TW202423415A - N-n-dimethyltryptamine (dmt) and dmt analog compositions, methods of making, and methods of use thereof - Google Patents
N-n-dimethyltryptamine (dmt) and dmt analog compositions, methods of making, and methods of use thereof Download PDFInfo
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- TW202423415A TW202423415A TW112141056A TW112141056A TW202423415A TW 202423415 A TW202423415 A TW 202423415A TW 112141056 A TW112141056 A TW 112141056A TW 112141056 A TW112141056 A TW 112141056A TW 202423415 A TW202423415 A TW 202423415A
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Abstract
Description
本發明係關於新穎N,N-二甲基色胺(下文中稱為「DMT」)組合物及治療神經疾病及病狀之方法。特定言之,本發明提供經改良之包含DMT之醫藥組合物,其呈允許DMT的經黏膜控制釋放形式且適用於治療神經疾病及病狀。The present invention relates to novel N,N-dimethyltryptamine (hereinafter referred to as "DMT") compositions and methods for treating neurological diseases and conditions. In particular, the present invention provides improved pharmaceutical compositions comprising DMT in a form that allows for transmucosal controlled release of DMT and is suitable for treating neurological diseases and conditions.
麥角酸二乙胺(「LSD」)、裸蓋菇素(psilocybin)及DMT係血清素藥劑,通常稱為「典型迷幻藥」或「致幻劑」,且能夠誘發定性改變的意識狀態,諸如欣快、恍惚、超越時空、精神體驗或自我界限的消解,而諸如鎮靜、麻醉或過度刺激之其他影響則微乎其微。化學上,血清素致幻劑為苯烷胺類或吲哚胺類,其中吲哚胺類別亦分成兩個亞群,即麥角靈及色胺。Lysergic acid diethylamide ("LSD"), psilocybin and DMT are serotonergic drugs, often referred to as "classic psychedelics" or "hallucinogens", and are capable of inducing qualitatively altered states of consciousness, such as euphoria, trance, time-space transcendence, spiritual experiences or the dissolution of ego boundaries, while other effects such as sedation, anesthesia or overstimulation are minimal. Chemically, serotonergic hallucinogens are either phenylalanamines or indoleamines, of which the indoleamine class is also divided into two subgroups, namely ergolines and tryptamines.
天然存在之致幻劑,諸如南美灌木綠色心蟲(Psychotria viridis)中含有的DMT、200多種蘑菇中含有的裸蓋菇素或美國西南部及墨西哥北部佩奧特仙人掌(Peyote cactus)中含有的麥司卡林(mescaline),幾個世紀以來一直被土著文化用於儀式或社會文化以及宗教聖禮。儘管在此等環境中使用天然存在之致幻劑被認為具有非特異性的「治癒」潛力,但直到1943年發現合成麥角靈麥角酸二乙胺(「LSD」)後,人們才開始對致幻劑針對特定疾病的治療性施用的潛力進行更科學的研究。Naturally occurring hallucinogens, such as DMT found in the South American bush worm (Psychotria viridis), psilocybin found in more than 200 species of mushrooms, or mescaline found in the peyote cactus of the southwestern United States and northern Mexico, have been used for centuries by indigenous cultures in ritual or socio-cultural and religious sacraments. Although the use of naturally occurring hallucinogens in these contexts was thought to have non-specific "healing" potential, it was not until the discovery of the synthetic ergoline lysergic acid diethylamide ("LSD") in 1943 that more scientific research began on the potential for therapeutic use of hallucinogens for specific medical conditions.
隨著人們對血清素系統及其在大腦功能中之作用的知識不斷增加,研究人員開始明確致幻藥物的分子活性。然而,該活性如何轉化為在精神病症中觀測到的治療效果仍不太明確。提出兩種主要概念:第一種概念被稱為「心理精神療法(psycholytic therapy)」,且其強調低劑量的致幻劑能夠促進心理防禦機制的放鬆,其與心理療法相結合,可產生深刻的內省洞察力,且使創傷復發並且隨後進行宣洩。因此,心理精神治療方法所考慮的基本機制係活化及加深同時進行的心理治療過程,且其需要多個用藥及治療階段。第二種概念被稱為「致幻療法(psychedelic therapy)」,且其強調以相對較高的單次劑量提供之致幻劑誘發所謂的「峰值致幻體驗」的能力。峰值體驗之特徵在於失去對時間及空間的判斷力,以及自我界限的消解,其最終往往會體驗到一種極樂的狀態,以及感受到自己係宇宙統一體中的一個完整且和諧的存在。因此,致幻性方法考慮的基本機制係產生一種獨特的、令人難以抗拒的體驗,直觀地感受到心理上的融合與和諧,以及隨之而來的自我完善、生活樂趣的增強以及內心的平和感。As knowledge of the serotonin system and its role in brain function increased, researchers began to define the molecular activity of psychedelic drugs. However, how this activity translates into the therapeutic effects observed in psychiatric disorders remains less clear. Two main concepts have been proposed: The first concept has been called "psycholytic therapy" and emphasizes that low doses of psychedelics can promote the relaxation of psychological defense mechanisms, which, combined with psychotherapy, can produce deep introspective insights and enable trauma reversal and subsequent catharsis. Therefore, the basic mechanism considered by the psychotherapeutic approach is the activation and deepening of the psychotherapeutic process simultaneously, and it requires multiple medications and treatment stages. The second concept is called "psychedelic therapy" and emphasizes the ability of hallucinogens, given in relatively high single doses, to induce so-called "peak psychedelic experiences." Peak experiences are characterized by a loss of perception of time and space and a dissolution of ego boundaries, often culminating in a state of ecstasy and a sense of being a complete and harmonious being in a cosmic unity. The basic mechanism contemplated by the psychedelic approach is thus the production of a unique and overwhelming experience of intuitive psychological integration and harmony, with attendant self-perfection, increased enjoyment of life, and a sense of inner peace.
儘管圍繞使用致幻劑治療精神病症的科學研究在20世紀60年代蓬勃發展,但此等物質的娛樂性使用亦在迅速增長,且不久致幻劑便被媒體描述為高度危險的濫用藥物。對社會秩序的危險感導致美國於1970年通過《受控物質法案》,根據該法案,LSD及其他致幻劑被列入最強限制性類別的目錄1中,該目錄中含有被認為不具有醫療用途且極有可能被濫用的藥物。在接下來的30年裏,關於致幻劑藥物的可能治療用途的研究進展甚微。Although scientific research surrounding the use of psychedelics to treat mental illness flourished in the 1960s, recreational use of these substances also grew rapidly, and soon psychedelics were being portrayed in the media as highly dangerous drugs of abuse. The perceived danger to social order led to the passage of the Controlled Substances Act in the United States in 1970, under which LSD and other psychedelics were placed on Schedule 1, the most restrictive category, which contains drugs that are considered to have no medical use and have a high potential for abuse. For the next 30 years, little progress was made in research into the possible therapeutic uses of psychedelic drugs.
最近,人們對致幻劑療法領域的興趣再次升溫,且典型致幻劑在治療精神病症方面已顯示出臨床前及臨床前景(Carhart-Harris及Goodwin, The Therapeutic Potential of Psychedelic Drugs: Past, Present and Future, Neuropsychopharmacology; 42, 2105-2113 (2017))。特定言之,裸蓋菇素在隨機雙盲研究中已證明在一系列抑鬱症及焦慮症評分量表中具有顯著改善作用(Griffiths等人, Psilocybin produces substantial and sustained decreases in depression and anxiety in patients with life-threatening cancer: a randomized double-blind trial, Journal of Psychopharmacology 30(12), 1181-1197 (2016))。Recently, there has been a resurgence of interest in the field of psychedelic therapy, and classic psychedelics have shown preclinical and clinical promise in the treatment of psychiatric disorders (Carhart-Harris and Goodwin, The Therapeutic Potential of Psychedelic Drugs: Past, Present and Future, Neuropsychopharmacology; 42, 2105-2113 (2017)). Specifically, psilocybin has been shown to produce significant improvements on a range of depression and anxiety rating scales in a randomized double-blind trial (Griffiths et al., Psilocybin produces substantial and sustained decreases in depression and anxiety in patients with life-threatening cancer: a randomized double-blind trial, Journal of Psychopharmacology 30(12), 1181-1197 (2016)).
亦瞭解,DMT作為致幻劑亦具有治療價值,目前正在進行療效試驗,以評估將DMT或DMT反丁烯二酸鹽靜脈內投與患有重度抑鬱症(「MDD」)之個體的效果。然而,儘管DMT的內在特性使其成為一種極具吸引力的可能藥物,尤其在治療神經疾病及病症方面,但目前的治療組合物及投與模式使治療變得複雜,且可能無法提供最佳治療效果。舉例而言,在吸食或經靜脈內遞送時,DMT的起效作用時間極快且作用持續時間短,因此便為確定DMT之具有適當劑量及投與頻率的合適投與方案以提供用於神經疾病及病狀之有效療法帶來了挑戰。此對於神經疾病及病狀而言尤其明顯,因為與經由注射或吸入而投與的單次劑量之DMT相比,在投藥後存在持續更長時間的治療性血液含量之DMT將使該等神經疾病及病狀受益。It is also understood that DMT has therapeutic value as a hallucinogen, and efficacy trials are currently underway to evaluate the effects of intravenous administration of DMT or DMT fumarate to individuals suffering from major depressive disorder ("MDD"). However, while the intrinsic properties of DMT make it an extremely attractive possible drug, particularly in the treatment of neurological diseases and disorders, current therapeutic compositions and modes of administration complicate treatment and may not provide optimal therapeutic effects. For example, when smoked or delivered intravenously, DMT has an extremely rapid onset of action and a short duration of action, thus creating a challenge in determining an appropriate dosing regimen with adequate dosing and frequency of administration for DMT to provide effective treatment for neurological diseases and conditions. This is particularly true for neurological diseases and conditions, as these neurological diseases and conditions would benefit from DMT being present in therapeutic blood levels for a longer period of time after administration than a single dose of DMT administered by injection or inhalation.
因此,迫切需要易於投與之用於治療神經疾病及病狀之DMT藥物。彼等既能最大限度地發揮藥效,亦能有效控制藥物副作用的藥物尤其令人感興趣,尤其為可經由方便的途徑投與(包括自我投與)的藥物。Therefore, there is an urgent need for DMT drugs that are easy to administer for the treatment of neurological diseases and conditions. Drugs that can maximize the efficacy of the drug while effectively controlling the side effects of the drug are particularly interesting, especially those that can be administered (including self-administration) via convenient routes.
已描述使用傳統聚合性調配物開發致幻劑調配物的若干嘗試。舉例而言,La Rosa等人的標題為「Oral Dissolvable Film Containing Psychedelic Compound」的美國公開案2021/0015738揭示了一種用於治療神經病的具有DMT之經口可溶解膜。經口可溶解膜包括:(a)塑化劑、(b)溶劑、(c)甜味劑、(d)調味劑、(e)黏合劑、(f)著色劑、(g)防腐劑及(h)選自由以下組成之群的致幻劑化合物:裸蓋菇素、脫磷酸裸蓋菇素(psilocin)、白賽汀(baeocystin)、麥司卡林、LSD、氯胺酮(ketamine)、丹酚A (salvinorinA)、鵝膏蕈氨酸(ibotenic acid)、毒蕈胺(muscimol)、DMT、MDMA、MDEA、MDA及其組合。Several attempts to develop psychedelic formulations using traditional polymeric formulations have been described. For example, U.S. Publication No. 2021/0015738, entitled "Oral Dissolvable Film Containing Psychedelic Compound" by La Rosa et al. discloses an orally dissolvable film with DMT for the treatment of neurological disorders. The orally dissolvable film comprises: (a) a plasticizer, (b) a solvent, (c) a sweetener, (d) a flavoring agent, (e) a binder, (f) a coloring agent, (g) a preservative, and (h) a hallucinogenic compound selected from the group consisting of psilocin, psilocin, baeocystin, mescaline, LSD, ketamine, salvinorin A, ibotenic acid, muscimol, DMT, MDMA, MDEA, MDA, and combinations thereof.
Espinoza的標題為「Oral Dissolvable Film With High Load of Polymeric Binder」的美國公開案2021/0322306揭示了一種組合物,其包含(a)膜基質,該基質包括一或多種黏合劑,其中至少一種黏合劑係具有至少45℃的玻璃轉化溫度(Tg)的聚合黏合劑;(b)溶劑;(c)活性醫藥成分(API);及(d)醫藥學上可接受的賦形劑,其包括黏膜黏附聚合物、塑化劑、填充劑、膨鬆劑、唾液刺激劑、穩定劑及增稠劑、膠凝劑、調味劑、掩味劑、著色劑、顏料、潤滑劑、釋放調節劑、佐劑、甜味劑、增溶劑及乳化劑、芳香劑、乳化劑、界面活性劑、pH調節劑、緩衝劑、脂質、助滑劑、穩定劑、抗氧化劑、防黏劑、保濕劑及防腐劑中的至少一種。Espinoza's U.S. Publication No. 2021/0322306, entitled "Oral Dissolvable Film With High Load of Polymeric Binder," discloses a composition comprising (a) a film matrix comprising one or more binders, at least one of which is a polymeric binder having a glass transition temperature (Tg) of at least 45°C; (b) a solvent; (c) an active pharmaceutical ingredient (API); and (d) a pharmaceutically acceptable excipient comprising a mucosal At least one of adhesion polymers, plasticizers, fillers, bulking agents, saliva stimulants, stabilizers and thickeners, gelling agents, flavoring agents, taste masking agents, coloring agents, pigments, lubricants, release regulators, adjuvants, sweeteners, solubilizers and emulsifiers, fragrances, emulsifiers, surfactants, pH regulators, buffers, lipids, slip agents, stabilizers, antioxidants, anti-adhesive agents, moisturizers and preservatives.
以上公開案並未研究其中所揭示之組合物的穩定性。仍需要能夠提供DMT之控制釋放之穩定DMT組合物,尤其用於經黏膜遞送。The above publications did not study the stability of the compositions disclosed therein. There remains a need for stable DMT compositions that can provide controlled release of DMT, especially for transmucosal delivery.
本發明在一個態樣提供一種醫藥組合物,其包含非晶形DMT或其醫藥學上可接受之鹽或前藥,及聚合載劑。非晶形DMT之特徵可在於不含任何可辨別峰之粉末X射線繞射圖及不存在結晶DMT的尖銳熔融吸熱及/或相變的跡象之差示掃描量熱法(DSC)光譜。穩定性之特徵可在於觀測此等特徵隨時間推移,尤其在加速老化之後。本發明人出乎意料地發現DMT可以非晶形式穩定於聚合載劑內,該聚合載劑適合於DMT之受控經黏膜釋放。穩定非晶形DMT組合物可以適合於經黏膜投與(例如經頰或舌下膜)之形式提供。The present invention provides, in one aspect, a pharmaceutical composition comprising amorphous DMT or a pharmaceutically acceptable salt or prodrug thereof, and a polymeric carrier. Amorphous DMT may be characterized by a powder X-ray diffraction pattern that does not contain any discernible peaks and a differential scanning calorimetry (DSC) spectrum that lacks the sharp melting endotherms and/or phase transitions of crystalline DMT. Stability may be characterized by observing these characteristics over time, especially after accelerated aging. The inventors have unexpectedly discovered that DMT can be stabilized in an amorphous form in a polymeric carrier that is suitable for controlled transmucosal release of DMT. Stable amorphous DMT compositions may be provided in a form suitable for transmucosal administration (e.g., buccal or sublingual membranes).
載劑可為黏膜黏附聚合物基質。在一些實施例中,載劑基質可包含纖維素衍生物、聚丙烯酸、聚丙烯酸酯、聚氧化乙烯、聚乙烯吡咯啶酮、聚乙烯醇、聚(乙烯基吡咯啶酮-共-乙酸乙烯酯)、羥丙基纖維素、羥丙基甲基纖維素、丙二醇海藻酸酯、黃蓍、海藻酸鹽、樹膠、可溶性澱粉、明膠、凝集素、果膠或聚葡萄胺糖或其混合物。The carrier may be a mucoadhesive polymer matrix. In some embodiments, the carrier matrix may include cellulose derivatives, polyacrylic acid, polyacrylate, polyethylene oxide, polyvinyl pyrrolidone, polyvinyl alcohol, poly (vinyl pyrrolidone-co-vinyl acetate), hydroxypropyl cellulose, hydroxypropyl methyl cellulose, propylene glycol alginate, tragacanth, alginate, gum, soluble starch, gelatin, lectin, pectin or polyglucosamine or a mixture thereof.
在一些實施例中,組合物可包括滲透增強劑、緩衝劑及唾液刺激劑。滲透增強劑可包括膽汁鹽、氯化十六烷基吡啶(CPC)、月桂基硫酸鈉(SLS)、Tween 80、L-薄荷醇、二甲亞碸(DMSO)、油醇、油酸、油醇油酸酯、乙醯丙酸、丙二醇、二丙二醇、乙醇或其混合物。緩衝劑可為檸檬酸、酒石酸、反丁烯二酸、檸檬酸鈉、酒石酸鈉或反丁烯二酸鈉或其混合物。唾液刺激劑可為檸檬酸、蘋果酸、乳酸、抗壞血酸或酒石酸或其混合物。In some embodiments, the composition may include a permeation enhancer, a buffer and a saliva stimulant. The permeation enhancer may include bile salt, cetylpyridinium chloride (CPC), sodium lauryl sulfate (SLS), Tween 80, L-menthol, dimethyl sulfoxide (DMSO), oleyl alcohol, oleic acid, oleyl oleate, acetyl propionic acid, propylene glycol, dipropylene glycol, ethanol or a mixture thereof. The buffer may be citric acid, tartaric acid, fumaric acid, sodium citrate, sodium tartrate or sodium fumarate or a mixture thereof. The saliva stimulant may be citric acid, malic acid, lactic acid, ascorbic acid or tartaric acid or a mixture thereof.
在一些實施例中,醫藥組合物亦可包括穩定性增強劑,其中穩定性增強劑為抗氧化劑或螯合劑。穩定性增強劑可為α-生育酚、生育酚乙酸酯、L-麩胱甘肽、L-半胱胺酸、抗壞血酸、抗壞血酸棕櫚酸酯、沒食子酸丙酯、丁基化羥基甲苯(BHT)、丁基化羥基大茴香醚(BHA)、Tocobiol或乙二胺四乙酸(EDTA)或其混合物。In some embodiments, the pharmaceutical composition may also include a stability enhancer, wherein the stability enhancer is an antioxidant or a chelating agent. The stability enhancer may be α-tocopherol, tocopheryl acetate, L-glutathione, L-cysteine, ascorbic acid, ascorbic acid palmitate, propyl gallate, butylated hydroxytoluene (BHT), butylated hydroxyanisole (BHA), Tocobiol or ethylenediaminetetraacetic acid (EDTA) or a mixture thereof.
組合物可進一步包含約0重量%至約10重量%、或約0.1重量%至約10重量%之緩衝劑、約2重量%至約9重量%之緩衝劑、或約3重量%至約8.5重量%之緩衝劑。The composition may further comprise about 0 wt % to about 10 wt %, or about 0.1 wt % to about 10 wt % of a buffer, about 2 wt % to about 9 wt % of a buffer, or about 3 wt % to about 8.5 wt % of a buffer.
組合物可進一步包含約0.1重量%至約5重量%之抗氧化劑。The composition may further comprise about 0.1 wt % to about 5 wt % of an antioxidant.
組合物可進一步包含約0重量%至約8重量%或約0.1重量%至約8重量%之唾液刺激劑。The composition may further comprise about 0 wt % to about 8 wt % or about 0.1 wt % to about 8 wt % of a saliva stimulating agent.
在一些實施例中,醫藥組合物可進一步包括親水性佐劑/添加劑或基質增溶劑以促進水進入且影響膜崩解。其可包括纖維素衍生物、澱粉衍生物、交聯聚維酮、交聯纖維素、交聯澱粉或海藻酸鹽、蔗糖、麥芽糖、麥芽糊精、異麥芽糖、抗壞血酸、酸、酸鹽、糖醇或其混合物。In some embodiments, the pharmaceutical composition may further include a hydrophilic adjuvant/additive or matrix solubilizer to promote water entry and affect film disintegration. It may include cellulose derivatives, starch derivatives, cross-linked polyvidone, cross-linked cellulose, cross-linked starch or alginate, sucrose, maltose, maltodextrin, isomaltose, ascorbic acid, acid, acid salt, sugar alcohol or a mixture thereof.
組合物可進一步包含約0重量%至約15重量%之親水性佐劑/添加劑或基質增溶劑。The composition may further comprise about 0 wt % to about 15 wt % of a hydrophilic adjuvant/additive or matrix solubilizer.
在一些實施例中,醫藥組合物可進一步包括塑化劑,其中塑化劑為聚乙二醇(PEG)、丙二醇、甘油、三醋精或蓖麻油或其混合物。In some embodiments, the pharmaceutical composition may further include a plasticizer, wherein the plasticizer is polyethylene glycol (PEG), propylene glycol, glycerol, triacetin or castor oil or a mixture thereof.
在一些實施例中,醫藥組合物可進一步包括天然及/或人工甜味劑及/或調味劑。甜味劑可包括蔗糖、右旋糖、果糖、葡萄糖、麥芽糖、麥芽糖醇、糖精、蔗糖素、紐甜(neotame)、環磺酸鹽(cyclamate)、阿斯巴甜(aspartame)或乙醯磺胺酸K或其混合物。調味劑包含天然及/或合成調味油、油樹脂及自植物之多個部位(諸如葉片、果實、花等)獲得之萃取物。調味劑可包括薄荷油、肉桂油、香草萃取物、薄荷醇、L-薄荷醇或其混合物。In some embodiments, the pharmaceutical composition may further include natural and/or artificial sweeteners and/or flavorings. Sweeteners may include sucrose, dextrose, fructose, glucose, maltose, maltitol, saccharin, sucralose, neotame, cyclamate, aspartame or acesulfame K or a mixture thereof. Flavorings include natural and/or synthetic flavoring oils, oleoresins and extracts obtained from various parts of plants (such as leaves, fruits, flowers, etc.). Flavorings may include peppermint oil, cinnamon oil, vanilla extract, menthol, L-menthol or a mixture thereof.
組合物可進一步包含約0重量%至約10重量%之甜味劑。The composition may further comprise about 0 wt % to about 10 wt % of a sweetener.
組合物可進一步包含約0重量%至約5重量%之調味劑。The composition may further comprise about 0 wt % to about 5 wt % of a flavoring agent.
在一些實施例中,醫藥組合物可進一步包括天然著色劑,諸如胭脂蟲紅染料、胡蘿蔔素、胭脂樹紅染料、焦糖染料等或合成著色劑,諸如D&C或FD&C紅、黃、綠、藍、無機/礦物色素(氧化鐵紅、氧化鐵黃、二氧化鈦等)。著色劑單獨或以組合形式使用。In some embodiments, the pharmaceutical composition may further include natural colorants such as cochineal dye, carotene, carmine dye, caramel dye, etc. or synthetic colorants such as D&C or FD&C red, yellow, green, blue, inorganic/mineral pigments (red iron oxide, yellow iron oxide, titanium dioxide, etc.). The colorants are used alone or in combination.
該組合物可進一步包含約0重量%至約5重量%之著色劑/色素。The composition may further comprise about 0 wt % to about 5 wt % of a colorant/pigment.
在某些實施例中,載劑可包括羥丙基纖維素、N-乙烯基-2-吡咯啶酮及乙酸乙烯酯之共聚物及羥丙基甲基纖維素。載劑可進一步包含聚乙二醇、L-麩胱甘肽、檸檬酸、蔗糖素、麥芽糖醇及L-薄荷醇。In certain embodiments, the carrier may include hydroxypropyl cellulose, copolymer of N-vinyl-2-pyrrolidone and vinyl acetate, and hydroxypropyl methyl cellulose. The carrier may further include polyethylene glycol, L-glutathione, citric acid, sucralose, maltitol, and L-menthol.
在一些實施例中,醫藥組合物可包含(1)約0.5重量%至約60重量%之非晶形N-N-二甲基色胺或其醫藥學上可接受之鹽或前藥;(2)約15重量%至約80重量%之黏膜黏附聚合物基質;及(3)約0.1重量%至約30重量%之滲透增強劑。組合物可包含約20重量%至約35重量%之N-N-二甲基色胺或其醫藥學上可接受之鹽或前藥。組合物可包含約50重量%至約60重量%之黏膜黏附聚合物基質。組合物可包含約0.5重量%至約20重量%之塑化劑。組合物可包含約0.5重量%至約5重量%之塑化劑。組合物可包含例如黏膜黏附聚合物基質,該黏膜黏附聚合物基質包含羥丙基纖維素、N-乙烯基-2-吡咯啶酮及乙酸乙烯酯之共聚物及羥丙基甲基纖維素。In some embodiments, the pharmaceutical composition may include (1) about 0.5% to about 60% by weight of amorphous N-N-dimethyltryptamine or a pharmaceutically acceptable salt or prodrug thereof; (2) about 15% to about 80% by weight of a mucoadhesive polymer matrix; and (3) about 0.1% to about 30% by weight of a penetration enhancer. The composition may include about 20% to about 35% by weight of N-N-dimethyltryptamine or a pharmaceutically acceptable salt or prodrug thereof. The composition may include about 50% to about 60% by weight of a mucoadhesive polymer matrix. The composition may include about 0.5% to about 20% by weight of a plasticizer. The composition may include about 0.5% to about 5% by weight of a plasticizer. The composition may comprise, for example, a mucoadhesive polymer matrix comprising hydroxypropyl cellulose, a copolymer of N-vinyl-2-pyrrolidone and vinyl acetate, and hydroxypropyl methyl cellulose.
在一些實施例中,醫藥組合物可包含N-N-二甲基色胺或其醫藥學上可接受之鹽或前藥,其能夠在向有需要之患者投與該組合物之後小於1分鐘內實質上完全溶解且釋放。In some embodiments, the pharmaceutical composition may include N-N-dimethyltryptamine or a pharmaceutically acceptable salt or prodrug thereof, which is capable of substantially complete dissolution and release in less than 1 minute after administration of the composition to a patient in need thereof.
在一些實施例中,醫藥組合物可包含N-N-二甲基色胺或其醫藥學上可接受之鹽或前藥,其能夠在向有需要之患者投與該組合物之後大於1分鐘且小於20分鐘內實質上完全溶解且釋放。In some embodiments, the pharmaceutical composition may include N-N-dimethyltryptamine or a pharmaceutically acceptable salt or prodrug thereof, which is capable of substantially complete dissolution and release in greater than 1 minute and less than 20 minutes after administration of the composition to a patient in need thereof.
在一些實施例中,醫藥組合物可包含N-N-二甲基色胺或其醫藥學上可接受之鹽或前藥,其能夠在向有需要之患者投與該組合物之後大於20分鐘且小於3小時內實質上完全溶解且釋放。In some embodiments, the pharmaceutical composition may include N-N-dimethyltryptamine or a pharmaceutically acceptable salt or prodrug thereof, which is capable of substantially complete dissolution and release within greater than 20 minutes and less than 3 hours after administration of the composition to a patient in need thereof.
在一些實施例中,組合物為經口膜。經口膜可具有約0.05 mm至約0.4 mm之膜厚度。In some embodiments, the composition is an oral film. The oral film may have a film thickness of about 0.05 mm to about 0.4 mm.
在一些實施例中,本發明係關於一種治療精神健康病狀或病症之方法,其包含投與治療有效量之上文組合物,其中該精神健康病狀或病症為重度抑鬱症。In some embodiments, the invention relates to a method of treating a mental health condition or disorder comprising administering a therapeutically effective amount of the above composition, wherein the mental health condition or disorder is major depressive disorder.
在一些實施例中,本發明係關於一種製備醫藥組合物之方法,其包含以下步驟:(1)將N-N-二甲基色胺或其醫藥學上可接受之鹽或前藥與賦形劑在溶劑中組合;(2)移除溶劑,得到包含非晶形N-N-二甲基色胺或其醫藥學上可接受之鹽或前藥的聚合基質。溶劑可包含於水中的甲醇或有機溶劑,其可例如包括比率為0:100或100:0的甲醇-水。該方法可包含藉由移除溶劑來澆鑄聚合基質。溶劑可包括沸點低於水的任何有機溶劑。In some embodiments, the present invention relates to a method for preparing a pharmaceutical composition, comprising the steps of: (1) combining N-N-dimethyltryptamine or a pharmaceutically acceptable salt or prodrug thereof with an excipient in a solvent; (2) removing the solvent to obtain a polymer matrix comprising amorphous N-N-dimethyltryptamine or a pharmaceutically acceptable salt or prodrug thereof. The solvent may comprise methanol or an organic solvent in water, which may, for example, comprise methanol-water in a ratio of 0:100 or 100:0. The method may comprise casting the polymer matrix by removing the solvent. The solvent may comprise any organic solvent having a boiling point lower than water.
本發明係關於非晶形DMT之組合物,該組合物能夠使DMT穩定為非晶形形式,且以適合之劑型(例如經黏膜劑型)提供DMT的受控釋放。本發明亦係關於製備此等非晶形DMT組合物之方法,及藉由向有需要之患者投與此等組合物來治療疾病及病症(例如神經病症)的方法。The present invention relates to compositions of amorphous DMT that stabilize DMT in an amorphous form and provide controlled release of DMT in a suitable dosage form (e.g., transmucosal dosage form). The present invention also relates to methods of preparing such amorphous DMT compositions and methods of treating diseases and disorders (e.g., neurological disorders) by administering such compositions to patients in need thereof.
在本發明通篇中,參考各種專利、專利申請案及公開案。此等專利、專利申請案及公開案之全部揭示內容以引用之方式併入至本發明中以用於所有目的,以更充分地描述截至本發明之日期一般為熟習此項技術者所已知之目前先進技術。在所引用之該等專利、專利申請案及公開案與本發明之間存在任何不一致的情況下,將以本發明為準。 定義 Throughout this invention, references are made to various patents, patent applications, and publications. The entire disclosures of such patents, patent applications, and publications are incorporated herein by reference for all purposes to more fully describe the state of the art as generally known to those skilled in the art as of the date of this invention. In the event of any inconsistency between such cited patents, patent applications, and publications and this invention, the present invention will control. Definitions
為方便起見,此處收集說明書、實例及申請專利範圍中採用的某些術語。除非另外定義,否則用於本發明中之所有技術及科學術語具有與本發明所屬的一般熟習此項技術者通常所理解相同的含義。For convenience, some terms used in the specification, examples and patent application are collected here. Unless otherwise defined, all technical and scientific terms used in the present invention have the same meaning as those generally understood by those skilled in the art to which the present invention belongs.
除非上下文另外明確規定,否則單數形式「一(a/an)」及「該」包括複數個參考物。舉例而言,術語「醫藥學上可接受之載劑」可包括複數個醫藥學上可接受之載劑,包括其混合物。Unless the context clearly dictates otherwise, the singular forms "a", "an" and "the" include plural references. For example, the term "a pharmaceutically acceptable carrier" may include a plurality of pharmaceutically acceptable carriers, including mixtures thereof.
術語「及/或」意欲意謂本發明之兩種組分中之任一者或兩者。The term "and/or" is intended to mean either or both of the two components of the present invention.
術語「個體(subject)」、「個體(individual)」及「患者(patient)」在本文中可互換使用且係指人類。The terms "subject," "individual," and "patient" are used interchangeably herein and refer to a human being.
術語「載劑」係指與治療劑一起投與之稀釋劑、佐劑、賦形劑或媒劑,且包括(但不限於)親水性物質、疏水性物質及兼具親水性及疏水性特性之物質(諸如乳化劑)的液體及粉末。The term "carrier" refers to a diluent, adjuvant, excipient or vehicle with which the therapeutic agent is administered, and includes, but is not limited to, liquids and powders of hydrophilic substances, hydrophobic substances, and substances having both hydrophilic and hydrophobic properties (such as emulsifiers).
如本文所用,術語「裝置」係指能夠將藥物遞送至有需要之患者的設備或系統。As used herein, the term "device" refers to an apparatus or system capable of delivering a drug to a patient in need thereof.
如本文中所使用之術語「投與(administer)」、「投與(administering)」或「投與(administration)」係指向患者投與化合物或該化合物之醫藥學上可接受之鹽,或包含該化合物或該化合物之醫藥學上可接受之鹽的組合物或調配物。As used herein, the terms "administer," "administering," or "administration" refer to administering a compound or a pharmaceutically acceptable salt of the compound, or a composition or formulation comprising the compound or a pharmaceutically acceptable salt of the compound, to a patient.
當提及治療時,術語「需要治療」及術語「有需要的」可互換使用且係指由照護者(例如醫師、護士、護士從業者)作出的判斷,使得患者將受益於治療。When referring to treatment, the term "requiring treatment" and the term "in need" are used interchangeably and refer to the judgment made by a caregiver (e.g., physician, nurse, nurse practitioner) that a patient will benefit from treatment.
術語「治療(treat)」及「治療(treatment)」係指治療性治療,包括防治性或預防性措施,其中目標係預防或減緩(減輕)非所要的與疾病或病狀相關之生理變化。有益的或所需的臨床結果包括(但不限於)症狀緩解、疾病或病狀之程度減弱、疾病或病狀穩定(亦即,其中疾病或病狀不再惡化)、疾病或病狀之進程延遲或減緩、疾病或病狀改善或緩和及疾病或病狀緩解(不論部分或總體)。「治療」亦可意謂與不接受治療之預期存活期相比延長存活期。需要治療之彼等者包括已患有該疾病或病狀以及易於患有該疾病或病狀之彼等者或應預防該疾病或病狀之彼等者。當關於抑鬱症時,「治療」亦包括減少至少一種抑鬱症之病徵或症狀。抑鬱症之病徵或症狀之實例包括情緒抑鬱、對活動的興趣減退、體重減輕或增加、食慾下降或增大、失眠或嗜睡、精神運動性激越或遲滯、疲勞或能量損失、無價值感或過度或不恰當的罪惡感、注意減退或寡斷或有自殺意念或行為。The terms "treat" and "treatment" refer to therapeutic treatment, including prophylactic or preventative measures, in which the goal is to prevent or slow down (lessen) undesirable physiological changes associated with a disease or condition. Beneficial or desired clinical results include, but are not limited to, relief of symptoms, reduction in the severity of the disease or condition, stabilization of the disease or condition (i.e., wherein the disease or condition does not get worse), delay or reduction in the progression of the disease or condition, improvement or palliation of the disease or condition, and remission (whether partial or total) of the disease or condition. "Treatment" may also mean prolonging survival as compared to expected survival if not receiving treatment. Those in need of treatment include those already suffering from the disease or condition as well as those who are susceptible to it or those in whom it should be prevented. When referring to depression, "treatment" also includes the reduction of at least one sign or symptom of depression. Examples of signs or symptoms of depression include depressed mood, loss of interest in activities, weight loss or gain, decreased or increased appetite, insomnia or hypersomnia, psychomotor agitation or retardation, fatigue or loss of energy, feelings of worthlessness or excessive or inappropriate guilt, decreased concentration or indecisiveness, or suicidal thoughts or behaviors.
如本文所用之術語「醫藥學上可接受」係指醫藥組合物之組分,其與調配物之其他成分相容且不會對接受者產生過多的有害影響。As used herein, the term "pharmaceutically acceptable" refers to components of a pharmaceutical composition that are compatible with the other ingredients of the formulation and do not produce undue deleterious effects to the recipient.
如本文所用之術語「有效量」或「治療有效量」係指在組織、系統或個體中引起生物或醫藥反應之活性劑之量,該組織、系統或個體為研究人員、保健提供商或個體所尋求的。As used herein, the term "effective amount" or "therapeutically effective amount" refers to the amount of an active agent that elicits the biological or medicinal response in a tissue, system or individual that is being sought by a researcher, healthcare provider or individual.
如本文所用之術語「神經疾病或病症」意謂以下疾病或病狀神經精神障礙,諸如抑鬱症(包括重度抑鬱症,諸如耐治療性抑鬱症、重度抑鬱障礙及持續性抑鬱障礙)、緊張性抑鬱症、由醫療條件引起的抑鬱障礙、產後抑鬱症、經前期情感障礙或季節性情感障礙、焦慮、焦慮症、社交焦慮症、一般焦慮症(GAD)、意志力缺乏症、躁鬱症(包括躁鬱症I及躁鬱症II)、創傷後應激障礙、軀體畸形障礙、情緒或情感異常(包括上述病症)、輕鬱症、分裂情感障礙、精神分裂症及其他精神病性障礙、恐慌症、創傷應激障礙、恐懼症及伴有異常情緒之人格障礙,諸如邊緣型人格障礙、分裂症以及分裂型人格障礙以及自殺意念,或對個人行為/情緒/專注能力產生負面影響的反覆思考/無益重複性想法、強迫症、成癮(包括藥物使用障礙,諸如對以下成癮:菸鹼、酒精、可卡因、類鴉片、安非他命、甲基安非他命、海洛因、嗎啡、苯環己哌啶、3,4-亞甲二氧基-甲基安非他命以及其他成癮物質)、成癮行為(包括飲食、賭博、性、色情、電子遊戲、工作、運動、精神癡迷、自殘、旅行及購物成癮)、飲食障礙(包括神經性厭食症、神經性貪食症及暴飲暴食症)以及疼痛(包括與偏頭痛或頭痛或慢性疼痛相關的疼痛)。As used herein, the term "neurological disease or condition" means a disease or condition including a neurological disorder such as depression (including major depression, such as treatment-resistant depression, major depressive disorder and persistent depressive disorder), tension depression, depressive disorder caused by a medical condition, postpartum depression, premenstrual affective disorder or seasonal affective disorder, anxiety, anxiety disorder, social Anxiety disorder, generalized anxiety disorder (GAD), avolitional disorder, bipolar disorder (including bipolar I and bipolar II), post-traumatic stress disorder, body dysmorphic disorder, mood or affective disorder (including the above), depression, schizoaffective disorder, schizophrenia and other psychotic disorders, panic disorder, traumatic stress disorder, phobia and personality disorder with abnormal emotions, all Such as borderline personality disorder, schizophrenia and schizotypal personality disorder and suicidal ideation, or rumination/unhelpful repetitive thoughts that negatively affect personal behavior/mood/ability to concentrate, obsessive-compulsive disorder, addiction (including substance use disorders such as addiction to nicotine, alcohol, cocaine, opioids, amphetamines, methamphetamines, heroin, morphine, phencyclidine, 3,4-MDMA and other addictive substances), addictive behaviors (including addictions to eating, gambling, sex, pornography, video games, work, exercise, obsessions, self-harm, travel, and shopping), eating disorders (including anorexia nervosa, bulimia nervosa, and binge eating disorder), and pain (including pain associated with migraines or headaches or chronic pain).
如本文所用,術語「耐治療性抑鬱」或「TRD」意謂對充分治療無滿意反應的抑鬱症。TRD為受多種抑鬱亞型、精神共病及共存醫療疾病影響之複雜現象。儘管TRD發作最常見於重度抑鬱症(MDD),但其亦見於躁鬱症之抑鬱期。As used herein, the term "treatment-resistant depression" or "TRD" means depression that has not responded satisfactorily to adequate treatment. TRD is a complex phenomenon that is influenced by multiple depressive subtypes, psychiatric comorbidities, and coexisting medical illnesses. Although TRD episodes are most commonly seen in major depressive disorder (MDD), they can also occur during the depressive phase of bipolar disorder.
如本文中所使用,術語「起效」意謂在投與後達成最大血漿濃度之時間(亦即Tmax)且亦可描述為「作用起效」。在本發明之上下文中,「快速起效」意指藥物在約20分鐘內(例如,在約2分鐘至10分鐘內)達成C max。然而,與藉由IV注射投與DMT相比,根據本發明之組合物投與後的起效沒有那麼快,因此對患者的「刺激」亦較小。在一些情況下,Tmax可在10分鐘與90分鐘之間。 As used herein, the term "onset of action" means the time to reach maximum plasma concentration after administration (i.e., Tmax) and can also be described as "onset of action". In the context of the present invention, "rapid onset" means that the drug reaches Cmax within about 20 minutes (e.g., within about 2 minutes to 10 minutes). However, compared to administration of DMT by IV injection, the onset of action of the composition according to the present invention after administration is not as rapid, and therefore the "irritation" to the patient is also less. In some cases, Tmax may be between 10 minutes and 90 minutes.
如本文所用,術語「偏移」意謂在DMT之濃度最後一次處於C max±10%與DMT之血漿濃度第一次降低至臨限水準(低於該水準則藥物不再具有任何有意義的治療作用(例如約250 nmol/L或47.07 ng/mL))之間的時間。在本發明之上下文中的「快速偏移」意謂小於約10分鐘。然而,儘管偏移快速,但偏移仍足夠長,以便藥物發揮合理的致幻劑效果持續時間。 As used herein, the term "excursion" means the time between the last time the concentration of DMT was within ±10% of Cmax and the first time the plasma concentration of DMT drops to a critical level below which the drug no longer has any significant therapeutic effect (e.g., about 250 nmol/L or 47.07 ng/mL). "Rapid excursion" in the context of the present invention means less than about 10 minutes. However, despite the rapid excursion, the excursion is still long enough for the drug to exert a reasonable duration of hallucinogenic effect.
術語「經頰遞送」或「經頰投與)製劑係指將醫藥劑型施用於患者之頰部及齒齦(亦即頰腔)之間的投與途徑。The term "transbuccal delivery" or "transbuccal administration" formulation refers to a route of administration in which the pharmaceutical dosage form is administered between the cheek and gum (i.e., the buccal cavity) of a patient.
術語「舌下遞送」係指將醫藥劑型施用於患者舌下的投與途徑。The term "sublingual delivery" refers to a route of administration in which a pharmaceutical dosage form is administered under the patient's tongue.
術語「N,N-二甲基色胺」或「DMT」包括式(I)之化合物: (I) 包括醫藥學上可接受之DMT形式,包括(但不限於)鹽、酯、多晶型物/固態形式、前藥。術語「DMT游離形式」或「DMT游離鹼」係指無醫藥學上可接受之鹽的式(I)之化合物。 The term "N,N-dimethyltryptamine" or "DMT" includes compounds of formula (I): (I) includes pharmaceutically acceptable forms of DMT, including but not limited to salts, esters, polymorphs/solid forms, and prodrugs. The term "DMT free form" or "DMT free base" refers to a compound of formula (I) without a pharmaceutically acceptable salt.
本文提及「DMT或其醫藥學上可接受之鹽」時使用的術語「醫藥學上可接受之鹽」意謂醫藥學上可接受之酸加成鹽。典型地,酸性試劑可用於製備DMT的鹽,特定言之,醫藥學上可接受之鹽。適合酸性試劑之實例包括反丁烯二酸、氫氯酸、酒石酸、檸檬酸、氫溴酸、硫酸、丁二酸、磷酸、乙酸、順丁烯二酸、乳酸、酒石酸及葡萄糖酸。通常,本發明之醫藥組合物中或根據本發明之各種態樣以其他方式使用的DMT鹽形式及其實施例為反丁烯二酸鹽、氫氯酸鹽、酒石酸鹽、丁二酸鹽或檸檬酸鹽,例如反丁烯二酸鹽的醫藥學上可接受之鹽。The term "pharmaceutically acceptable salt" used herein when referring to "DMT or a pharmaceutically acceptable salt thereof" means a pharmaceutically acceptable acid addition salt. Typically, an acidic reagent can be used to prepare a salt of DMT, specifically, a pharmaceutically acceptable salt. Examples of suitable acidic reagents include fumaric acid, hydrochloric acid, tartaric acid, citric acid, hydrobromic acid, sulfuric acid, succinic acid, phosphoric acid, acetic acid, maleic acid, lactic acid, tartaric acid, and gluconic acid. Typically, the DMT salt form and embodiments thereof used in the pharmaceutical compositions of the present invention or in other ways according to various aspects of the present invention is a fumarate, hydrochlorate, tartrate, succinate or citrate, such as a pharmaceutically acceptable salt of a fumarate.
如本文中所使用,術語「非晶形」係指一種固體,其缺乏結晶材料之三維長程有序性,分子排列更為隨機,且其物理特性(諸如溶解性等)與其相應的晶體狀態截然不同。As used herein, the term "amorphous" refers to a solid that lacks the three-dimensional long-range order of a crystalline material, has a more random arrangement of molecules, and has physical properties (such as solubility) that are distinct from those of its corresponding crystalline state.
術語「微環境pH」亦稱為「局部pH」,亦稱為「表面pH」,係指當基質水合及/或溶解時,緊鄰活性劑之載劑/聚合基質區域的pH值,例如,在使用者的口中。緩衝劑亦影響經頰膜之崩解時間。The term "microenvironmental pH" also referred to as "local pH" or "surface pH" refers to the pH of the area of the carrier/polymer matrix immediately adjacent to the active agent as the matrix hydrates and/or dissolves, for example, in the user's mouth. Buffers also affect the disintegration time of buccal films.
如本文中所使用,「經黏膜型膜」係指能夠嵌入活性成分的聚合膜,該活性成分允許黏膜黏附、完全溶解或溶出、擴散及經黏膜遞送活性成分供全身吸收。As used herein, "transmucosal film" refers to a polymeric film capable of embedding an active ingredient that allows mucosal adhesion, complete dissolution or dissolution, diffusion, and transmucosal delivery of the active ingredient for systemic absorption.
如本文所用,術語「經黏膜」係指跨黏膜投與之任何途徑。實例包括(但不限於)經頰、舌下、齒齦、舌上、經鼻、經陰道及經直腸。在此實施例中,投與途徑為經頰或舌下的。As used herein, the term "transmucosal" refers to any route of administration across the mucosa. Examples include, but are not limited to, buccal, sublingual, gingival, supragingual, nasal, vaginal, and rectal. In this embodiment, the route of administration is buccal or sublingual.
術語「黏膜黏附」係指聚合物在黏液流體存在下發生水合且黏附於黏膜表面的現象。可在水性環境中容易形成凝膠之聚合物可在施用之黏膜部位引起脫水。吸入膜中的水將有助於溶解活性成分。一旦活性成分被吸收,則由於濃度梯度,剩餘膜吸收更多水。此過程產生調配物與黏液之混合物,且因此可增加與黏膜之接觸時間。參見例如Mucoadhesive drug delivery systems, Flávia Chiva Carvalho, Marcos Luciano Bruschi , Raul Cesar Evangelista, Maria Palmira Daflon Gremião, BJPS,第46卷,第1期,2010年1月/3月。The term "mucoadhesion" refers to the phenomenon that polymers become hydrated and adhere to mucosal surfaces in the presence of mucus fluids. Polymers that readily form gels in aqueous environments can cause dehydration at the mucosal site of application. Water absorbed into the membrane will help dissolve the active ingredient. Once the active ingredient is absorbed, the remaining membrane absorbs more water due to the concentration gradient. This process produces a mixture of formulation and mucus, and thus can increase the contact time with the mucosa. See, e.g., Mucoadhesive drug delivery systems, Flávia Chiva Carvalho, Marcos Luciano Bruschi, Raul Cesar Evangelista, Maria Palmira Daflon Gremião, BJPS, Vol. 46, No. 1, January/March 2010.
術語「聚合載劑基質或黏膜黏附聚合基質」係指包含具有不同功能特性(諸如(但不限於)黏膜黏附、穩定(化學及物理穩定劑)、膠凝、成膜、釋放控制、膨脹等)之聚合物之組合的載劑。 醫藥組合物及遞送 The term "polymeric carrier matrix or mucoadhesive polymeric matrix" refers to a carrier comprising a combination of polymers having different functional properties such as (but not limited to) mucoadhesion, stabilization (chemical and physical stabilizers), gelation, film formation, release control, swelling, etc. Pharmaceutical Compositions and Delivery
在一個態樣中,本發明涉及經口黏膜調配物,其中以治療有效方式釋放包含DMT之活性成分。In one aspect, the present invention relates to an oral mucosal formulation in which an active ingredient comprising DMT is released in a therapeutically effective manner.
DMT為天然存在之分子且為具有快速起效及相對較短持續時間作用的已知致幻劑藥物。DMT在經口投與時不具有活性,且在胃腸道(GI)及肝臟中轉化為非活性代謝物,隨後可充分滲透至大腦,導致較低的口服生物可用性。因此,在本發明中研究替代投與途徑(諸如經黏膜(例如經頰/舌下/齒齦/黏膜(在口腔黏膜上)或經舌頭)以藉由避開GI及肝的首過代謝來提高DMT生物可用性。參見DMT文獻之代謝GAP分析,Gina Patel, Mpharm, PhD, President and CEO, Patel Kwan Consultancy, 2020年8月25日。DMT is a naturally occurring molecule and a known hallucinogenic drug with rapid onset and relatively short duration of action. DMT is inactive when administered orally and is converted to inactive metabolites in the gastrointestinal tract (GI) and liver, which then penetrate well into the brain, resulting in low oral bioavailability. Therefore, alternative routes of administration such as transmucosal (e.g., buccal/sublingual/gingival/mucosal (on the oral mucosa) or transtongue) are investigated in the present invention to increase DMT bioavailability by avoiding first-pass metabolism in the GI and liver. See Metabolic GAP Analysis of DMT Literature, Gina Patel, Mpharm, PhD, President and CEO, Patel Kwan Consultancy, August 25, 2020.
咸信DMT在整個生物膜中具有良好滲透性。然而,DMT游離形式展現較差的水溶性,且因此DMT在經頰調配物中的滲透性取決於DMT在頰黏膜中的溶解度。因此,需要增強DMT在頰黏膜處吸收部位處之溶解度以達成其生物可用性。可採用若干途徑以增強DMT在經頰部位處之溶解度,諸如採用(但不限於)改變DMT之物理形式、鹽、前藥形式、改變微環境pH值、增溶劑、微粉化、奈米粒子、乳化液等。在本發明之一個態樣中,經頰調配物的設計目標為改變多晶型形式/固態形式,較佳為非晶形形式,以改良其溶解度且因此改良頰黏膜內之整體滲透性以獲得所需藥物動力學。It is believed that DMT has good permeability throughout the biomembrane. However, the free form of DMT exhibits poor water solubility, and therefore the permeability of DMT in buccal formulations depends on the solubility of DMT in the buccal mucosa. Therefore, it is necessary to enhance the solubility of DMT at the absorption site at the buccal mucosa to achieve its bioavailability. Several approaches can be used to enhance the solubility of DMT at the buccal site, such as (but not limited to) changing the physical form of DMT, salts, prodrug forms, changing the microenvironment pH, solubilizers, micronization, nanoparticles, emulsions, etc. In one aspect of the invention, the buccal formulation is designed to target a polymorphic form/solid state, preferably an amorphous form, to improve its solubility and thus improve overall permeability within the buccal mucosa to obtain desired pharmacokinetic.
DMT游離鹼為親脂性分子(logP-2.573),其具有小主鏈(Mol wt. 188.27 g/mol)。本發明人發現DMT可以若干多晶形式存在,包括至少形式I-IV,其中DMT之形式IV在不同研究形式中最穩定。本發明人亦發現,非晶形N,N-DMT呈現低玻璃轉化溫度(-18℃)且容易結晶,尤其在高於Tg之溫度下。出於此原因,在無穩定劑之情況下,DMT的穩定性預計不足以以非晶形式可靠地遞送給病患。DMT free base is a lipophilic molecule (logP -2.573) with a small main chain (Mol wt. 188.27 g/mol). The inventors have discovered that DMT can exist in several polycrystalline forms, including at least Forms I-IV, with Form IV of DMT being the most stable of the different forms studied. The inventors have also discovered that amorphous N,N-DMT exhibits a low glass transition temperature (-18°C) and readily crystallizes, especially at temperatures above Tg. For this reason, the stability of DMT is not expected to be sufficient for reliable delivery to patients in an amorphous form without a stabilizer.
本發明人已發現,藉由控制DMT併入聚合膜中之條件,有可能獲得一種膜,其包括呈穩定非晶形式之DMT,適用於經黏膜投與。舉例而言,達成穩定的含DMT膜之條件可包括單獨使用特定量之特定溶劑或與修飾組合物之pH組合使用。可將此等條件提供至澆鑄溶液內之溶解的DMT,由此澆鑄溶液模製成適合形式,且蒸發溶劑使得產生聚合膜。替代地或另外,該方法可包括在適合溶劑中噴霧乾燥聚合物或穩定劑及DMT以便併入DMT之穩定非晶形式。在一些實施例中,所得經噴霧乾燥之材料可直接併入聚合膜或錠劑或其他適合之劑型中。The inventors have discovered that by controlling the conditions under which DMT is incorporated into a polymeric film, it is possible to obtain a film comprising DMT in a stable amorphous form suitable for transmucosal administration. For example, the conditions under which a stable DMT-containing film is achieved may include the use of a specific amount of a specific solvent alone or in combination with the pH of the modified composition. These conditions may be provided to the dissolved DMT in a casting solution, whereby the casting solution is molded into a suitable form, and the solvent is evaporated so that a polymeric film is produced. Alternatively or in addition, the method may include spraying a dry polymer or stabilizer and DMT in a suitable solvent to incorporate a stable amorphous form of DMT. In some embodiments, the resulting spray-dried material can be directly incorporated into a polymeric film or tablet or other suitable dosage form.
如關於本申請案之實例進一步詳細解釋,在DMT/聚合物組合物形成期間適當控制pH及/或溶劑條件為達成穩定非晶形DMT/聚合物組合物中之重要因素。本發明人已發現,降低DMT/聚合物組合物之pH可導致DMT分子以可不利地影響經黏膜遞送的方式的電離。在此態樣中,在製備穩定的非晶形DMT/聚合物組合物時,在DMT/聚合物形成過程中調節pH值的一些組合且使用適當的溶劑可能係合乎需要的。As explained in further detail in the examples of the present application, proper control of pH and/or solvent conditions during the formation of the DMT/polymer composition is an important factor in achieving a stable amorphous DMT/polymer composition. The inventors have discovered that lowering the pH of the DMT/polymer composition can cause ionization of the DMT molecules in a manner that can adversely affect transmucosal delivery. In this regard, some combination of adjusting the pH during the DMT/polymer formation process and using an appropriate solvent may be desirable in preparing a stable amorphous DMT/polymer composition.
在一個態樣中,本發明涵蓋將DMT併入組合物及劑型中,包括(但不限於)快速溶解錠劑、微孔中空纖維、口嚼錠、錠劑、快速或迅速崩解錠劑、粉片、圓片、粉劑、黏膜黏附凝膠、軟膏、糊劑、海綿、乳化液、單層膜、雙層膜、多層膜、漱口劑、氣霧劑、噴霧、滴劑、膠質糖、雙層或多層錠劑、黏膜黏附錠劑等。在一個實施例中,較佳調配物為經頰/舌下膜。視溶解於口腔中之時間而定,此等膜可分為三個主要類別。快速釋放(QR)膜在幾秒鐘內溶解,一般不超過一分鐘;另一種係中度釋放膜,需要幾分鐘至至多20分鐘;而持續釋放(SR)膜的溶解速度比中度釋放膜慢,需要20分鐘以上至長達數小時。In one aspect, the present invention encompasses incorporating DMT into compositions and dosage forms, including but not limited to fast dissolving tablets, microporous hollow fibers, chewable tablets, tablets, fast or rapidly disintegrating tablets, powder tablets, discs, powders, mucoadhesive gels, ointments, pastes, sponges, emulsions, monolayer films, bilayer films, multilayer films, mouthwashes, aerosols, sprays, drops, gums, bilayer or multilayer tablets, mucoadhesive tablets, etc. In one embodiment, the preferred formulation is a buccal/sublingual film. These films can be divided into three main categories, depending on how long they take to dissolve in the mouth. Quick-release (QR) films dissolve in a few seconds, usually less than a minute; intermediate-release films, which take a few minutes to up to 20 minutes; and sustained-release (SR) films, which dissolve more slowly than intermediate-release films, taking more than 20 minutes to several hours.
QR膜可在幾秒鐘內釋放口腔中之活性物質,與經頰膜或舌下黏膜的接觸時間較短或無接觸時間。然而,中度釋放膜或SR膜在黏膜表面之接觸時間較長,從而增加活性成分通過黏膜直接吸收的機會。包含適合於經頰及舌下投與之非晶形DMT或其醫藥學上可接受之鹽的醫藥組合物包括快速溶解錠劑、粉片、膜、條帶或貼片、口內崩解錠劑、經口凝膠、藥用棒棒糖、噴霧劑、滴劑、膠質糖及其他保留在經頰或舌下黏膜表面上之調配物。QR films can release active substances in the oral cavity within a few seconds, with short or no contact time with the buccal membrane or sublingual mucosa. However, intermediate release films or SR films have a longer contact time on the mucosal surface, thereby increasing the chance of direct absorption of the active ingredient through the mucosa. Pharmaceutical compositions containing amorphous DMT or its pharmaceutically acceptable salt suitable for buccal and sublingual administration include rapidly dissolving tablets, powders, films, strips or patches, orally disintegrating tablets, oral gels, medical lollipops, sprays, drops, gums and other formulations that remain on the buccal or sublingual mucosal surface.
在一些實施例中,經頰/舌下膜之實例包括快速/迅速釋放膜(僅QR膜)及中度釋放組合物,其包含以固體溶液或懸浮液形式或部分可溶形式存在於黏膜黏附性聚合載劑基質中之藥物,其中在投與口腔中之膜後,該膜在指定時間內崩解以釋放藥物且使其可用於經由口腔黏膜吸收。QR膜及中度釋放膜經設計以在投與之後提供活性成分之瞬時釋放。In some embodiments, examples of buccal/sublingual films include fast/rapid release films (QR films only) and intermediate release compositions, which include a drug in a mucoadhesive polymeric carrier matrix in the form of a solid solution or suspension or in a partially soluble form, wherein after administration of the film in the oral cavity, the film disintegrates within a specified time to release the drug and make it available for absorption through the oral mucosa. QR films and intermediate release films are designed to provide instantaneous release of the active ingredient after administration.
在一個態樣中,本發明涵蓋一種非晶形DMT/聚合物組合物,其包括基質聚合物或黏膜黏附聚合物、滲透增強劑、塑化劑、抗氧化劑、緩衝劑及視情況存在之甜味劑、唾液刺激劑、著色劑、親水性佐劑/添加劑及/或調味劑中之一或多者。In one aspect, the present invention encompasses an amorphous DMT/polymer composition comprising a matrix polymer or a mucoadhesive polymer, a penetration enhancer, a plasticizer, an antioxidant, a buffer, and optionally one or more of a sweetener, a saliva stimulant, a colorant, a hydrophilic adjuvant/additive, and/or a flavoring agent.
適合的黏膜黏附聚合物包括一或多種選自以下之聚合物:纖維素衍生物、聚丙烯酸、聚丙烯酸酯、聚氧化乙烯、聚乙烯吡咯啶酮、聚(乙烯基吡咯啶酮-共-乙酸乙烯酯)、聚乙烯醇、丙二醇海藻酸酯、黃蓍、海藻酸鹽、樹膠(包括卡拉樹膠、瓜爾樹膠、黃原膠)、可溶性澱粉、明膠、凝集素、果膠及聚葡萄胺糖。在一些實施例中,黏膜黏附聚合物包含一或多種選自親水性聚合物、多醣及其衍生物及水凝膠之聚合物。在一些實施例中,黏膜黏附聚合物包含一或多種選自以下之聚合物:聚丙烯酸、聚丙烯酸酯、纖維素(例如羧基纖維素(例如羧甲基纖維素鈉))、羥烷基纖維素(例如羥丙基纖維素、羥乙基纖維素及羥乙基乙基纖維素)、聚乙烯吡咯啶酮、聚(乙烯吡咯啶酮--共-乙酸乙烯酯)及聚乙烯醇。在一些實施例中,黏膜黏附聚合物包含一或多種選自以下之聚合物:卡波莫(Carbopol) (聚丙烯酸)、羧甲基纖維素、羧乙基纖維素、羥丙基纖維素、羥丙基甲基纖維素及樹膠。在一些實施例中,黏膜黏附係歸因於含有硫醇基之物質,諸如(但不限於) N-乙醯基半胱胺酸、麩胱甘肽、硫醇化聚卡波非(thiolated polycarbophil) (丙烯酸及二乙烯基乙二醇之共聚物)、硫醇化聚葡萄胺糖、硫醇化羧甲基纖維素鈉、硫醇化海藻酸鈉、硫醇化羥丙基纖維素鈉、硫醇化透明質酸及硫醇化果膠。參見例如Thiolation of Biopolymers for Developing Drug Delivery Systems with Enhanced Mechanical and Mucoadhesive Properties: A Review, Vivek Puri, Ameya Sharma, Pradeep Kumar, Inderbir Singh. Polymers 2020, 12, 1803; doi:10.3390/polym12081803。在一些實施例中,黏膜黏附聚合物係水溶脹性的。通常,黏膜黏附聚合物單獨存在或以膜組合物之重量計以約15%至約80%之總量組合存在。Suitable mucoadhesive polymers include one or more polymers selected from the following: cellulose derivatives, polyacrylic acid, polyacrylates, polyethylene oxide, polyvinyl pyrrolidone, poly (vinyl pyrrolidone-co-vinyl acetate), polyvinyl alcohol, propylene glycol alginate, tragacanth, alginates, gums (including caraway gum, guar gum, xanthan gum), soluble starch, gelatin, lectin, pectin and polyglucosamine. In some embodiments, the mucoadhesive polymer comprises one or more polymers selected from hydrophilic polymers, polysaccharides and their derivatives and hydrogels. In some embodiments, the mucoadhesive polymer comprises one or more polymers selected from the group consisting of polyacrylic acid, polyacrylate, cellulose (e.g., carboxycellulose (e.g., sodium carboxymethylcellulose)), hydroxyalkylcellulose (e.g., hydroxypropylcellulose, hydroxyethylcellulose, and hydroxyethylethylcellulose), polyvinylpyrrolidone, poly(vinylpyrrolidone-co-vinyl acetate), and polyvinyl alcohol. In some embodiments, the mucoadhesive polymer comprises one or more polymers selected from the group consisting of Carbopol (polyacrylic acid), carboxymethylcellulose, carboxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, and resin. In some embodiments, mucoadhesion is due to substances containing thiol groups, such as (but not limited to) N-acetylcysteine, glutathione, thiolated polycarbophil (copolymer of acrylic acid and divinyl glycol), thiolated polyglucosamine, thiolated sodium carboxymethyl cellulose, thiolated sodium alginate, thiolated sodium hydroxypropyl cellulose, thiolated hyaluronic acid, and thiolated pectin. See, e.g., Thiolation of Biopolymers for Developing Drug Delivery Systems with Enhanced Mechanical and Mucoadhesive Properties: A Review, Vivek Puri, Ameya Sharma, Pradeep Kumar, Inderbir Singh. Polymers 2020, 12, 1803; doi:10.3390/polym12081803. In some embodiments, the mucoadhesive polymer is water soluble. Typically, the mucoadhesive polymer is present alone or in combination in a total amount of about 15% to about 80% by weight of the film composition.
膜組合物可進一步包括滲透增強劑。舉例而言,在一些實施例中,膜組合物包含滲透增強劑,例如包含一或多種選自以下之滲透增強劑:膽汁鹽,諸如去氧膽酸鈉(SDC),包括甘胺去氧膽酸鈉(SGDC)、牛磺去氧膽酸鈉(STDC)及其他;合成界面活性劑,諸如氯化十六烷基吡啶(CPC)、月桂基硫酸鈉(SLS)、Tween 80及其他,但不限於L-薄荷醇、二甲亞碸(DMSO)、油醇、油酸、油醇油酸酯、乙醯丙酸、丙二醇、二丙二醇、乙醇及界面活性劑。在一些實施例中,滲透增強劑以膜組合物之約0.1重量%至約30重量%的量存在。The membrane composition may further include a permeation enhancer. For example, in some embodiments, the membrane composition comprises a permeation enhancer, such as one or more permeation enhancers selected from the following: bile salts, such as sodium deoxycholate (SDC), including sodium glycoside deoxycholate (SGDC), sodium taurodeoxycholate (STDC) and others; synthetic surfactants, such as cetylpyridinium chloride (CPC), sodium lauryl sulfate (SLS), Tween 80 and others, but not limited to L-menthol, dimethyl sulfoxide (DMSO), oleyl alcohol, oleic acid, oleyl oleate, acetyl propionic acid, propylene glycol, dipropylene glycol, ethanol and surfactants. In some embodiments, the permeation enhancer is present in an amount from about 0.1% to about 30% by weight of the membrane composition.
在一些實施例中,膜組合物可進一步包括抗氧化劑,例如包含一或多種抗氧化劑,諸如α-生育酚、生育酚乙酸酯、L-麩胱甘肽、L半胱胺酸、抗壞血酸、抗壞血酸棕櫚酸酯、沒食子酸丙酯、丁基化羥基甲苯(BHT)、丁基化羥基大茴香醚(BHA)、Tocobiol及乙二胺四乙酸(EDTA)。在一些實施例中,抗氧化劑以膜組合物之約0.1重量%至約5重量%的量存在。In some embodiments, the membrane composition may further include an antioxidant, such as one or more antioxidants, such as α-tocopherol, tocopheryl acetate, L-glutathione, L-cysteine, ascorbic acid, ascorbyl palmitate, propyl gallate, butylated hydroxytoluene (BHT), butylated hydroxyanisole (BHA), Tocobiol and ethylenediaminetetraacetic acid (EDTA). In some embodiments, the antioxidant is present in an amount of about 0.1% to about 5% by weight of the membrane composition.
膜組合物可進一步包括塑化劑。塑化劑藉由降低膜之玻璃轉化溫度來改良膜之可撓性且降低膜之脆度。舉例而言,在一些實施例中,膜組合物包含塑化劑,例如包含一或多種選自以下之塑化劑,但不限於聚乙二醇(PEG),諸如PEG 300、PEG 400等;丙二醇、甘油、三醋精、蓖麻油。在一些實施例中,塑化劑以膜組合物之約0.5重量%至約20重量%的量存在。The film composition may further include a plasticizer. The plasticizer improves the flexibility of the film and reduces the brittleness of the film by lowering the glass transition temperature of the film. For example, in some embodiments, the film composition comprises a plasticizer, such as one or more plasticizers selected from, but not limited to, polyethylene glycol (PEG), such as PEG 300, PEG 400, etc.; propylene glycol, glycerol, triacetin, castor oil. In some embodiments, the plasticizer is present in an amount of about 0.5% to about 20% by weight of the film composition.
膜組合物可進一步包括甜味劑以改良味道。刺激唾液產生增加了唾液產量,其將有助於膜較快溶解且有助於活性的較快吸收。在一些實例中,天然或人工甜味劑用於改良調配物之適口性。舉例而言,在一些實施例中,膜組合物包含甜味劑,例如包含選自(但不限於)以下中之一或多者:蔗糖、右旋糖、果糖、葡萄糖、液體葡萄糖、麥芽糖、麥芽糖醇、糖精、蔗糖素、紐甜、環磺酸鹽、阿斯巴甜及乙醯磺胺酸K等。在一些實施例中,甜味劑以膜組合物之約0重量%至約10重量%的量存在。The film composition may further include a sweetener to improve taste. Stimulating saliva production increases saliva production, which will help the film dissolve faster and help the faster absorption of the activity. In some examples, natural or artificial sweeteners are used to improve the palatability of the formulation. For example, in some embodiments, the film composition includes a sweetener, such as one or more selected from (but not limited to) the following: sucrose, dextrose, fructose, glucose, liquid glucose, maltose, maltitol, saccharin, sucralose, neotame, cyclamate, aspartame and acesulfame K, etc. In some embodiments, the sweetener is present in an amount of about 0% by weight to about 10% by weight of the film composition.
膜組合物可進一步包括唾液刺激劑。在一些實例中,檸檬酸、蘋果酸、乳酸、抗壞血酸、丁二酸、反丁烯二酸及酒石酸用作唾液刺激劑。刺激劑單獨使用或以乾燥膜組合物重量之約0%至約8%或約0.1至約8% w/w之間的量組合使用。The film composition may further include a saliva stimulant. In some examples, citric acid, malic acid, lactic acid, ascorbic acid, succinic acid, fumaric acid, and tartaric acid are used as saliva stimulants. The stimulants are used alone or in combination in an amount of about 0% to about 8% or about 0.1 to about 8% w/w of the dry film composition weight.
膜組合物可進一步包括調味劑。在一些實例中,天然及/或合成調味油、油樹脂及自植物之多個部分(諸如葉片、果實、花等)獲得的萃取物(諸如薄荷油、肉桂油、香草萃取物、薄荷醇、L-薄荷醇或其混合物)用作調味劑。在一些實施例中,調味劑以膜組合物之約0重量%至約5重量%的量存在。The film composition may further include a flavoring agent. In some examples, natural and/or synthetic flavoring oils, oleoresins, and extracts obtained from various parts of plants (such as leaves, fruits, flowers, etc.) (such as peppermint oil, cinnamon oil, vanilla extract, menthol, L-menthol, or mixtures thereof) are used as flavoring agents. In some embodiments, the flavoring agent is present in an amount of about 0% to about 5% by weight of the film composition.
膜組合物可進一步包括親水性佐劑/添加劑或基質增溶劑以促進水進入且影響膜崩解。在一些實例中,纖維素衍生物、澱粉衍生物、交聯聚維酮、交聯纖維素、交聯澱粉或海藻酸鹽、蔗糖、麥芽糖、麥芽糊精、異麥芽糖、抗壞血酸、酸、酸鹽、糖醇或其混合物用作親水性佐劑/添加劑或基質增溶劑。在一些實施例中,親水性佐劑/添加劑或基質增溶劑以膜組合物之約0重量%至約15重量%的量存在。The film composition may further include a hydrophilic adjuvant/additive or matrix solubilizer to promote water entry and affect film disintegration. In some examples, a cellulose derivative, a starch derivative, a crosslinked polyvidone, a crosslinked cellulose, a crosslinked starch or alginate, sucrose, maltose, maltodextrin, isomaltose, ascorbic acid, an acid, an acid salt, a sugar alcohol or a mixture thereof is used as a hydrophilic adjuvant/additive or matrix solubilizer. In some embodiments, the hydrophilic adjuvant/additive or matrix solubilizer is present in an amount of about 0% to about 15% by weight of the film composition.
膜組合物可進一步包括天然著色劑,諸如胭脂蟲紅染料、胡蘿蔔素、胭脂樹紅染料、焦糖染料等或合成著色劑,諸如D&C或FD&C紅、黃、綠、藍、無機/礦物色素(氧化鐵紅、氧化鐵黃、二氧化鈦等)。著色劑單獨或以組合形式使用。在一些實施例中,著色劑以膜組合物之約0重量%至約5重量%的量存在。The film composition may further include natural colorants such as cochineal dye, carotene, carmine dye, caramel dye, etc. or synthetic colorants such as D&C or FD&C red, yellow, green, blue, inorganic/mineral pigments (red iron oxide, yellow iron oxide, titanium dioxide, etc.). The colorants are used alone or in combination. In some embodiments, the colorant is present in an amount of about 0% to about 5% by weight of the film composition.
DMT係弱鹼,pKa為8.86。膜之pH對平衡其在部位的離子化與未離子化形式起著極其重要的作用。在本發明中,維持微環境pH以達成離子化與未離子化形式之間的平衡,從而達成整個黏膜的滲透。DMT is a weak base with a pKa of 8.86. The pH of the membrane plays an extremely important role in balancing the ionized and unionized forms of DMT in the membrane. In the present invention, the pH of the microenvironment is maintained to achieve a balance between the ionized and unionized forms, thereby achieving permeation of the entire mucosa.
在一個態樣中,聚合膜表面pH/擴散環境(亦稱為微環境pH)可維持在接近於唾液之生理pH的所要pH。微環境pH可藉由調節聚合膜pH來調節及/或維持,所利用的方法包括(但不限於)在調配物中使用酸、鹼、緩衝劑。In one aspect, the polymer membrane surface pH/diffusion environment (also referred to as microenvironment pH) can be maintained at a desired pH close to the physiological pH of saliva. The microenvironment pH can be adjusted and/or maintained by adjusting the polymer membrane pH, including but not limited to using acids, bases, buffers in the formulation.
膜組合物可包括酸、鹼或緩衝劑,其可影響pH且有助於在口腔中之施用部位維持所需微量環境pH。在一些實施例中,膜組合物包含酸、鹼或緩衝劑,但不限於檸檬酸、酒石酸、反丁烯二酸、檸檬酸鈉、酒石酸鈉、反丁烯二酸鈉等。緩衝劑單獨使用或以膜組合物之約0%至約10%或約0.1至約10% w/w之間的量組合使用。The film composition may include an acid, base, or buffer, which can affect the pH and help maintain the desired microenvironmental pH at the site of application in the oral cavity. In some embodiments, the film composition comprises an acid, base, or buffer, but is not limited to citric acid, tartaric acid, fumaric acid, sodium citrate, sodium tartrate, sodium fumarate, etc. Buffers are used alone or in combination in an amount between about 0% to about 10% or about 0.1 to about 10% w/w of the film composition.
此外,可在活性膜頂部上添加非活性背層,使其成為雙層膜,以減少或防止在黏膜表面施用時來自膜背側的侵蝕。背層可進一步有助於改善膜之味道。In addition, an inactive backing layer can be added on top of the active film to make it a double layer film to reduce or prevent erosion from the back side of the film when applied to the mucosal surface. The backing layer can further help improve the taste of the film.
待併入聚合膜中之活性物質(例如DMT或其適合形式)之量視待投與之所需劑量而定。舉例而言,DMT或其適合形式可以膜之約0.5重量%至約60重量%存在。The amount of active substance (e.g., DMT or a suitable form thereof) to be incorporated into the polymeric film depends on the desired dosage to be administered. For example, DMT or a suitable form thereof may be present in about 0.5% to about 60% by weight of the film.
經頰或舌下膜之另一益處為,與需要共同投與單胺氧化酶抑制劑以實現DMT口服生物可用性的口服劑量相比,經頰或舌下膜僅需要較少劑量便能達成所需生物可用性。參見例如N, N-Dimethyltryptamine (DMT), an Endogenous Hallucinogen: Past, Present, and Future Research to Determine Its Role and Function. Steven A. Barker, Front. Neurosci., 2018年8月6日| https://doi.org/10.3389/fnins.2018.00536。Another benefit of the buccal or sublingual film is that a smaller dose is required to achieve the desired bioavailability of DMT compared to the oral dose required to co-administer a monoamine oxidase inhibitor to achieve oral bioavailability of DMT. See, e.g., N, N-Dimethyltryptamine (DMT), an Endogenous Hallucinogen: Past, Present, and Future Research to Determine Its Role and Function. Steven A. Barker, Front. Neurosci., August 6, 2018 | https://doi.org/10.3389/fnins.2018.00536.
在一些實施例中,經頰或舌下膜以約0.01 mm至約1.5 mm,且更尤其約0.05至約0.4 mm範圍內之厚度製備。此外,膜厚度可基於藥物-聚合混合物在10%至90%至此等範圍之間變化。In some embodiments, the buccal or sublingual film is prepared with a thickness ranging from about 0.01 mm to about 1.5 mm, and more particularly from about 0.05 to about 0.4 mm. In addition, the film thickness can vary between 10% to 90% of these ranges based on the drug-polymer mixture.
評估所製備之膜的物理化學特性,諸如外觀、崩解時間、溶解、分析、水含量、降解產物、多晶形式評估、機械特性,諸如耐折強度、伸長率、拉伸強度等及通過豬頰黏膜或滲透膜之活體內滲透性。 DMT 溶解度評估 The prepared films were evaluated for physicochemical properties such as appearance, disintegration time, dissolution, analysis, water content, degradation products, polymorphic form evaluation, mechanical properties such as flexural strength, elongation, tensile strength, etc. and in vivo permeability through the buccal mucosa or permeable membranes. DMT solubility evaluation
已在各種溶劑中藉由製備超飽和混合物進行DMT之溶解度研究且使用HPLC進行分析。結果如下所示。The solubility study of DMT has been conducted in various solvents by preparing supersaturated mixtures and analyzed using HPLC. The results are shown below.
用不同溶劑溶解DMT之結果展示於表1中。
按原樣對DMT API結晶形式進行溶解度研究,且結果顯示較差水/水溶性。因此,亟需改良DMT API在膜調配物中的溶解度,以獲得更好的生物可用性。Solubility studies were conducted on the crystalline form of DMT API as is and the results showed poor water/aqueous solubility. Therefore, there is a great need to improve the solubility of DMT API in membrane formulations for better bioavailability.
本工作亦旨在將API轉化為其非晶形式以改良調配物中之溶解度並且在整個存放期中維持相同形式。已選擇適合的製造方法以將DMT轉化成非晶形式,且調配物中已併入聚合物之各種組合以在存放期期間穩定膜中之非晶形式。聚合物之選擇包括一或多種選自以下之聚合物:纖維素衍生物、聚丙烯酸、聚丙烯酸酯、聚氧化乙烯、聚乙烯吡咯啶酮、聚(乙烯基吡咯啶酮-共-乙酸乙烯酯)、聚乙烯醇、丙二醇海藻酸酯、黃蓍、海藻酸鹽、樹膠(包括卡拉樹膠、瓜爾樹膠、黃原膠)、可溶性澱粉、明膠、凝集素、果膠及聚葡萄胺糖。在一些實施例中,聚合物包含一或多種選自親水性聚合物、多醣及其衍生物及水凝膠之聚合物。在一些實施例中,聚合物包含一或多種選自以下之聚合物:聚丙烯酸、聚丙烯酸酯、纖維素(例如羧基纖維素(例如羧甲基纖維素鈉))、羥烷基纖維素(例如羥丙基纖維素、羥乙基纖維素及羥乙基乙基纖維素))、聚乙烯吡咯啶酮及聚乙烯醇。在一些實施例中,聚合物包含一或多種選自以下之聚合物:卡波莫(聚丙烯酸)、羧甲基纖維素、羧乙基纖維素、羥丙基纖維素、羥丙基甲基纖維素及樹膠。The present work also aims to convert the API into its amorphous form to improve the solubility in the formulation and maintain the same form throughout the shelf life. Suitable manufacturing methods have been selected to convert DMT into an amorphous form and various combinations of polymers have been incorporated into the formulation to stabilize the amorphous form in the film during the shelf life. The selection of polymers includes one or more polymers selected from the following: cellulose derivatives, polyacrylic acid, polyacrylates, polyethylene oxide, polyvinyl pyrrolidone, poly (vinyl pyrrolidone-co-vinyl acetate), polyvinyl alcohol, propylene glycol alginate, tragacanth, alginates, gums (including caraway gum, guar gum, xanthan gum), soluble starch, gelatin, lectin, pectin and polyglucosamine. In some embodiments, the polymer comprises one or more polymers selected from hydrophilic polymers, polysaccharides and their derivatives, and hydrogels. In some embodiments, the polymer comprises one or more polymers selected from the following: polyacrylic acid, polyacrylate, cellulose (e.g., carboxycellulose (e.g., sodium carboxymethylcellulose)), hydroxyalkyl cellulose (e.g., hydroxypropyl cellulose, hydroxyethyl cellulose, and hydroxyethylethyl cellulose)), polyvinyl pyrrolidone, and polyvinyl alcohol. In some embodiments, the polymer comprises one or more polymers selected from the following: carbomer (polyacrylic acid), carboxymethyl cellulose, carboxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, and resin.
此外,已在50℃/75%RH下使用HPLC方法分析用於調配具有所需特性之經黏膜型膜的若干賦形劑與DMT之相容性,以偵測雜質含量。結果顯示於下表2中。
在不同應力條件下進行DMT之強制降解研究且使用HPLC分析樣品。結果顯示於下表3中。
已顯示,如上表中之資料所表明,DMT在力降解研究時高度易於氧化。重要的係在調配物中併入抗氧化劑以防止在存放期期間DMT的氧化且形成穩定膜。It has been shown, as indicated by the data in the table above, that DMT is highly susceptible to oxidation in force degradation studies. It is important to incorporate an antioxidant in the formulation to prevent oxidation of DMT during shelf life and to form a stable film.
根據溶解度、強制降解及相容性研究,已選擇各種功能性及非功能性賦形劑連同若干其他賦形劑用於進一步研究。 DMT 膜製造方法 Based on solubility, forced degradation and compatibility studies, various functional and non-functional excipients have been selected for further study along with several other excipients. DMT membrane fabrication process
不同製造技術,諸如溶劑澆鑄方法、熱熔擠壓、半固體澆鑄、固態分散擠壓、軋製方法等可用於DMT聚合物的形成,例如用於製備黏膜(例如,經頰、舌下等)膜製造。溶劑澆鑄方法為用於製造經頰膜之最佳方法且已在過去進行充分研究。使用溶劑澆鑄方法製造DMT之經頰膜。呈形式I (Investigations into the polymorphic properties of N,N-dimethyltryptamine by X-ray diffraction and differential scanning calorimetry, Gaujac等人(2013))或呈形式IV之DMT以及賦形劑與適合溶劑系統混合以形成與呈溶液形式之DMT的均勻混合物。使所得混合物經受除氣,用於澆鑄膜,使其乾燥,獲得含有呈非晶形式之DMT之膜。隨後將膜切割成具有所需尺寸之條帶以產生具有所需之DMT膜強度。Different manufacturing techniques, such as solvent casting, hot melt extrusion, semi-solid casting, solid dispersion extrusion, rolling methods, etc. can be used for the formation of DMT polymers, for example, for the preparation of mucosal (e.g., buccal, sublingual, etc.) film manufacturing. The solvent casting method is the best method for making buccal films and has been well studied in the past. Buccal films of DMT were made using the solvent casting method. DMT in form I (Investigations into the polymorphic properties of N,N-dimethyltryptamine by X-ray diffraction and differential scanning calorimetry, Gaujac et al. (2013)) or in form IV and a plasticizer are mixed with a suitable solvent system to form a homogeneous mixture with DMT in solution form. The resulting mixture is degassed, used to cast a film, dried, and a film containing DMT in amorphous form is obtained. The film is then cut into strips of the desired size to produce a DMT film with the desired strength.
在本工作中,已選擇溶劑以使DMT完全溶解於混合物中,且在澆鑄及乾燥時蒸發溶劑以在聚合物基質中形成非晶形DMT。已利用諸如PXRD及DSC之熟知技術確認向非晶形式的轉化。In the present work, the solvent has been chosen so that DMT is completely dissolved in the mixture and the solvent evaporates upon casting and drying to form amorphous DMT in the polymer matrix. The conversion to the amorphous form has been confirmed using well-known techniques such as PXRD and DSC.
在本發明之一些實例中,單獨的DMT及含有呈非晶形及/或結晶形式之DMT的膜已與其他賦形劑組合製備以達成溶解性及滲透性。 實例 1 In some examples of the present invention, DMT alone and films containing DMT in amorphous and/or crystalline form have been prepared in combination with other excipients to achieve solubility and permeability. Example 1
在一例示性實施例中,根據下表4中給出之配方製備DMT聚合膜。
使用以上組合物如下製備膜:DMT及賦形劑與基於水之檸檬酸鹽緩衝劑或甲醇-水(70:30)溶劑混合物混合以形成均勻混合物。將所得混合物脫氣。使用脫氣混合物澆鑄膜,乾燥且切割成條帶。The membranes were prepared using the above composition as follows: DMT and excipients were mixed with water-based citrate buffer or methanol-water (70:30) solvent mixture to form a homogeneous mixture. The resulting mixture was degassed. The degassed mixture was used to cast membranes, dried and cut into strips.
此外,使用離體滲透研究(亦即使用如下文呈現之豬頰黏膜)評估DMT通過所製備之膜的滲透率。使用Franz擴散池或使用利用動物黏膜(例如豬或綿羊頰黏膜)之腔室或藉由使用市售合成膜(例如Permeapad®)對離體滲透率進行充分研究。Franz擴散池由兩個隔室組成;一個隔室為供體隔室,另一隔室為18 mL容量且具有0.785 cm 2有效擴散區域之受體隔室。藉由水套將溫度維持在37℃。此技術亦可建立良好鑑別工具以使調配物組合物最佳化,以達成所需滲透性且測定膜保留在頰表面處所需的時間,以提供所需DMT吸收速率及程度。使用水性以及水醇性混合物製備之膜展現出DMT通過豬頰黏膜之滲透率,如圖1中所示。 實例 2 In addition, the permeation rate of DMT through the prepared membranes was evaluated using in vitro permeation studies (i.e., using porcine buccal mucosa as presented below). In vitro permeation is well studied using Franz diffusion cells or using chambers that utilize animal mucosa (e.g., porcine or sheep buccal mucosa) or by using commercially available synthetic membranes (e.g., Permeapad®). Franz diffusion cells consist of two compartments; one compartment is the donor compartment and the other compartment is the recipient compartment with a capacity of 18 mL and an effective diffusion area of 0.785 cm 2. The temperature is maintained at 37° C. by a water jacket. This technique also establishes a good identification tool to optimize the formulation composition to achieve the desired permeability and to determine the time required for the membrane to remain at the buccal surface to provide the desired rate and extent of DMT absorption. The membranes prepared using aqueous and hydroalcoholic mixtures exhibited permeation of DMT through the porcine buccal mucosa, as shown in Figure 1. Example 2
在一例示性實施例中,根據下表5中給出之配方,使用不同基質形成聚合物或其組合來評估DMT聚合膜形成:
使用以上組合物如下製備膜:DMT及賦形劑與甲醇-水(70:30)溶劑混合物混合以形成均勻混合物。將所得混合物脫氣。使用脫氣混合物澆鑄膜,乾燥且切割成條帶。使用所有如上表中所呈現之組合物成功地製備DMT膜。 實例 3 The membranes were prepared using the above compositions as follows: DMT and excipients were mixed with a methanol-water (70:30) solvent mixture to form a homogeneous mixture. The resulting mixture was degassed. The degassed mixture was used to cast a membrane, dried and cut into strips. DMT membranes were successfully prepared using all the compositions presented in the above table. Example 3
在各種實施例中,觀測到DMT在氧化應力下廣泛降解。因此,將抗氧化劑/螯合劑併入經頰/舌下膜中以使DMT穩定。使用不同抗氧化劑,使用實例2中所描述之溶劑澆鑄方法製備膜,其具有如下表6中所示之組合物。
在40
oC/75% RH下利用HPLC方法對所製備膜之穩定性進行了8週的評估,以偵測雜質含量,如下表7中所示。
根據以上穩定性結果,發現抗氧化劑改良聚合膜中DMT之穩定性。 實例 4 Based on the above stability results, it was found that antioxidants improved the stability of DMT in the polymer film. Example 4
此外,在各種含量之L-麩胱甘肽下研究DMT之穩定性。因此,DMT膜使用溶劑澆鑄方法製備,且利用如下表8中所描述的HPLC方法評估穩定性。
使用如下表9中所示之HPLC方法在50℃之較高溫度下對所製備之膜的穩定性評估1週。
在50℃溫度下,含量為0.83%及1.3%之L-麩胱甘肽在1週內展示出良好穩定性。 實例 5 At 50°C, L-glutathione with a content of 0.83% and 1.3% showed good stability within 1 week. Example 5
為評估DMT之物理形式對崩解、溶解及通過豬頰黏膜的滲透性之影響,根據下表10中給出之配方,使用含或不含檸檬酸之不同溶劑組合物來製備DMT聚合物膜。
如下製備使用以上組成之DMT膜:DMT及賦形劑與水(100%)或甲醇-水(50:50)溶劑混合物混合以形成均勻混合物(亦稱作摻合物)。將所得混合物脫氣。使用脫氣混合物澆鑄膜,乾燥且切割成條帶。使用PXRD來表徵膜之DMT形式,如圖2及圖3A至圖3B中所示。圖2顯示DMT聚合物膜調配物23之PXRD光譜(DMT之結晶峰存在)。圖3A顯示聚合物膜調配物22之PXRD光譜(DMT之結晶峰不存在)。圖3B顯示聚合物膜調配物24之PXRD光譜(DMT之結晶峰不存在)。DMT membranes using the above composition were prepared as follows: DMT and the excipient were mixed with water (100%) or a methanol-water (50:50) solvent mixture to form a uniform mixture (also referred to as an admixture). The resulting mixture was degassed. The degassed mixture was used to cast a film, dried and cut into strips. PXRD was used to characterize the DMT form of the membrane, as shown in FIG. 2 and FIG. 3A to FIG. 3B. FIG. 2 shows the PXRD spectrum of DMT polymer membrane formulation 23 (the crystallization peak of DMT is present). FIG. 3A shows the PXRD spectrum of polymer membrane formulation 22 (the crystallization peak of DMT is not present). FIG. 3B shows the PXRD spectrum of polymer membrane formulation 24 (the crystallization peak of DMT is not present).
基於PXRD結果,確認DMT以非晶形式存在於調配物22及24中。在調配物22及24中,DMT完全以溶液形式存在於摻合物中,從而產生具有非晶形DMT之膜。在調配物24中,儘管不包括甲醇,但DMT完全溶解於摻合物中,主要歸因於存在檸檬酸,其藉由降低摻合物pH來幫助DMT在100%水相中完全溶解且最終產生具有非晶形DMT之膜。Based on the PXRD results, it was confirmed that DMT existed in a non-crystalline form in formulations 22 and 24. In formulations 22 and 24, DMT existed completely in the blend in solution, resulting in a film having amorphous DMT. In formulation 24, although methanol was not included, DMT was completely dissolved in the blend, mainly due to the presence of citric acid, which helped DMT to completely dissolve in the 100% aqueous phase by lowering the pH of the blend and ultimately produced a film having amorphous DMT.
而在調配物23中,由於缺乏有助於DMT完全溶解於摻合物中所必需的甲醇及檸檬酸,DMT以結晶形式存在。In Formulation 23, DMT existed in a crystalline form due to the lack of methanol and citric acid which are necessary to facilitate complete dissolution of DMT in the admixture.
基於以上結果,推斷DMT應完全溶解於摻合物中以獲得具有非晶形DMT之膜調配物。Based on the above results, it was inferred that DMT should be completely dissolved in the blend to obtain a film formulation with amorphous DMT.
此外,如圖4A至圖4B中所示評估所製備之膜的膜崩解及溶解,以瞭解DMT物理形式對膜調配物的影響。In addition, the prepared films were evaluated for film disintegration and dissolution as shown in FIG. 4A-4B to understand the effect of the physical form of DMT on the film formulation.
調配物24之崩解時間Disintegration time of formulation 24
基於上文呈現之崩解結果,證實具有非晶形API之膜(調配物22及24)在PBS (pH 7.0)中,在5分鐘內快速崩解且形成澄清溶液,而具有結晶API之膜(調配物23)在PBS (pH 7.0)中,在約15分鐘時展示延遲的崩解且即使在35分鐘之後膜殘餘物仍未完全溶解。較長崩解時間對於DMT膜調配物而言係不合需要的,因為其會增加吞咽未溶解的殘餘物的幾率,該殘餘物最終在胃腸道及肝臟中失去活性。調配物22至24之崩解結果展示於圖5中。Based on the disintegration results presented above, it was confirmed that the films with amorphous API (Formulations 22 and 24) disintegrated rapidly and formed clear solutions in PBS (pH 7.0) within 5 minutes, while the film with crystalline API (Formulation 23) showed delayed disintegration in PBS (pH 7.0) at about 15 minutes and the film residues were not completely dissolved even after 35 minutes. Longer disintegration times are undesirable for DMT film formulations because they increase the probability of swallowing undissolved residues, which eventually lose activity in the gastrointestinal tract and liver. The disintegration results of formulations 22 to 24 are shown in Figure 5.
40 mg DMT膜(調配物22、23及24)在500 mL緩衝液(pH 6.8)中的溶解曲線Dissolution curves of 40 mg DMT films (Formulations 22, 23, and 24) in 500 mL buffer (pH 6.8)
基於以上所呈現之溶解結果,證實具有非晶形API之膜(調配物22及24)展示出快速藥物釋放,且超過80%之藥物在5分鐘內溶解。另一方面,與非晶形API膜相比,具有結晶API之膜(調配物23)在5 min及10 min時間點期間顯示出較慢溶解。在15分鐘時,所有三種調配物均展示完全藥物釋放,其係歸因於膜在500 mL溶解介質體積中之完全漏槽條件。Based on the dissolution results presented above, it was confirmed that the films with amorphous API (Formulations 22 and 24) showed rapid drug release, with more than 80% of the drug dissolved within 5 minutes. On the other hand, the film with crystalline API (Formulation 23) showed slower dissolution during the 5 min and 10 min time points compared to the amorphous API film. At 15 minutes, all three formulations showed complete drug release, which was attributed to the complete sink condition of the film in a 500 mL dissolution medium volume.
此外,評估所有製備之膜通過豬頰黏膜之滲透性,且與API於PBS (pH 7.0)中之分散液之滲透性進行比較,如圖6中所示。在一個態樣中,本發明涉及一種DMT聚合膜,當在磷酸鹽緩衝溶液0.01 M pH=7中經由豬黏膜量測時,其在60分鐘內釋放約5%或更少的DMT,在180分鐘內釋放約15%或更少的DMT,如圖6中所示。將發現調配物22及24滿足此等條件,而調配物23或未存在於聚合物基質中的DMT活性醫藥成分(API)不滿足此等條件。調配物23展現與DMT API相當之滲透性。舉例而言,在約180分鐘時調配物23展現約29%釋放,而DMT API展現約33%釋放,如圖6中所示。In addition, all prepared membranes were evaluated for permeability through porcine buccal mucosa and compared to the permeability of a dispersion of the API in PBS (pH 7.0), as shown in FIG6 . In one aspect, the present invention relates to a DMT polymeric membrane that releases about 5% or less of DMT in 60 minutes and about 15% or less of DMT in 180 minutes when measured through porcine mucosa in a phosphate buffer solution 0.01 M pH=7, as shown in FIG6 . It will be found that formulations 22 and 24 meet these conditions, while formulation 23 or the DMT active pharmaceutical ingredient (API) not present in a polymer matrix does not meet these conditions. Formulation 23 exhibits permeability comparable to that of the DMT API. For example, at about 180 minutes, Formulation 23 exhibited about 29% release, while the DMT API exhibited about 33% release, as shown in FIG. 6 .
基於以上呈現之結果,對於具有非晶形DMT (調配物22及24)的膜、結晶DMT (調配物23)的膜及DMT於PBS (pH 7.0)中之分散液,DMT均展現通過豬頰黏膜的滲透性。Based on the results presented above, DMT exhibited permeability through the buccal mucosa for the membranes with amorphous DMT (Formulations 22 and 24), the membrane with crystalline DMT (Formulation 23), and the dispersion of DMT in PBS (pH 7.0).
另外,發現DMT膜(調配物23)及DMT於PBS (pH 7.0)中之分散液的滲透性比調配物22及24膜高,其可歸因於供體腔室介質之pH。調配物23及DMT於PBS中之分散液分別展現8.9及9.5之pH,其接近DMT之8.68之pKa,且因此咸信對於調配物23及DMT分散液,在供體腔室中可能存在更多的未離子化DMT,從而導致滲透性高於調配物22及24膜,後兩者的pH值分別為7.6及7.8,由此可能存在更多的離子化DMT。In addition, the permeability of the DMT membrane (Formulation 23) and the dispersion of DMT in PBS (pH 7.0) was found to be higher than that of the membranes of Formulations 22 and 24, which can be attributed to the pH of the donor chamber medium. Formulations 23 and the dispersion of DMT in PBS exhibited pH of 8.9 and 9.5, respectively, which is close to the pKa of DMT of 8.68, and therefore it is believed that for Formulations 23 and DMT dispersions, there may be more unionized DMT in the donor chamber, resulting in higher permeability than the membranes of Formulations 22 and 24, which have pH values of 7.6 and 7.8, respectively, and thus there may be more ionized DMT.
此外,為理解膜pH對活體外滲透性之影響,如實例6中所示製備具有不同表面pH之膜。 實例 6 In addition, in order to understand the effect of membrane pH on in vivo permeability, membranes with different surface pH were prepared as shown in Example 6. Example 6
在一例示性實施例中,根據下表中給出之配方製備DMT聚合物膜。製備具有不同含量之檸檬酸的膜以產生在pH 5至10範圍內的pH且評估pH對滲透性之影響,如表11中所示。
使用以上組合物如下製備DMT膜:DMT及賦形劑與甲醇-水(70:30)溶劑混合物混合以形成均勻混合物。將所得混合物脫氣。使用脫氣混合物澆鑄膜,乾燥且切割成條帶。針對表面pH及以上組合物表中呈現之資料來量測膜。DMT membranes were prepared using the above composition as follows: DMT and excipients were mixed with a methanol-water (70:30) solvent mixture to form a homogeneous mixture. The resulting mixture was degassed. The degassed mixture was used to cast membranes, dried and cut into strips. The membranes were measured for surface pH and the data presented in the above composition table.
此外,使用離體滲透研究(亦即如下文呈現之豬頰黏膜或Permeapad®)評估DMT通過所製備之膜的滲透率。In addition, the permeation rate of DMT through the prepared membranes was evaluated using in vitro permeation studies (i.e., porcine buccal mucosa or Permeapad® as presented below).
Permeapad® (認證編號014557268)為由支撐層及脂質層組成之障壁。障壁由大豆磷脂醯膽鹼S-100作為脂質層製成。簡言之,將脂質薄層施用至有機溶液中之親水性支撐片(Pütz GmbH, Taunusstein, Germany)。使溶劑蒸發以形成障壁。在滲透墊中測定模型藥物美托洛爾(metoprolol)之滲透率,且與TR146細胞層、離體豬頰黏膜及哥廷根(Göttingen)小型豬中滲透率之文獻資料進行比較。結果顯示Permeapad®與各別活體外研究之間有良好相關性,其表明Permeapad®似乎適用作此鹼性藥物物質之pH依賴性滲透率的預測分析。建議將Permeapad®作為用於美托洛爾之經頰吸收的初步滲透性工具。當比較Papp與以凝膠形式向小型豬經頰投與之美托普洛的絕對生物可用性時,獲得極佳的2 IVIVC (R=0.98),表明在美托洛爾Permeapad®的情況下,與任何其他提及的方法相比,可用於以更快且更省力的方法模擬頰黏膜。參見Use of Permeapad® for prediction of buccal absorption: A comparison to in vitro, ex vivo and in vivo method, Hanady Ajine Bibi a, René Holm b,1, Annette Bauer-Brandl a,Permeapad® (Certification No. 014557268) is a barrier consisting of a support layer and a lipid layer. The barrier is made of soybean phospholipid acetylcholine S-100 as the lipid layer. Briefly, a thin lipid layer is applied to a hydrophilic support pad (Pütz GmbH, Taunusstein, Germany) in an organic solution. The solvent is allowed to evaporate to form the barrier. The permeability of the model drug metoprolol was determined in the pad and compared with literature data on permeability in TR146 cell layers, isolated porcine buccal mucosa and Göttingen minipigs. The results showed a good correlation between Permeapad® and the respective in vitro studies, which indicates that Permeapad® seems suitable for use as a predictive assay for the pH-dependent permeability of this alkaline drug substance. Permeapad® is recommended as a preliminary permeability tool for buccal absorption of metoprolol. When comparing Papp with the absolute bioavailability of metoprolol administered buccally in gel form to minipigs, an excellent 2 IVIVC (R=0.98) was obtained, indicating that in the case of metoprolol Permeapad® can be used to simulate the buccal mucosa in a faster and less laborious manner than any other mentioned method. See Use of Permeapad® for prediction of buccal absorption: A comparison to in vitro, ex vivo and in vivo method, Hanady Ajine Bibi a, René Holm b,1, Annette Bauer-Brandl a,
圖7A顯示DMT膜在磷酸鹽緩衝溶液(0.01 M,pH=7)中通過豬頰黏膜的滲透率。圖7B顯示在磷酸鹽緩衝溶液(0.01M pH=7)中,pH值對DMT膜通過人工PermeaPad膜的滲透率的影響。Figure 7A shows the permeability of DMT membrane through porcine buccal mucosa in phosphate buffer solution (0.01 M, pH = 7). Figure 7B shows the effect of pH on the permeability of DMT membrane through artificial PermeaPad membrane in phosphate buffer solution (0.01 M pH = 7).
在50℃ RH下利用HPLC方法對所製備膜之穩定性進行數週的評估,以偵測雜質含量,如下表12中所示。
表面pH已顯示對滲透率之影響。與pH 5.7膜相比,含有兩種極端含量之檸檬酸0% w/w及9.3% w/w的膜表面pH為9.2,顯示更好的滲透率。具有檸檬酸含量為5.0%及8.2% w/w檸檬酸之調配物在口腔中產生接近於唾液pH的pH,分別為pH 8.2及7.5,且兩種調配物皆顯示出令人滿意的人工膜滲透率,如圖所示。所有調配物在50℃溫度下1週的穩定性均展示出有希望的資料。基於滲透率及穩定性研究,含有檸檬酸含量為4.0至9.0% w/w、更佳含量為5.0至8.5% w/w之調配物為較佳的。 實例 7 Surface pH has been shown to have an effect on permeability. Membranes containing two extreme levels of citric acid, 0% w/w and 9.3% w/w, had a surface pH of 9.2 and showed better permeability compared to the pH 5.7 membrane. Formulations with citric acid levels of 5.0% and 8.2% w/w produced a pH close to saliva pH in the oral cavity, pH 8.2 and 7.5, respectively, and both formulations showed satisfactory artificial membrane permeability, as shown in the figure. The stability of all formulations at 50°C for 1 week showed promising data. Based on the permeability and stability studies, the formulation containing citric acid in an amount of 4.0 to 9.0% w/w, and more preferably 5.0 to 8.5% w/w, is preferred. Example 7
在一例示性實施例中,根據下表13中給出之配方製備DMT聚合物膜。
利用如下表15至20中所呈現之歸類方法,針對5 mg及40 mg強度,在2至8C、25℃/60%RH、40℃/75%RH下評估所製備膜之穩定性。
另外,在製造頰膜期間,DMT之結晶形式(形式I或IV)用於製造聚合膜,且製造方法在膜調配物中產生DMT的非晶形式。使用如下文所提出之PXRD及DSC光譜確認非晶形式之轉化。特定言之,應注意,PXRD繞射圖不含結晶峰。而DSC光譜缺乏結晶DMT之尖銳熔融吸熱及/或相變跡象(例如,玻璃轉化溫度)。如圖8中所示,DMT轉化為非晶形式對於頰膜調配物達成高水溶性至關重要,以確保藥物在頰腔中之黏膜表面溶解,從而促進DMT之經黏膜滲透及全身性吸收。DMT聚合物膜(批次# RD-2021DEC-01P4)之PXRD光譜展示於圖9中,確認不存在結晶峰,包括任何與DMT相關的峰。Additionally, during the manufacture of the buccal film, a crystalline form of DMT (Form I or IV) is used to make the polymeric film, and the manufacturing process produces an amorphous form of DMT in the film formulation. The conversion to the amorphous form is confirmed using PXRD and DSC spectra as presented below. Specifically, it should be noted that the PXRD diffraction pattern does not contain crystalline peaks. And the DSC spectrum lacks the sharp melting endotherm and/or phase transition signs (e.g., glass transition temperature) of crystalline DMT. As shown in FIG8 , the conversion of DMT to an amorphous form is critical for achieving high water solubility in the buccal film formulation to ensure that the drug dissolves at the mucosal surface in the buccal cavity, thereby promoting transmucosal penetration and systemic absorption of DMT. The PXRD spectrum of the DMT polymer film (Batch # RD-2021DEC-01P4) is shown in Figure 9, confirming the absence of crystalline peaks, including any peaks associated with DMT.
在本發明中,已使用各種聚合物之組合成功地產生DMT之非晶形式。此外,如圖10A至圖10B中所示,即使在加速儲存條件(亦即室溫(25℃/60%RH))下且甚至在40℃/75% RH之最差條件下,添加此等聚合物(至多6 M)亦有助於在膜中保持穩定非晶形式。圖10A顯示聚合物膜(批次# RD-2021Dec-01P4)在6個月40℃/75%相對濕度下的DSC光譜。圖10B顯示DMT聚合物膜(批次# RD-2021Dec-01P4)在6個月40℃/75%相對濕度下的DSC光譜。In the present invention, a combination of various polymers has been used to successfully produce an amorphous form of DMT. In addition, as shown in Figures 10A to 10B, the addition of these polymers (up to 6 M) helps to maintain a stable amorphous form in the film even under accelerated storage conditions, i.e., room temperature (25°C/60% RH) and even under the worst conditions of 40°C/75% RH. Figure 10A shows the DSC spectrum of the polymer film (batch # RD-2021Dec-01P4) at 40°C/75% relative humidity for 6 months. Figure 10B shows the DSC spectrum of the DMT polymer film (batch # RD-2021Dec-01P4) at 40°C/75% relative humidity for 6 months.
圖11A顯示DMT聚合物膜(批次# RD-2021Dec-01P4)在6個月25℃/60%相對濕度下的PXRD光譜,其顯示不存在結晶峰,包括任何指示DMT的峰。圖11B顯示DMT聚合物膜(批次# RD-2021Dec-01P4)在6個月40℃/75%相對濕度下的PXRD光譜,其顯示不存在結晶峰,包括任何指示DMT的峰。Figure 11A shows a PXRD spectrum of a DMT polymer film (batch # RD-2021Dec-01P4) at 25°C/60% relative humidity for 6 months, which shows the absence of crystallization peaks, including any peaks indicative of DMT. Figure 11B shows a PXRD spectrum of a DMT polymer film (batch # RD-2021Dec-01P4) at 40°C/75% relative humidity for 6 months, which shows the absence of crystallization peaks, including any peaks indicative of DMT.
在皮氏培養皿中用20mL pH值為7.0之磷酸鹽緩衝鹽水對頰膜進行崩解測試。發現膜崩解時間介於3至10分鐘之間。The buccal films were tested for disintegration in 20 mL of phosphate buffered saline, pH 7.0, in a Petri dish. The film disintegration time was found to be between 3 and 10 minutes.
此外,在pH值為6.8之磷酸鹽緩衝鹽水中量測口頰膜及純API (結晶DMT)的溶解度,發現分別為24.6mg/mL及2.3mg/mL。此改良之溶解度亦表明與聚合膜之結晶形式相比,DMT在聚合膜中之溶解度增加數倍。In addition, the solubility of buccal membrane and pure API (crystalline DMT) was measured in phosphate buffered saline at pH 6.8 and found to be 24.6 mg/mL and 2.3 mg/mL, respectively. This improved solubility also indicates that the solubility of DMT in the polymeric membrane is increased several times compared to the crystalline form of the polymeric membrane.
此外,在500 mL pH值為6.8之磷酸鹽緩衝液中,使用USP 2型溶解設備以50 rpm的速度對5mg及40mg聚合物膜進行溶解。溶解資料呈現於下圖中。膜顯示出快速溶解,且藥物在15分鐘內完全釋放。在2-8℃、25℃/60 % RH及40℃/75 % RH下對此等膜之穩定性進行6個月的評估,所有膜均顯示出快速溶解,且在15分鐘內藥物釋放超過85%,其進一步證實膜調配物中非晶形式滯留。圖12顯示5 mg及40 mg DMT膜在500 mL緩衝液(pH=6.8)中的溶解曲線。In addition, 5 mg and 40 mg polymer films were dissolved in 500 mL of phosphate buffer at pH 6.8 using a USP Type 2 dissolution apparatus at 50 rpm. The dissolution data are presented in the figure below. The films showed rapid dissolution and the drug was completely released within 15 minutes. The stability of these films was evaluated for 6 months at 2-8°C, 25°C/60% RH and 40°C/75% RH, and all films showed rapid dissolution and more than 85% drug release within 15 minutes, which further confirmed the retention of amorphous form in the film formulation. Figure 12 shows the dissolution curves of 5 mg and 40 mg DMT films in 500 mL buffer (pH=6.8).
此外,使用EpiOral活體外組織模型評估所製備之頰膜的活體外耐受性以及使用MTT分析評估細胞存活率。研究設計及細胞存活率結果分別示於圖13A及圖13B中。In addition, the in vitro tolerance of the prepared buccal membranes was evaluated using the EpiOral in vitro tissue model and the cell viability was evaluated using the MTT assay. The study design and cell viability results are shown in Figures 13A and 13B, respectively.
研究使用含1.0% Triton X100之陽性對照及不含調配物之陰性對照。如以上研究設計中所示在不同時間點,樣品包括酸性及鹼性溶液中之純API以及安慰劑,及經調配之DMT膜。The study used a positive control containing 1.0% Triton X100 and a negative control without formulation. Samples included pure API in acidic and alkaline solutions as well as placebo and formulated DMT membrane at different time points as indicated in the study design above.
基於細胞存活率之結果呈現為上表中之條形圖,當與陰性對照及陽性對照相比時,其在10、20及至多60分鐘時顯示有前景的值。膜顯示小於10分鐘之較快崩解時間,且在5分鐘內溶解約90%。發現DMT聚合物膜在20分鐘時間點展現超過80%之細胞存活率,且基於崩解及溶解資料,預期膜將在20分鐘內溶解於頰黏膜中。因此,DMT聚合物膜在臨床研究期間不大可能引起頰黏膜刺激。The results based on cell viability are presented as a bar graph in the table above, which showed promising values at 10, 20 and up to 60 minutes when compared to negative and positive controls. The films showed a relatively fast disintegration time of less than 10 minutes, and were approximately 90% dissolved within 5 minutes. The DMT polymer film was found to exhibit over 80% cell viability at the 20 minute time point, and based on the disintegration and dissolution data, it is expected that the film will dissolve in the buccal mucosa within 20 minutes. Therefore, the DMT polymer film is unlikely to cause buccal mucosal irritation during the clinical study.
基於物理化學表徵、活體外耐受性及離體滲透率資料,預期來自膜調配物之非晶形式DMT將在經頰部位處充分溶解/快速溶解。此外,基於良好表面pH值,溶解形式之DMT應呈現快速經黏膜滲透率(快速起效)及活體內生物可用性。 實例 8 Based on the physicochemical characterization, in vitro tolerability, and in vitro permeability data, it is expected that the amorphous form of DMT from the film formulation will dissolve well/rapidly at the buccal site. In addition, based on the favorable surface pH, the dissolved form of DMT should exhibit rapid transmucosal permeability (rapid onset of action) and in vivo bioavailability. Example 8
替代地或另外,非晶形DMT亦可使用噴霧乾燥製程製造。簡言之,將聚合物及/或穩定劑與DMT混合於適合溶劑/混合物中以形成溶液,隨後在受控條件下進行噴霧乾燥,以形成穩定非晶形DMT粉末。此聚合物之組合物顯示於下表21中。
此外,非晶形DMT可使用直接壓錠製程調配為錠劑。簡言之,將噴霧乾燥之N,N二甲基色胺粉末與填充劑/稀釋劑、黏合劑、崩解劑、助滑劑及潤滑劑摻合,以產生粉末摻合物,其經後續壓縮以形成錠劑。此類錠劑之組合物展示於下表21中。
此外,非晶形DMT亦可調配為聚合膜、錠劑(諸如快速或迅速崩解錠劑)、快速溶解錠劑、口內崩解錠劑、雙層或多層錠劑、黏膜黏附錠劑等或任何其他適合之劑型。In addition, amorphous DMT can also be formulated into polymer films, tablets (such as fast or rapidly disintegrating tablets), fast dissolving tablets, orally disintegrating tablets, double-layer or multi-layer tablets, mucoadhesive tablets, etc., or any other suitable dosage form.
考慮本文中所揭示之本發明之說明書及實踐,熟習此項技術者將清楚本發明之其他實施例及用途。本文中所引用之所有參考文獻(包括所有美國及外國專利及專利申請案)全部具體地且完整地以引用之方式併入本文中。希望將本說明書及實例僅視為例示性的,其中本發明之真正範圍及精神藉由以下申請專利範圍指出。Other embodiments and uses of the invention will become apparent to those skilled in the art from consideration of the specification and practice of the invention disclosed herein. All references cited herein (including all U.S. and foreign patents and patent applications) are specifically and entirely incorporated herein by reference. It is intended that the specification and examples be regarded as illustrative only, with the true scope and spirit of the invention being indicated by the following claims.
圖1顯示DMT調配物(1)檸檬酸/檸檬酸鹽及(2)甲醇/水通過製備的豬頰黏膜之膜的滲透率。Figure 1 shows the permeation rates of DMT formulations (1) citric acid/citrate salt and (2) methanol/water through prepared porcine buccal mucosal membranes.
圖2顯示DMT聚合膜調配物23之PXRD光譜,其顯示存在指示DMT的結晶峰。FIG. 2 shows the PXRD spectrum of DMT polymer film formulation 23, which shows the presence of crystalline peaks indicative of DMT.
圖3A顯示DMT聚合膜調配物22之PXRD光譜,其顯示不存在結晶峰,包括任何指示DMT的峰。FIG. 3A shows the PXRD spectrum of DMT polymer film formulation 22, which shows the absence of crystalline peaks, including any peaks indicative of DMT.
圖3B展示DMT聚合膜調配物24之PXRD光譜,其顯示不存在結晶峰,包括任何指示DMT的峰。FIG. 3B shows the PXRD spectrum of DMT polymer film formulation 24, which shows the absence of crystalline peaks, including any peaks indicative of DMT.
圖4A顯示調配物22及23之崩解測試。FIG. 4A shows the disintegration test of formulations 22 and 23.
圖4B顯示調配物24之崩解測試。FIG. 4B shows the disintegration test of formulation 24.
圖5為顯示調配物22、23及24在pH 6的500 mL緩衝液中40 mg DMT膜之溶解曲線的圖。FIG. 5 is a graph showing the dissolution curves of 40 mg DMT film of Formulations 22, 23 and 24 in 500 mL buffer at pH 6.
圖6為顯示調配物22、23及24以及API (DMT於PBS中)在pH=7的磷酸鹽緩衝溶液中通過豬黏膜的DMT滲透率的圖。FIG. 6 is a graph showing the DMT permeation rate through porcine mucosa of Formulations 22, 23 and 24 and API (DMT in PBS) in a phosphate buffer solution at pH = 7.
圖7A顯示DMT膜在磷酸鹽緩衝溶液(0.1 M,pH=7)中通過豬頰黏膜的滲透率。Figure 7A shows the permeability of DMT membrane through porcine buccal mucosa in phosphate buffer solution (0.1 M, pH = 7).
圖7B顯示在0.01M pH=7磷酸鹽緩衝溶液中,pH值對DMT膜通過人工PermeaPad膜的滲透率的影響。Figure 7B shows the effect of pH on the permeability of DMT membrane through artificial PermeaPad membrane in 0.01 M pH = 7 phosphate buffer solution.
圖8顯示DMT聚合膜(批次# RD-2021Dec-01P4)之DSC光譜。Figure 8 shows the DSC spectrum of DMT polymer film (Batch # RD-2021Dec-01P4).
圖9顯示DMT聚合膜(批次# RD-2021Dec-01P4)之PXRD光譜。Figure 9 shows the PXRD spectrum of DMT polymer film (Batch # RD-2021Dec-01P4).
圖10A顯示DMT聚合膜(批次# RD-2021Dec-01P4)在6個月25℃/60%相對濕度下的DSC光譜。FIG. 10A shows the DSC spectrum of DMT polymer film (Batch # RD-2021Dec-01P4) at 25°C/60% relative humidity for 6 months.
圖10B顯示DMT聚合膜(批次# RD-2021Dec-01P4)在6個月40℃/75%相對濕度下的DSC光譜。FIG. 10B shows the DSC spectrum of DMT polymer film (Batch # RD-2021Dec-01P4) at 40°C/75% relative humidity for 6 months.
圖11A顯示DMT聚合膜(批次# RD-2021Dec-01P4)在6個月25℃/60%相對濕度下的PXRD光譜,其顯示不存在結晶峰,包括任何指示DMT的峰。FIG. 11A shows the PXRD spectrum of a DMT polymer film (Batch # RD-2021Dec-01P4) at 25° C./60% relative humidity after 6 months, which shows the absence of crystalline peaks, including any peaks indicative of DMT.
圖11B顯示DMT聚合膜(批次# RD-2021Dec-01P4)在6個月40℃/75%相對濕度下的PXRD光譜,其顯示不存在結晶峰,包括任何指示DMT的峰。FIG. 11B shows the PXRD spectrum of a DMT polymer film (Batch # RD-2021Dec-01P4) at 40° C./75% relative humidity after 6 months, which shows the absence of crystalline peaks, including any peaks indicative of DMT.
圖12顯示5 mg及40 mg DMT膜在500 mL緩衝液(pH=6.8)中的溶解曲線。Figure 12 shows the dissolution curves of 5 mg and 40 mg DMT membranes in 500 mL buffer (pH = 6.8).
圖13A顯示使用EpiOral活體外組織模型評估所製備之頰膜的活體外耐受性以及使用MTT分析評估細胞存活率的研究設計。Figure 13A shows the study design for evaluating the in vitro tolerance of prepared buccal membranes using the EpiOral in vitro tissue model and evaluating cell viability using the MTT assay.
圖13B顯示根據圖13A所示之研究設計進行給藥後的細胞存活率測試結果。FIG. 13B shows the results of a cell viability test after drug administration according to the study design shown in FIG. 13A .
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