less than 20%.

The pharmacokinetic parameter other than the C _max, t _max and t _first taken as observed from each subject plasma concentration time profile of using a standard non-compartment analysis was induced. The actual time when t _max was reported was used. The final rate constant (λ _z ) was estimated by log linear regression, ie, the slope of the natural log concentration versus time curve (λ _z = -1 * slope). In the final step, linear regression used the last 3 to 6 data points at a minimum of 3 points. The final t ½ is calculated as t ½ = ln (2) / λ _z .

The area under the plasma concentration time curve for the final quantifiable plasma concentration (AUC _final ) was obtained using the linear up and log down methods and was calculated as infinity using the C _final /? _Z (final quantifiable plasma concentration divided by? _Z ) AUC _INF , the total AUC, was obtained by extrapolation. AUC _{extrapolation} (1 AUC _{t final} / AUC _INF ) * 100, the extracted portion of AUC, was obtained. The total area under the first instantaneous curve, AUMC _INF , was calculated in a manner similar to AUC _INF and MRT was obtained as the AUMC _INF / AUC _INF corrected retention time (MRT _{i .v.} ) Over the duration of the 30 min IV infusion. The clearance (CL) was calculated as dose / AUC _INF for IV administration and in the same manner for the sublingual dose. The clearance for the non-IV path was expressed as the ratio CL / F, i.e., the clearance and bioavailability (the latter is not known). Of the V _z for the distribution was calculated as CL / λ _z. MAT for the sublingual administration was obtained as the difference between MRTs for the administration of 2 routes, MRT _SL- MRT _IV . The bioavailability of ketamine (F) was calculated as the ratio of IV and subcutaneous dose-adjusted AUC _INF according to AUC _SL / AUC _IV * dose _IV / dose _SL .

Safety and Tolerance

Safety assessments included planned adverse event (AE) probes, spontaneous AE reporting, routine research, 12-lead ECG and 24-hour vital sign assessment from the start of the dose. A total physical examination was performed before the first dosing event and 24 hours after the second dosing event.

Topical tolerability was assessed by using the Riccart scale at 5, 10, 15, 30 and 45 minutes and 1 hour before dosing, and after dosing. Modified bond and ladder scales for assessing sedation and altered perception by using three factors "Boundary "," Satisfaction ", and " 2, 2.5, 3, 4, 6, 8, 12 and 24 hours.

Statistical analysis

Standard summary statistics were calculated by treatment for each pharmacokinetic change. A 90% confidence interval (CI) was calculated for bioavailability.

result

Individual values and summary statistics for applicant characteristics are reported in Table 5.

Object demographics Object randomization number Age (years) Weight (kg) Height (cm) BMI (㎡) One 19 74.6 184.0 22.0 2 31 100.0 183.2 29.9 3 23 77.0 173.0 25.7 4 19 74.7 168.0 26.4 5 41 87.8 183.5 26.1 6 20 85.0 183.0 25.4 7 21 79.1 185.0 23.1 8 25 108.5 191.0 30.0 n 8 8 8 8 Average (SD) 25 (7.6) 85.8 (12.49) 181.3 (7.29) 26.1 (2.83) Min-max 19-41 74.6-108.5 168.0-191.0 22.0-30.0

Plasma concentrations of racemic (RS) ketamine

The geometric mean (g average) by overlapping of individual RS ketamine plasma concentrations for all subjects after IV for the entire sampling period is shown in FIG. For clarity, the first 12 hours after dosing are shown separately in Figure 53. The geometric mean by overlapping of individual RS ketamine plasma concentrations for all subjects over the entire sampling period after SL administration is shown in Figure 54 and the first 12 hours is shown in Figure 55. [

The IV and SL plasma concentration time curves were similar in shape except for four subjects with 2 to 3 peaks for the SL pathway. After _Cmax , the concentration was biphasically reduced for both IV and SL (albeit with a more pronounced trend for IV).

The first quantifiable concentration after IV and SL dosing was 5 minutes for all subjects, indicating a rapid uptake to SL dose. Plasma concentrations were below the quantification limit in 6 subjects at 24 hours for SL dosing and in 1 subject at 12 hours. After IV administration, all subjects were quantifiable at 12 hours and quantifiable at 4 subjects at 24 hours.

After IV administration, C _max occurred at the end of injection (No. 6) in all but one subject and the C _max was observed in samples taken at 5 minutes after 30 minutes of injection.

For the SL capacity, the median time of the main peak, t _max , was 0.75 h, the fastest peak was detected at 0.25 h, and the last peak was detected at 1 h after dosing. Subjects 4, 5, 6 and 7 had a number of ancillary peaks in their plasma concentration time profiles observed during the first 3 hours after dose administration. The individual _tmax values are shown in Fig.

Table 6 provides individual estimates and summary statistics for the major pharmacokinetic variables. The individual AUC _INF values for both routes for administration are shown in FIG. Extrapolated portion of the AUC _extrapolated AUC I is very small for both the route of administration, which indicates the quality in the AUC values estimated. For IV, the AUC _{extrapolation} was 3 to 7% and 2 to 9% for SL.

An individual estimate of CL for the IV path is provided in FIG. After SL dosing, CL proved to be false by F, and therefore can not be compared to the value obtained after IV dosing. The median CL for IV dosing was 37.7 l / hr.

The final half-lives after IV and SL dosing were similar and median values were 4.5 and 3.4 hours, respectively. A similar half-life for the IV and SL pathways indicates that the absorption is fast, or that the slower absorption half-life dominates the final phase of the plasma concentration time curve and thus represents a significantly longer half-life than IV administration. Individual values for both administration routes are provided in FIG.

Individual pharmacokinetic variables and summary statistics of RS ketamine after administration of 10 mg and 25 mg SL as a 30 min IV infusion for 8 healthy volunteers Object C _{max, IV} t _{max, IV} C _{max, SL} t _{max, SL} AUC _INF _IV AUC _INF _SL CL V _z t _{1/2, IV} t _{1/2, S} (ng / mL) (hr) (ng / mL) (hr) (hr * ng / mL) (hr * ng / mL) (L / hr) (L) (hr) (hr) One 226.68 0.5 88.76 0.58 282.73 202.89 35.37 126 2.5 2.9 2 163.26 0.5 128.28 0.25 243.24 162.52 41.11 158 2.7 1.8 3 190.27 0.5 78.72 0.75 254.59 184.28 39.28 283 5.0 3.2 4 124.24 0.5 60.24 One 270.02 203.47 37.03 253 4.7 5.5 5 120.38 0.5 50.02 0.75 289.22 171.90 34.58 300 6.0 3.5 6 101.88 0.6 76.12 One 299.44 211.33 33.40 164 3.4 2.3 7 83.18 0.5 51.79 One 261.00 186.14 38.31 385 7.0 4.6 8 81.12 0.52 61.17 0.5 167.21 161.64 59.81 375 4.3 5.1 G average ^a 128.07 0.50 71.08 0.75 254.98 184.65 39.22 237 4.5 3.4 Min-max 81.12-226.68 0.50-0.60 50.02-128.28 0.25-1.00 167.21-299.44 161.64-211.33 33.40-59.80 126-385 2.5-7.0 1.8-5.5 CV (%) 16 NA 14 21 8 4 8 18 16 17 a Provide the g average for all variables except t _max and t _1/2 that represent the median
NA Not applicable

Bioavailability and Absorption

In most subjects, SL wafers were dissolved within 30 seconds to 1 minute.

Individual estimates of bioavailability are shown in Figure 60 and individual bioavailability and MAT (mean absorption time) values are provided in Table 7 along with summary statistics. Object number 8 had significantly higher bioavailability, i.e., 38%, than other subjects. This subject was not significantly different from the other subjects except for those with the highest extrapolated area (9% for SL and 7% for IV and double peak for SL capacity). The median bioavailability and 90% CI [lower limit, upper limit] were 29 [27, 31]%, indicating very low variability among subjects.

Median, minimum and maximum RS ketamine bioavailability (F), and mean absorption time (MAT) after 25 mg SL administration for 8 healthy volunteers. Object F (%) MAT (hr) One 28 1.1 2 27 -0.83 3 29 -1.1 4 30 0.86 5 23 -1.1 6 29 -0.56 7 29 0.20 8 38 0.64 median 29 -0.18 Min-max 23-38 -1.1-1.1 90% CI [lower limit, upper limit] [27, 31] NA * *Not applicable

MAT indicates the average time the ketamine molecule passes from the site of administration, the SL space, for the systemic cycle. The individual MRT values were similar for the administration of the two routes, with median values of 3.9 for IV and 3.8 hours for SL, indicating fast absorption. The small difference between MRT and SL for IV, that is, a small MAT shows fast absorption. Taking the difference between two similar values can result in negative values due to naturally occurring variability, as can be seen from some MAT values.

In summary, the PK of SL wafers is characterized by rapid absorption and low variability in bioavailability. This translates from exposure to low volatility with low volatility in the clearance. Low volatility increases accuracy in predicting total exposure and thus increases the pharmacokinetic effect of SL wafers, which could be expected to increase its availability in clinical settings.

Pharmacokinetic result

Bond and Ladder Mood Assessment Scale

The bond-and-ladder scale includes a total of 16 100-mm lines anchored to one of the ends by the antonym. Participants displayed their current subjective state on the line in the opposite sense. Each line was scaled in millimeters from the negative antonym to the mark. From the scores obtained, three measurements derived from the factor analysis were isolated. These are described by the bond and ladder as follows:

인자1: "경계"(경계-경면, 주의-꿈 꾸는 듯함, 기면-활동적, 혼란스러움-냉철함, 잘 조화됨-서투름, 둔감함-기민함, 강함-미약함, 흥미로움-지루함, 무능함-능숙함으로써 표시함);

Argument 1: "boundary" (border-mirror, attention-dreaming, sleeping-active, confused-cool, well-coordinated-awkward, insensitive-agile, strong-feeble, interesting-bored, incompetent) box);

인자 2: "만족"(만족-불만족, 곤란함-조용함, 행복-슬픔, 길항적-우호적, 고립-사교적) 및

Factor 2: "Satisfaction" (satisfaction - dissatisfaction, difficulty - quietness, happiness - sadness, antagonistic - friendly, isolated -

인자 3: "평온"(평온-흥분, 긴장-이완); 각각의 인자에 대한 스코어는 인자에 기여하는 개개 척도에 대한 부정적 반의어로부터 중요하지 않은 평균 밀리미터 수(최대 100㎜)를 나타낸다.

Factor 3: "tranquility" (tranquility - excitement, tension - relaxation); The score for each factor represents the number of non-significant mean millimeters (up to 100 mm) from the negative antonym of each scale contributing factor.

Thus the maximum score for factor 1 is 900; 500 for factor 2, and 200 for factor 3.

The mood scale did not show a clear trend for effects. After SL administration, the parameters "Boundary" and "Satisfaction" repeatedly fluctuated to approximately the pre-dose level over the 24 hour observation period, while "Serenity" showed an initial decrease for the first hour after dosing, It is possible that excitation and topical tolerance observations caused by dosing for 60 minutes, followed by a steady increase, and complete recovery up to 2.5 hours after dosing. Formation of the profile after IV dosing was similar to that of the SL dose. Figures 61 and 62 show the profiles of mean (SD) values for each factor of the mood assessment scale after IV and SL dosing, respectively.

Locality Tolerable  Deformed Lee Curt  Measure

The modified Riccart scale was used to assess the following symptoms: ball irritation, burning sensation; Sediments and areas. As expected, the values were generally 0 for all values after IV administration (although there is a sporadic value of 1 or 2). After SL administration, the values were generally zero or sporadically 1 or 2 for the "ball stimulus", similar to the "burning sensation", although single values of 3 in 10 minutes were reported by subject 3. For "zones ", values generally have a value of 0, but exhibit the same tendency for IV with sporadic values of 1 or 2. However, the values for "biting" were different from those of IV: all the subjects had a non-zero post-dosing value, even though the peak was in the range of 1 to 9 (reporting peaks 1 and 3 respectively) And the remainder was 5 or more. The highest value was 5 minutes in 4 subjects; 10 minutes in 2 subjects; One subject reported 15 minutes, and one subject reported a value of 9 for both 5 minutes and 10 minutes. All values returned to zero by one hour (Figure 63).

There were no clinically relevant changes or trends in ECG, vital signs, hematology, clinical chemistry, or urinalysis abnormalities.

In summary, sublingual wafer formulations of ketamine have been developed as potential adjuvants in acute and chronic pain management and other disorders. Median bioavailability from this example is 29% with very low variability among subjects, which is advantageous for relatively narrow therapeutic index drugs such as ketamine. The low variability also increases the use of the wafers for renewable exposure and thus increases the analgesic effect. Ketamine, administered as a 25 mg sublingual wafer to healthy volunteers as expected based on existing ketamine clinical trials, was safe and well tolerated, except for weak and transient CNS-type symptoms. Local tolerability was excellent and any local irritation effect is expected to be attenuated and degraded within 30 to 60 minutes after dosing.

Example 3

The formulations of the present invention in the form of solid formulations (wafers) containing sildenafil were prepared according to the methods and ingredients as set forth in Table 8 below:

Composition of sildenafil-dense soluble solid dosage form
(Equivalent strength to 25 mg sildenafil base) ingredient Amount (g) weight% Sodium carbonate BP / USP One 0.07 Carboxymethylcellulose sodium 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 Sildenafil BP / USP 125 8.54 Purified water BP / USP 1000 68.35

A solid formulation (wafers) containing sildenafil (25 mg) was produced using the method of Example 1 above.

The following additional formulations were prepared by the methods described above. Essentially Samples 1 to 6 are based on the formulations described above with the addition of flavoring and / or coloring agents.

Subsequently, various batches of the sildenafil-readily solid-formulated wafers were prepared based on the formulations shown in Table 8 and prepared as described in Example 1 above. Batch numbers and ingredients are listed in Table 9.

The composition of the sildenafil formulation used for the study
(Equivalent strength to 25 mg sildenafil base) Batch 071501B Batch 071502B Batch
0820A Batch
0820B Batch
20120628 ingredient Amount (g) Amount (g) Amount (g) Amount (g) Amount (g) Amylopectin 1.0 1.0 1.0 0.00 1.0 Mannitol 3.0 3.0 3.0 3.0 3.0 Lactose 2.0 2.0 2.0 2.0 2.0 Glycine 0.2 0.2 0.5 0.3 0.2 PEG 2000 0.1 0.1 0.1 0.1 0.1 Carboxymethylcellulose sodium 0.04 0.04 0.04 0.04 0.04 Sodium carbonate 0 0.02 0 0 0.02 Starch 1.0 0 0 0 0 Citric acid 0 0 0 0 0.2 Avicel 0.2 0.2 0.00 0.2 0.2 Active pharmaceutical ingredient 0 0 0 0 2.5
Sildenafil (base) Purified water 40 40 40 40 40

시험관내 연구

In vitro study

Weight uniformity

The uniformity of the weight of the sildenafil wafers was tested as provided in Example 1. Twenty wafers from the formulations listed in Table 9 were individually weighed and the average weight and relative standard deviation were calculated. All manufactured wafers from different formulations were within an allowable weight deviation of 0.25 to 2%.

Hardness

The hardness of the wafers was also tested according to the method given in Example 1. The hardness values from the different formulations ranged from 0.5 to 4.0 kg. Batch 20120628 provides the hardness of the wafers at 0.5 to 1.0 kg, and this formulation was used in subsequent clinical trials. This formulation allows a fast dissolution rate and allows for easy manipulation.

Heterogeneity

The strength of the sildenafil wafers (including their ability to reduce solid materials to smaller operations) was measured according to the method given in Example 1. Samples of 20 sildenafil wafers had weight loss percentages of 8 to 20%.

Moisture analysis

The moisture content of the sildenafil wafers was analyzed as provided in Example 1. The results indicated that the residual moisture content was about 4%.

Scanning electron microscope analysis

The surface morphology and cross-sections of the selected wafer wafer formulation samples were observed using the method provided in Example 1. The SEM image shown in Figs. 64 and 65 shows a clear difference in form between the blank and the sildenafil wafer.

Powder X-ray diffraction ( XRD )

Powder X-ray diffraction experiments were performed using the method of Example 1.

The physical state of the material in the sildenafil wafer was evident in the X-ray diffraction spectrum. The spectra of three different formulations as made according to Table 9 are shown in Figures 66, 67 and 68. All the powder patterns of the prepared wafers were observed to have dominant strong scattering peaks located at 2-theta of 9.58, 19, 68 and 20.05 degrees, indicating the crystalline properties of the excipient Avicel. This discovery was also supported by data generated from SEM. In fact, the excipients used in the formulation, such as glycine, lactose, mannitol and microcrystalline cellulose, are naturally crystalline. However, it became amorphous after freeze-drying.

Decay and dissolution analysis

Disintegration and dissolution tests were carried out according to Example 1.

For the collapse test, the sildenafil containing wafers of the present invention could be completely dissolved in about 15 seconds, after which no residue remained.

For dissolution test:

A dissolution test was performed using Device I (BP 2009, basket device). For both tests, a Löker dissolution unit (Hessenstam, Germany) was used. The temperature of the medium was maintained at 37 ± 0.5 ° C. Sildenafil containing wafers (batch 20120628) were used to determine drug release levels from the formulations. The dissolution rate of the sildenafil wafers was determined using the method provided in Example 2.

The calibration curve (7-point calibration) for sildenafil at a concentration of 5-100 μg / ml was linear [Y = 32.973X-36538, (r = 0.9999), Y represents the peak area of sildenafil, Indicating the concentration]. The analysis standard curve is shown in Fig.

The prepared sildenafil wafers (batch 20120628) exhibited a weight deviation of +/- 2.55% and the average percentage of sildenafil content in the wafers was 98.67% (limiting the BP standard for uniformity content to 85 to 115%). The mean decay time (BP decay device) was less than 5 seconds; The dissolution study also showed a fast release rate of sildenafil. Nearly 95% of sildenafil dissolved within 1 minute. This may indicate a change in the sildenafil crystal form of the wafer, which was also evident at the X-ray. The X-ray spectrum showed amorphization of sildenafil during the freeze-drying process.

The dissolution profile is shown in FIG.

Sildenafil wafers are solid dispersions of sildenafil hydrochloride into a porous matrix. After administration, this formulation collapses in the oral cavity, rapidly dissolves the sildenafil to be adsorbed by diffusion into the systemic circulation, and avoids the first-pass effect. The present invention is likely to provide an alternative drug administration route and results in lower rates of side effects.

Example 4

Formulations of the present invention in the form of solid formulation (wafer) containing adrenaline were prepared according to the methods and ingredients as set forth in Table 10 below:

Composition of Adrenergic Soluble Solid Formulation
(Equivalent to 40 mg adrenaline base) Component (BP / USP) Amount (g) weight% Sodium carbonate One 0.07 Carboxymethylcellulose sodium 2 0.15 Polyethylene Glycol 2000 5 0.36 Glycine One 0.07 Microcrystalline cellulose 2 0.15 Amylopectin 50 3.64 Adrenaline (bass) 100 7.28 Lactose 100 7.28 Mannitol 150 10.92 Purified water 1000 70.08

A ready-to-use formulation (wafer) containing adrenaline was generated using the method of Example 1 above.

The following additional formulations were prepared by the methods described above. Samples 1 to 6 were based on the formulation described above (strength equivalent to 40 mg adrenaline base), flavor and / or colorant added.

The various strengths of the adrenaline acid tartrate solid dosage form (wafer) were then prepared based on the formulations shown in Table 10 and prepared as described in Example 1 above. Batch numbers and components are listed in Table 11.

The adrenaline composition used for the study Batch
(Equivalent to 40 mg adrenaline base) Batch
(Equivalent to 40 mg adrenaline base) Batch
(Equivalent strength to 60 mg adrenaline base) ingredient Amount (g) Amount (g) Amount (g) Amylopectin 1.0 1.0 1.2 Mannitol 3.0 3.0 2.9 Lactose 2.0 2.0 1.9 Glycine 0.2 0.2 0.3 Polyethylene Glycol 2000 0.1 0.1 0.1 Carboxymethylcellulose sodium 0.04 0.04 0.04 Sodium carbonate 0.02 0.02 0.05 Avicel 0.2 0.2 0.2 Glyceryl triacid 2.0 2.0 2.0 Adrenaline bitartrate 3.638 3.638 5.458 Purified water 38 38 37

Example 5

Phase I pharmacokinetics and bioavailability studies of sublingual fentanyl wafers in healthy volunteers

방법

Way

Research Object

All applicants agreed in writing to the approved subject consent before receiving the test procedure. The subjects included in the study were 19 to 32 years old and had a body mass index of 18 to 30 kg / m 2 and did not show any history of drug or alcohol dependence or misuse, or drug or alcohol dependency or misuse, There was a normal finding for the test, no SL (sublingual) or buccal ulcer or disease, and no evidence of a negative for the phosphorus, B and C hepatitis virus tests.

Twenty-four volunteers who met the inclusion and exclusion criteria were enrolled in this study. The SD of the under-curve area (AUC), a significant difference of 35% and 20%, provides 84% validation (α = 0.05).

Research design

This was a single center (Linear Clinical Research Limited, Perth, Australia), randomized, open label, single dose, two-treatment, two-period, two-way crossover study. Following randomization, the subjects were divided into two groups with a 1: 1 ratio using a random number computer-generated table. The volunteers provided IV fentanyl citrate or sub-fentanyl citrate wafers (based on the batch: 1003FEN formulation of Example 1; equivalent to 100 μg of fentanyl). Each volunteer received an alternate route after a subsequent 7-day washout period.

The wafers were administered by placing them under the tongue. The applicant was asked to avoid swallowing for at least 10 minutes. To block any systemic effects of fentanyl, naltrexone tablets (50 mg) were orally administered every 12 hours from the first day before to the evening of the second day (12 hours after the last fentanyl dose).

Prior to the commencement of the study, a dedicated IV cannula was placed in the forearm for subsequent venous blood sampling. Blood samples (7 ml) were taken from pre-dosing prior to the start of the wafer administration and then taken at 2, 5, 10, 15, 20, 30, 45, 60, 120, 180, 360, 460, 600, 720, 960 and 1440 min. For IV infusion, blood samples were taken in pre-doses, 2 minutes and 3 minutes after initiation, and 5 minutes (final infusion), followed by 7,10,15,20,25,30,45,60 , 120, 180, 360, 460, 600, 720, 840, 960 and 1440 minutes.

After collection, the blood samples were immediately centrifuged at 2000 to 2500 g for 15 minutes at 4 DEG C, and then the plasma was extracted and placed in a polypropylene storage tube. Plasma was stored at -80 ° C ± 10 ° C until transferred to the Biological Analytical Laboratories. The sample extracts were analyzed on an API 4000 LC-MS / MS system (Applied Biosystems, Foster City, Calif.) And then analyzed using d5-fentanyl as internal standard using Shimadzu Prominence high performance liquid ≪ / RTI > chromatography system. The assay had a detection limit of 10 pg / ml. The precision was determined by double analysis of plasma containing 10, 40 and 400 pg / ml fentanyl. The results were precisely within ± 6.2%, ± 3.3% and ± 1.7% of the mean measured concentration values of 10, 40 and 400 pg / ml, respectively, of 102%, 99.9% and 101.4% at nominal concentrations of 10, 40 and 400 pg / %. The number of replicates at each concentration was 6.

Pharmacokinetic analysis

Pharmacokinetic parameters were determined using Phoenix WinNonlin version 6.1 (Certara (trademark) Company, Pharsight, St. Louis, MO). Pharmacokinetic data were C _max, t _max, AUC _{0 to 12, AUC 0-t, AUC} 0-∞, k el , and t _1/2. The first detectable fentanyl plasma concentration after SL administration (C ₁ ) and C ₁ (t ₁ ) was read directly from the plasma fentanyl concentration-time curve. The final removal rate constant ( _kel ) was determined as the slope of the regression line most suitable for the log-linear final removal step. All adaptations were performed using the integrated weights of the data. It got a final elimination half-life (t _1/2) from k _el, was as ln 2 / k _el. The AUC _{0 to 12} and the AUC _0-t values were obtained using the trapezoidal rule. The extrapolation to AUC _0-∞ was calculated from AUC _0-t + C _t / k _el .

Safety and Tolerance

Safety and tolerability were assessed by monitoring vital signs (arterial blood pressure and heart rate) after administration of fentanyl. The entire physiological test was performed before drug administration and 48 hours after administration. Laboratory tests and 12-lead ECG were performed at baseline and at completion of the study. Abnormal cases were evaluated using direct observation, voluntary reporting, and nonspecific questions.

Statistical analysis

Summary statistics were calculated by the treatment of each pharmacokinetic parameter. By comparing the bioavailability of the fentanyl SL and IV dosage for administration SL C _max, AUC _{0 to 12,} as the ratio of AUC _0-t and AUC _0-∞ it was determined separately for each subject. Overall, using a linear model for the bio-availability of the target object in the processing, period, sequence, and order log- converted C _max, AUC _{0 to 12,} AUC _0-t, and the inverse of the difference between the process for the AUC _0-∞ values - Estimated as a conversion. A 90% confidence interval (CI) was also calculated and a P value of less than 0.05 was considered statistically significant. All analyzes were performed using SAS version 9.2 (SAS Institute Inc., 2008). Differences in formulations were assessed using Student t-test.

결과

result

Twenty-four patients were randomized to 12 patients for the SL: IV order and 12 patients for the IV: SL order. Two volunteers did not complete SL or arm IV administration of the study and excluded from all analyzes. The applicant characteristics are reported in Figure 79.

Pharmacokinetic result

The mean plasma (± SEM) fentanyl concentration vs. time curve for the IV and SL pathways is shown in FIG. The individual subject plasma concentration profile is shown for the SL pathway in FIG. Plasma pharmacokinetic parameters for fentanyl C _max, t _max, represents the mean (± 1 SD) for AUC _{0 to 12,} AUC _0-t, and AUC _0-∞ in Fig. 82. After SL administration, the first detectable plasma fentanyl concentration (C _1st ) was observed from 2 minutes to 10 minutes after administration. The cumulative percentage of 22 volunteers and their mean plasma fentanyl concentration (C _1st ) were 12.5% (32.4 pg / ml), 62.5% (30.7 pg / ml) 100.0% (49.0 pg / ml).

The mean time to peak plasma concentration (t _max ) after initiation of IV and SL administration was 0.12 hours and 0.92 hours (P < 0.0001), respectively (FIG. 82). Average for IV administration and SL (± SD) final half-life (t _^1/2) were respectively 13.07 ± 3.00 12.49 ± 5.24 hours and sigan (P = 0.889). The mean (± SD) final elimination rate constants ( _kel ) for IV and SL dosing were 0.055 ± 0.012 h ^-1 and 0.064 ± 0.025 h ^-1 , respectively (P = 0.317).

The bioavailability by the percentage ratio of SL / AUC IV for _{0 to 12,} AUC _0-t, and AUC _0-∞ values were evaluated. The average bioavailability of SL fentanyl was estimated _to be 72.1% (CI, 65.3% to 79.6%) from AUC 0-12 and 73.2% (CI, 66.3% to 80.9%) from AUC _0-t . Absolute bioavailability was 78.9% (CI, 51.1% to 121.7%) based on the AUCO- _∞ value.

The C _max of SL fentanyl was 18.8% (CI, 14.4% to 24.6%) of the IV administration value and the mean time to maximum concentration was 0.9 hours. For IV administration, _Cmax generally occurred at the end of the infusion with a rapid decrease over 30 minutes immediately after dosing. From approximately 2 hours after dosing, the mean concentration-time profile was similar to that of the two regimens.

Tolerance

All reported cases were mild to moderate. The mean (± SD) time for wafers for dissolution in SL pouches was 73 ± 76 seconds.

This study was designed as an I phase study to determine the basic pharmacokinetic parameters of recently developed fast dissolving fentanyl wafers. We also collected some data on product object approvals.

The C _max and t _max values for the SL fentanyl (100 μg) wafers were similar to the data reported from the previously studied SL fentanyl (100 μg) tablets (FIG. 83). The C _max and t _max values provide an indication of the rate of absorption of the drug. The wafers have similar C _max , t _max and AUC values (P = 0.573, 0.331 and 0.103, respectively) as compared to SL tablets; Absolute bioavailability data were available for SL purification. Over a 10-hour collection period, the SL tablets were evaluated in cancer patients, it was noted that each of 6.1 and leads to a different t _^1/2 values of 12.5 hours for the tablet and the wafer (P = 0.0013).

After SL administration, rapid absorption of fentanyl was demonstrated by detectable plasma concentrations in 2 to 10 minutes (t & lt _{; RTI ID} = 0.0 & gt _{; 1} ), & lt _{; / RTI} &gt; C ₁ of _the wafer formulation was similar to that of the SL tablet. This reflects the high permeability of the fentanyl into the abundant blood flow (and good venous outflow) of the SL mucosa bypassing the "first" effect of the liver. The SL mucosa (100-200 μm) is thicker than the nasal mucosa (40-80 μm); Thus, a slower rate of uptake is expected compared to that reported after IN administration (t _max for IN fentanyl 4.2-11.4 min compared to 54.6 min for SL fentanyl in this study).

The high bioavailability of fentanyl from wafers suggests that wafer fentanyl is reliably absorbed sublingually and is less likely to be partially swallowed, thus avoiding first pass metabolism. No attempt has been made in this study as to the availability of absorbed bioavailability for these absorption pathways. The analgesic efficacy of the wafer formulation is satisfactory based on earlier preliminary studies performed in postoperative patients.

This SL fentanyl wafer caused a rapid detectable plasma fentanyl concentration in healthy volunteers within 10 minutes of administration, indicating the potential for treatment of breakthrough pain. Bioavailability was 78.9% for IV administration.

Claims (26)

A solid dosage form suitable for release of a biologically active material in the mouth,
a) at least one biologically active substance, and
b) at least one substrate former,
Wherein the formulation is substantially dissolved in the oral cavity and the biologically active material is selected from the group consisting of at least one cyclic guanosine monophosphate (cGMP) phosphodiesterase type 5 (PDE5) inhibitor , An active substance that binds to one or more adrenergic receptors, and an N-methyl-D-aspartate receptor antagonist. 2. The solid dosage form of claim 1, wherein the solid dosage form is a fast dissolving solid dosage form. The method according to claim 1, wherein the N-methyl-D-aspartate receptor antagonist is selected from the list comprising dextromethorphan, dextrorphan or ketamine. Formulation. 2. The solid dosage form of claim 1, wherein the active substance that binds to the at least one adrenergic receptor is adrenaline (epinephrine) or an adrenaline salt. The solid dosage form of claim 1 wherein the cyclic guanosine monophosphate (cGMP) phosphodiesterase type 5 (PDE5) inhibitor is sildenafil or a pharmaceutically acceptable salt thereof. 10. A method of making a solid dosage form suitable for release of a biologically active material in the oral cavity, said formulation being substantially soluble in said oral cavity,
a) combining at least one substrate former with a biologically active material to form a homogeneous mixture; And
b) freeze-drying the mixture to produce a solid dosage form of the present invention,
Wherein the biologically active material is selected from the group consisting of at least one cyclic guanosine monophosphate (cGMP) phosphodiesterase type 5 (PDE5) inhibitor, at least one adrenergic receptor binding substance, and N-methyl-D-aspartate Receptor antagonist. &Lt; Desc / Clms Page number 15 &gt; 7. The method of claim 6, wherein the solid dosage form is a fastidious solid dosage form. 7. The method of claim 6, wherein said N-methyl-D-aspartate receptor antagonist is selected from the list comprising dextromethorphan, dextrorphan or ketamine. 7. The method of claim 6, wherein the active substance that binds to the at least one adrenergic receptor is an adrenaline or an adrenergic salt. 7. The method of claim 6, wherein the cyclic guanosine monophosphate (cGMP) phosphodiesterase type 5 (PDE5) inhibitor is sildenafil or a pharmaceutically acceptable salt thereof. As a kit,
a) a solid dosage form suitable for the release of a biologically active substance in the oral cavity; And
b) Include instructions for use,
Wherein the formulation is substantially soluble in the oral cavity,
(i) at least one biologically active substance, and
(ii) at least one substrate former,
Wherein the biologically active material is selected from the group consisting of at least one cyclic guanosine monophosphate (cGMP) phosphodiesterase type 5 (PDE5) inhibitor, at least one adrenergic receptor binding substance, and N-methyl-D-aspartate &Lt; / RTI &gt; receptor antagonist. 12. The kit of claim 11, wherein the solid dosage form is a ready-to-use solid dosage form. 12. The kit of claim 11, wherein the N-methyl-D-aspartate receptor antagonist is selected from the list comprising dextromethorphan, dextrorphan or ketamine. 12. The kit of claim 11, wherein the active substance that binds to the at least one adrenergic receptor is an adrenaline or an adrenergic salt. 12. The kit of claim 11, wherein the cyclic guanosine monophosphate (cGMP) phosphodiesterase type 5 (PDE5) inhibitor is sildenafil or a pharmaceutically acceptable salt thereof. A solid dosage form wafer suitable for the release of a biologically active material in the mouth,
a) at least one biologically active substance, and
b) at least one substrate former,
Wherein the wafer is substantially dissolved in the oral cavity and wherein the biologically active material is selected from the group consisting of at least one cyclic guanosine monophosphate (cGMP) phosphodiesterase type 5 (PDE5) inhibitor, an activity to bind at least one adrenergic receptor Substance, and an N-methyl-D-aspartate receptor antagonist. 17. The solid formulation wafers of claim 16, wherein the solid formulation is a ready-to-use solid formulation. 17. The solid formulation wafer of claim 16, wherein said N-methyl-D-aspartate receptor antagonist is selected from the list comprising dextromethorphan, dextrorphan or ketamine. 17. The solid formulation wafer of claim 16, wherein the active substance that binds to the at least one adrenergic receptor is an adrenaline or an adrenergic salt. 17. The solid formulation wafers of claim 16, wherein the cyclic guanosine monophosphate (cGMP) phosphodiesterase type 5 (PDE5) inhibitor is sildenafil or a pharmaceutically acceptable salt thereof. 16. A pharmaceutical composition comprising the solid formulation of any one of claims 1 or 16. The method of claim 1, 6, 11, or 16, wherein the formulation is adapted not to leave residues of the formulation detectable by the patient in the oral cavity. . 18. The composition of claim 1, 6, 11, or 16 wherein said formulation is less than 2 minutes after administration of the formulation once it is in the oral cavity; 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. &Lt; RTI ID = 0.0 &gt; 11. &lt; / RTI &gt; 18. The composition of claim 1, 6, 11, or 16 wherein said formulation once placed within the mouth is less than 2 minutes after administration of said formulation; 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. &Lt; Desc / Clms Page number 24 &gt; 18. The method of claim 1, 6, 11, or 16 wherein said formulation is to provide an effective plasma concentration of a biologically active material within a period of 2 hours, 30 minutes, 20 minutes, or 15 minutes , Solid formulation, method, kit or wafer. Provide an effective plasma concentration of 25% for a period of less than 10 minutes.

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