KR20060136367A - Transdermal pharmaceutical spray formulations comprising a VP/VA copolymer and a non-aqueous vehicle - Google Patents
Transdermal pharmaceutical spray formulations comprising a VP/VA copolymer and a non-aqueous vehicle Download PDFInfo
- Publication number
- KR20060136367A KR20060136367A KR1020067008565A KR20067008565A KR20060136367A KR 20060136367 A KR20060136367 A KR 20060136367A KR 1020067008565 A KR1020067008565 A KR 1020067008565A KR 20067008565 A KR20067008565 A KR 20067008565A KR 20060136367 A KR20060136367 A KR 20060136367A
- Authority
- KR
- South Korea
- Prior art keywords
- formulation
- transdermal
- copolymer
- weight
- present
- Prior art date
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Abstract
약학적 활성제를 포함하는 경피용 스프레이 제제들 및 이를 투여하는 방법들이 제공된다. 제제들은 약학적 활성제, VP/VA 공중합체 및 비-수성 부형제를 포함한다. 제제들은 또한 약학적 활성제의 재결정화를 방지하기 위하여 핵형성-방지제 및 피부를 통한 약물 전달률을 증가시키기 위하여 침투 증강제를 더 포함한다. 피부에 적용시, 본 발명의 제제들은 건조되어 치료 부위에서 필름을 제공한다.Transdermal spray formulations comprising a pharmaceutical active and methods of administering the same are provided. Formulations include pharmaceutical actives, VP / VA copolymers and non-aqueous excipients. The formulations also further comprise a nucleation-preventing agent to prevent recrystallization of the pharmaceutical active and a penetration enhancer to increase drug delivery rate through the skin. When applied to the skin, the formulations of the invention are dried to provide a film at the treatment site.
경피용 제제, 비-수성 부형제, 약학적 활성제, 약학적 활성 필름, 핵형성- 방지제(anti-nucleating agent)Transdermal preparations, non-aqueous excipients, pharmaceutical actives, pharmaceutically active films, anti-nucleating agents
Description
본 발명은 일반적으로 경피용 약물 전달 제제들에 관한 것이다. 보다 상세하게는, 본 발명은 약학적 활성제(pharmaceutically active agent)를 피부에 전달하는 스프레이 제제들에 관한 것이다. 국소 및 전신(systemic) 활성제들을 포함하는, 피부를 통한, 경피 또는 국소 적용에 적합한 임의의 약물이 본 발명의 제제들에 사용될 수 있다.The present invention generally relates to transdermal drug delivery agents. More specifically, the present invention relates to spray formulations for delivering a pharmaceutically active agent to the skin. Any drug suitable for transdermal or topical application through the skin, including topical and systemic actives, can be used in the formulations of the present invention.
기술적으로 적용가능한 경우, 국소 증상 및 전신 증상들 모두에 대한 약물들의 국소 또한 경피 전달은 경구 투여에 비하여 다수의 장점들을 제공한다. 경피 전달의 잇점들은 증가된 환자의 순응도(compliance), 국소화된 약물의 표적화(localized drug targeting), 흡수율의 제어, 및 간에서의 초회 통과 대사 효과(first pass metabolism effects in the liver)에 의한 감소된 생체이용률(bioavailability)의 방지를 포함한다. 전통적인 국소 전달 부형제류는 연고류, 크림류, 로션류, 페이스트류 및 겔류를 포함한다.Where technically applicable, topical and transdermal delivery of drugs for both local and systemic symptoms provide a number of advantages over oral administration. The benefits of transdermal delivery are reduced by increased patient compliance, localized drug targeting, control of absorption, and first pass metabolism effects in the liver. Prevention of bioavailability. Traditional topical delivery excipients include ointments, creams, lotions, pastes and gels.
보다 최근에는, 제어된-방출(controlled-release)을 하는 국소용 패치류를 이용할 수 있게 되었다. 국소용 패치류는 제어되는, 지속적인 방출 방식으로 피부에 활성 물질들을 전달할 수 있고 활성 물질들의 일정한 치료적 수준들(sustained therapeutic levels)의 장기 전달에 효과적임이 입증되었다.More recently, topical patches with controlled-release have become available. Topical patches have been demonstrated to be able to deliver active substances to the skin in a controlled, sustained release manner and to be effective for long term delivery of sustained therapeutic levels of active substances.
국소 투여 및 경피용 패치들을 위한 외인성 제제들(external preparations)의 분야에 선행 기술이 존재한다. 유럽출원공개 제0812588호는 기관 이식에서의 거부 반응들을 억제하거나 자기면역성 질환들 또는 과민성 질환들을 치료하는 것을 목적으로 하는 제제를 개시한다.Prior art exists in the field of external preparations for topical administration and transdermal patches. EP-A-0812588 discloses agents aimed at inhibiting rejection reactions in organ transplantation or for treating autoimmune diseases or hypersensitivity diseases.
니코틴과 같은 휘발성 액체 약물을 환자에게 경피 투여하는 경피용 패치가 국제출원공개 제0033812호에 개시되어 있다.A transdermal patch for transdermal administration of a volatile liquid drug such as nicotine to a patient is disclosed in WO0033812.
국제출원공개 제03035510호는 하나의 용기로부터 복수개의 경피 경점막 약물-함유 패치들을 편리하게 분배하는 분배기(dispenser)를 개시한다.International Application Publication No. 03035510 discloses a dispenser for conveniently dispensing a plurality of transdermal transmucosal drug-containing patches from one container.
진통제, 마취제 및 가려움 완화제(antipruritic)로서의 용도를 위한 스프레이 또는 경피용 처방(transdermal formula)의 제형인 에뮤-오일에 기반한 제제들이 미국특허 제6,528,040호에 개시되어 있다.Formulations based on emu-oil, in the form of spray or transdermal formulas for use as analgesics, anesthetics and antipruritic, are disclosed in US Pat. No. 6,528,040.
프로필노르아포모르핀(propylnorapomorphine)을 포함하는 경피용 패치 및 국소 조성물들이 유럽출원공개 제1098637호 및 관련 출원들에 개시되어 있다.Transdermal patches and topical compositions comprising propylnorapomorphine are disclosed in EP 1098637 and related applications.
일본특허출원 제2002-84701호는 여드름의 국소 치료용 패치를 개시한다. 지연형 과민증 유도제(delayed-type hypersentivity inducer)를 포함하는 국소용 패치 제제 및 이를 사용하는 방법들이 국제출원공개 제02072081호에 개시되어 있다. 국소용 마취 패치는 또는 미국 특허 제6,274,167호에 개시되어 있다.Japanese Patent Application No. 2002-84701 discloses a patch for topical treatment of acne. Topical patch preparations comprising delayed-type hypersentivity inducers and methods of using the same are disclosed in WO02002081. Topical anesthesia patches are also disclosed in US Pat. No. 6,274,167.
국제출원공개 제0137890호는 상처 치료 개선 및 약물 투여를 위한 추진제-불포함 스프레이-온 피부 패치 조성물(propellant-free spray-on skin patch composition)을 개시한다. 유럽출원공개 제0560014호, 제6400352 및 제409550호는 국제출원공개 제0137890호의 조사 보고서에서 인용된 주요한 선행기술 문헌들에 속한다.WO 0137890 discloses a propellant-free spray-on skin patch composition for wound healing improvement and drug administration. European Application Publication Nos. 0560014, 6400352 and 409550 belong to the major prior art documents cited in the survey report of International Application Publication No. 037890.
전술된 선행기술은 경피용 패치들에 대한 최근의 증가된 관심을 보여주나, 국소용 패치들은 상대적으로 생산비용이 높고, 시간이 경과됨에 따라 피부에 대한 점착성이 감소되는 특성을 종종 보인다. 패치 제거로 또는 피부에 남아있는 접착성 잔류물로부터 유발되는 염증이 알려져 있다. 또한, 패치들이 사용 후에 어린이 또는 동물들에 끼칠 수 있는 위험을 방지하기 위해 안전한 처리를 보장하는 적절한 조치들이 취해져야 한다.While the prior art described above shows recent increased interest in transdermal patches, topical patches are relatively expensive to produce and often exhibit the property of decreased adhesion to the skin over time. Inflammation caused by patch removal or from adhesive residues remaining on the skin is known. In addition, appropriate measures should be taken to ensure safe handling in order to avoid the risk that patches can pose to children or animals after use.
약물류의 경피 전달을 위한 다수의 국소용 제제들이 제안되었다. 그러나, 이와 같은 선행 제제들 각각은 실질적으로 수용성 용액들이고 수용성 약물들의 전달에만 적합하다는 점에서 제한적이다. 또한, 그들이 체온에서 피부에 접착할 수 있는 비-유동성(non-flowing) 겔들을 형성할 수 있으나, 상기 겔들은 피부 상에 접촉시 습윤상태로 남게 되고, 드레싱으로 도포되지 않으면 쉽게 씻겨질 수 있기 때문에 대상자가 처치된 영역과의 접촉을 피할 것이 요구된다.Many topical formulations have been proposed for transdermal delivery of drugs. However, each of these prior agents is limited in that they are substantially water soluble solutions and only suitable for delivery of water soluble drugs. In addition, they can form non-flowing gels that can adhere to the skin at body temperature, but the gels remain wet when contacted on the skin and can be easily washed off unless applied with a dressing. Therefore, it is required that the subject avoid contact with the treated area.
본 발명은 선행기술의 문제들을 극복하거나 또는 완화시킨다.The present invention overcomes or mitigates the problems of the prior art.
본 발명의 제1 태양에서, 경피용 스프레이 제제가 제공되며, 그 경피용 스프레이 제제는 약학적 활성제; VP/VA 공중합체 및 비-수성 부형제를 포함한다.In a first aspect of the present invention, a transdermal spray formulation is provided, the transdermal spray formulation comprising a pharmaceutically active agent; VP / VA copolymers and non-aqueous excipients.
비-수성 부형제는 바람직하게는 제제의 중량 기준으로 적어도 약 60%를 구성한다.The non-aqueous excipient preferably comprises at least about 60% by weight of the formulation.
경피용 스프레이 제제는 또한 핵형성-방지제(anti-nucleating agent)를 포함할 수 있다.Transdermal spray formulations may also include anti-nucleating agents.
경피용 스프레이 제제는 또한 침투 증강제(penetration enhancer)를 포함할 수 있다. Transdermal spray formulations may also include penetration enhancers.
본 발명의 또 다른 태양에서, 본 발명의 경피용 제제를 이를 필요로 하는 대상자의 피부 상에 분무하는 단계를 포함하는 약학적 활성제를 투여하는 방법이 제공된다.In another aspect of the invention, there is provided a method of administering a pharmaceutically active agent comprising spraying a transdermal formulation of the invention onto the skin of a subject in need thereof.
본 발명의 또 다른 태양에서, 유효한 양의 약학적 활성제, VP/VA 공중합체 및 비-수성 부형제를 포함하는 경피용 제제를 이를 필요로 하는 대상자의 피부 상에 분무하는 단계를 포함하는, 약학적 활성 필름(pharmaceutically active film)을 형성하는 방법이 제공된다.In another aspect of the invention, the method comprises spraying a transdermal formulation comprising an effective amount of a pharmaceutically active agent, a VP / VA copolymer, and a non-aqueous excipient onto the skin of a subject in need thereof. A method of forming an active film is provided.
본 발명은 경피용 약물 전달 제제들을 제공한다. 상세하게는, 본 발명은 경피 약물 전달을 위한 비-수성 스프레이 제제들을 제공한다. 보다 상세하게는, 본 발명은 약학적 활성제를 피부에 전달하는 스프레이 제제들에 관한 것이다. 약학적 활성제 외에, 본 발명의 제제들은 VP/VA 공중합체 및 비-수성 부형제를 포함하며, 상기 비-수성 부형제는 바람직하게는 포유류의 체온에서 휘발된다. 적용되면, 본 발명의 제제들은 신속하게 건조되어 미세하게 분산된 입자들인 활성제를 포함하는 필름 패치를 형성한다. 필름 패치는 물에서 용이하게 세척된다. 일부 구체예들에서, 본 발명에 따라 제조된 패치들은 통상적으로 사용되는 국소 투여 방법들과 비교할 때 활성제의 개선된 생체 이용률을 제공한다.The present invention provides transdermal drug delivery agents. In particular, the present invention provides non-aqueous spray formulations for transdermal drug delivery. More specifically, the present invention relates to spray formulations for delivering a pharmaceutically active agent to the skin. In addition to the pharmaceutically active agents, the formulations of the present invention include VP / VA copolymers and non-aqueous excipients, wherein the non-aqueous excipients are preferably volatilized at the body temperature of a mammal. When applied, the formulations of the present invention rapidly dry to form a film patch comprising the active agent which is finely dispersed particles. Film patches are easily washed in water. In certain embodiments, patches made in accordance with the present invention provide improved bioavailability of the active agent as compared to conventional topical methods of administration.
본 명세서에서 사용되는 바와 같이, "약학적 활성제(pharmaceutically active agent)"는 생체외 ( in vitro ) 또는 생체내 ( in vivo ) 시스템들에서 생물학적 효과를 생성하는 작용제(agent)를 의미한다. 이 용어는 대상자에서 치료적 반응, 예방적 반응, 약학적 반응 또는 생리적 반응 중 적어도 하나에 영향을 미치는 화합물들을 포함하도록 의도된다. 보다 상세하게는, 국소 또는 전신의 약학적 반응을 일으킬 수 있는 임의의 활성제는 본 발명의 사상의 범위 내에 속한다. 활성제들은 단독으로 또는 둘 또는 그 이상의 작용제들 또는 약물들의 혼합물로서 사용될 수 있다는 점에 유념해야 한다.As used herein, "pharmaceutically active agent" is ex vivo ( in vitro) or in vivo (in in vivo ) means an agent that produces a biological effect. The term is intended to include compounds that affect at least one of a therapeutic response, prophylactic response, pharmaceutical response or physiological response in a subject. More specifically, any active agent capable of causing a local or systemic pharmaceutical reaction is within the scope of the present invention. It should be noted that the active agents can be used alone or as a mixture of two or more agents or drugs.
본 발명이 속하는 기술 분야의 당업자들이 이해하는 바와 같이, 특정 약학적 활성제의 경피 투여의 적절성은 수개의 인자들의 고려를 필요로 한다. 예를 들면, 약학적 활성제를 본 발명의 제제들에 포함시키기 전에, 작용제는 피부를 통한 투과성, 피부 염증 또는 과민 반응 유발 가능성, 약동학적 특성들(pharmacokinetic properties), 약력학적 특성들(pharmacodynamic properties), 치료 영역(therapeutic window) 및 체내에서의 대사 반응들이 지속적인 투여와 일치하는지 여부에 대해 평가되어야 한다.As will be appreciated by those skilled in the art to which the present invention pertains, the suitability of transdermal administration of certain pharmaceutical actives requires consideration of several factors. For example, prior to incorporating the pharmaceutical active agent into the formulations of the invention, the agent may be permeable through the skin, the likelihood of causing skin inflammation or hypersensitivity reactions, pharmacokinetic properties, pharmacodynamic properties The metabolic response in the therapeutic window and in the body should be assessed for consistency with continuous administration.
본 발명의 경피용 스프레이 제제들에서 사용될 수 있는 적합한 약학적 활성제들의 비-한정적인 예들은 항염제류, 진통제류, 항관절염제류, 항경련제류, 항우울제류, 항정신병제류, 진정제류, 항불안제류, 마약 길항제류, 항파킨슨증후군제류, 콜린성 효현제류, 화학요법제류, 면역억제제류, 항바스러스제류, 항생제류, 식욕 억제제류, 항구토제류, 항콜린제류, 항히스타민제류, 항편두통제류, 관상 혈관, 뇌혈관 또는 말초 혈관 확장제류, 호르몬제류, 피임제류, 항혈전제류, 이뇨제류, 항고혈압제류, 심혈관계 약물류 및 아편계 약물류를 포함하나, 이에 한정되지 않는다. 적합한 약학적 활성제류는 수성 매질에 가용성인 것들과 비-수성 매질에 가용성인 것들을 모두 포함한다. 본 발명의 일구체예에 따르면, 약학적 활성제는 에스트라디올, 테스토스테론, 옥시부티닌, 부프레노르핀, 및 펜타닐로 구성되는 군의 하나 또는 그 이상으로부터 적합하게 선택된다. 이와 같은 적합한 화합물들 중에서 특별히 바람직한 것은 에스트라디올이다.Non-limiting examples of suitable pharmaceutical actives that can be used in the transdermal spray formulations of the invention include anti-inflammatory agents, analgesics, anti-arthritis agents, anticonvulsants, antidepressants, antipsychotics, sedatives, anti-anxiety agents, Drug antagonists, anti-Parkinson's syndrome drugs, cholinergic agonists, chemotherapy drugs, immunosuppressants, anti-virus drugs, antibiotics, appetite suppressants, antiemetic drugs, anticholinergic drugs, antihistamines, antimigraine drugs, coronary vessels, Cerebrovascular or peripheral vasodilators, hormonal drugs, contraceptive drugs, antithrombotic drugs, diuretics, antihypertensive drugs, cardiovascular drugs and opioid drugs. Suitable pharmaceutical actives include both those soluble in aqueous media and those soluble in non-aqueous media. According to one embodiment of the invention, the pharmaceutically active agent is suitably selected from one or more of the group consisting of estradiol, testosterone, oxybutynin, buprenorphine, and fentanyl. Particularly preferred among such suitable compounds is estradiol.
본 발명의 약학적 활성제들은 제제 중량의 약 40%까지의 양으로 존재할 수 있다. 에스트라디올 제제들은 적합하게는 제제 중량의 약 1% 내지 약 5%의 에스트라디올을 포함한다.The pharmaceutical actives of the present invention may be present in amounts up to about 40% of the weight of the formulation. Estradiol formulations suitably comprise from about 1% to about 5% of estradiol by weight of the formulation.
본 발명의 제제에 포함되는 약학적 활성제들은 원하는 용해도 및 방출 특성들에 따라 다양한 제형들로 적합하게 포함될 수 있다. 적합한 제형들의 비-한정적인 예들은 중성 분자들, 분자 복합체들의 구성성분들, 및 그들의 약학적으로 허용가능한 염류, 유리 산류 또는 염기류, 또는 4급 염류들, 또는 그 조합들을 포함한다. 원하는 체류 및 방출 특성들을 가지며, 체내의 pH 및 온도에서 쉽게 대사되는 약학적으로 허용가능한 에테르류, 에스테르류, 아미드류와 같은 약물들의 단순한 유도체들이 사용될 수 있다. 효소들, 활성-전 제형들(pro-active forms) 또는 약물 전구체류(pro-drugs)도 또한 본 발명에서의 사용에 적합하다.Pharmaceutically active agents included in the formulations of the present invention may be suitably included in a variety of formulations depending on the desired solubility and release properties. Non-limiting examples of suitable formulations include neutral molecules, components of molecular complexes, and their pharmaceutically acceptable salts, free acids or bases, or quaternary salts, or combinations thereof. Simple derivatives of drugs such as pharmaceutically acceptable ethers, esters, amides which have the desired retention and release properties and which are readily metabolized at pH and temperature in the body can be used. Enzymes, pro-active forms or drug pro-drugs are also suitable for use in the present invention.
본 발명의 제제들은 VP/VA 공중합체류를 포함한다. 용어 "VP/VA" 또는 "비닐 피롤리돈/비닐 아세테이트"는 단량체로서 비닐피롤리돈(N-비닐피롤리돈, N-비닐-2-피롤리돈 및 N-비닐-2-피롤리디논이라고도 부름)을 포함하는, 공중합체를 의미한다. 공중합체 비닐피롤리돈-비닐 아세테이트는 일반적으로 제약업계에서 코폴리비돈(Copolyvidon(e)), 코폴리비도늄 또는 VP-VA(또는 본 명세서에서 사용된 바와 같이 VP/VA)라는 명칭들로 공지되어 있다. VP/VA 계열 제품들은 필름-형성제(film-former)에서 바람직한 역할을 수행한다. 분자 내에서 비닐아세테이트의 비율 증가에 따라 흡습성은 감소된다. VP/VA의 이 특성은 스프레이류 또는 로션류에서 작용할 때 매우 유용하다. 또한, VP/VA 공중합체류는 에어로졸, 수성 용매 시스템 및 유기 용매 시스템들을 포함하는, 상이한 정도의 방수를 요구하는 다양한 제품들의 일차 필름 형성제들이다. 이와 같은 중합체들은 필름 유연성, 양호한 접착성, 광택, 물에 의한 재습윤성(water remoistenability) 및 경도를 보인다.Formulations of the present invention include VP / VA copolymers. The term "VP / VA" or "vinyl pyrrolidone / vinyl acetate" refers to vinylpyrrolidone (N-vinylpyrrolidone, N-vinyl-2-pyrrolidone and N-vinyl-2-pyrrolidinone as monomer). It also means a copolymer, containing). Copolymer vinylpyrrolidone-vinyl acetate is generally referred to in the pharmaceutical industry under the names Copolyvidon (e), Copolyvidonium or VP-VA (or VP / VA as used herein). Known. VP / VA family products play a desirable role in film-formers. Hygroscopicity decreases with increasing proportion of vinyl acetate in the molecule. This property of VP / VA is very useful when working in sprays or lotions. VP / VA copolymers are also primary film formers of various products that require different degrees of water resistance, including aerosols, aqueous solvent systems and organic solvent systems. Such polymers exhibit film flexibility, good adhesion, gloss, water remoistenability and hardness.
VP/VA 공중합체는 제제 중량의 약 0.1% 내지 약 20% 사이의 양으로 존재할 수 있다. 또 다른 구체예에서, VP/VA 공중합체는 제제 중량의 약 0.1% 내지 약 5% 사이의 양으로 존재할 수 있다. 또 다른 구체예에서, VP/VA 공중합체는 제제 중량의 약 0.1% 내지 약 2% 사이의 양으로 존재할 수 있다.The VP / VA copolymer may be present in an amount between about 0.1% and about 20% of the weight of the formulation. In another embodiment, the VP / VA copolymer may be present in an amount between about 0.1% and about 5% of the formulation weight. In another embodiment, the VP / VA copolymer may be present in an amount between about 0.1% and about 2% of the weight of the formulation.
VP/VA 공중합체는 비닐 아세테이트 대비 비닐피롤리돈의 임의의 비율을 포함할 수 있다. 바람직하게는, VP/VA 공중합체는 50 중량% 내지 70 중량%의 비닐피롤리돈을 포함할 수 있다. 일구체예에서, VP/VA 공중합체는 60 중량%의 비닐피롤리돈을 포함한다.The VP / VA copolymer may comprise any ratio of vinylpyrrolidone to vinyl acetate. Preferably, the VP / VA copolymer may comprise 50% to 70% by weight of vinylpyrrolidone. In one embodiment, the VP / VA copolymer comprises 60% by weight of vinylpyrrolidone.
바람직한 VP/VA 공중합체류는 26과 38 사이의 K 값을 가질 수 있다. 바람직한 VP/VA 공중합체류는 26과 34 사이의 K값을 가진다.Preferred VP / VA copolymers may have a K value between 26 and 38. Preferred VP / VA copolymers have a K value between 26 and 34.
하나의 적합한 VP/VA 공중합체는 VA64 (분말)로, 60% 비닐피롤리돈 및 40% 비닐 아세테이트를 포함하고 26과 34 사이의 K값을 갖는다.One suitable VP / VA copolymer is VA64 (powder), which contains 60% vinylpyrrolidone and 40% vinyl acetate and has a K value between 26 and 34.
본 발명의 제제들은 또한 비-수성 부형제를 포함한다. 본 명세서에서 사용되는 바와 같이, "비-수성 부형제(non-aqueous vehicle)"는 실질적으로 물을 포함하지 않는 부형제를 의미하도록 의도된다. 본 명세서에서 사용되는 바와 같이, "실질적으로 물을 포함하지 않는(substantially water-free)"은 물이 총 부형제 중량의 약 10% 미만을 구성하는 것을 의미한다. 적합하게는, 물은 중량 기준으로 총 부형제의 약 5% 미만을 구성한다. 가장 적합하게는, 물은 중량 기준으로 총 부형제의 약 1% 미만을 구성한다. 본 발명에 따라 적합하게 사용되는 부형제류는 포유류의 피부 온도, 즉, 약 33℃ 내지 약 35℃에서 휘발성인 비-수성 용매들이다. 피부에 적용되면, 비-수성 부형제는 증발하고, 활성제가 경피 흡수가 가능한 미세 입자들로서 분산되어 있는 중합체의 필름을 남긴다. 적합한 비-수성 부형제들의 비-한정적인 예들은 용매류인 에탄올, 아세테이트 및 메틸알, 및 그들의 혼합물들을 포함한다.The formulations of the present invention also include non-aqueous excipients. As used herein, "non-aqueous vehicle" is intended to mean an excipient that is substantially free of water. As used herein, "substantially water-free" means that water constitutes less than about 10% of the total excipient weight. Suitably, water constitutes less than about 5% of the total excipients by weight. Most suitably, water constitutes less than about 1% of the total excipients by weight. Excipients suitably used according to the invention are non-aqueous solvents which are volatile at the skin temperature of the mammal, ie from about 33 ° C to about 35 ° C. When applied to the skin, the non-aqueous excipient evaporates, leaving a film of polymer in which the active agent is dispersed as fine particles capable of transdermal absorption. Non-limiting examples of suitable non-aqueous excipients include solvents ethanol, acetate and methylal, and mixtures thereof.
본 발명에 따라, 주어진 제제를 위해 사용되는 비-수성 부형제의 종류 및 양은 약학적 활정제의 용해도를 포함한 수개의 인자들에 의해 결정될 것이다. 특별히 적합한 비-수성 부형제들은 약학적 활성제 및 VP/VA 공중합체를 모두 용해시킨다.According to the present invention, the type and amount of non-aqueous excipient used for a given formulation will be determined by several factors including the solubility of the pharmaceutical glidant. Particularly suitable non-aqueous excipients dissolve both the pharmaceutically active agent and the VP / VA copolymer.
본 제제들에서 사용되는 비-수성 부형제는 제제의 중량 대비 적어도 약 60%의 양으로 존재해야 한다. 일부 구체예들에서, 비-수성 부형제는 제제 중량 대비 적어도 약 70%, 적어도 약 80%, 또는 적어도 약 90%를 구성한다.The non-aqueous excipient used in the present formulations should be present in an amount of at least about 60% by weight of the formulation. In certain embodiments, the non-aqueous excipient comprises at least about 70%, at least about 80%, or at least about 90% by weight of the formulation.
본 발명의 제제들은 또한 핵형성-방지제류 및/또는 침투 증강제류와 같은 추가적인 성분들을 포함할 수 있다. 본 명세서에서 사용되는 바와 같이, "핵형성-방지제(anti-nucleation agent)"는 비-수성 부형제로부터 약학적 활성제의 결정화를 방지하기 위해 제제에 포함되는 임의의 물질을 의미한다. 적합하게는, 핵형성- 방지제는 중량 기준으로 제제의 약 1% 내지 약 10%의 양으로 존재해야 한다. 바람직한 구체예에서, 핵형성-방지제는 중량 기준으로 제제의 약 5%를 구성한다. 본 발명에 유용한 적합한 핵형성-방지제는 폴리비닐피롤리돈(PVP)이다. 용어 "폴리비닐피롤리돈(polyvinylpyrrolidone)" 또는 "PVP"는 비닐피롤리돈(N-비닐피롤리돈, N-비닐-2-피롤리돈 및 N-비닐-2-피롤리돈이라고도 부름)을 단량체로서 포함하는 단일중합체(homopolymer) 또는 공중합체인, 중합체를 의미한다. PVP 중합체류는 가용성 및 불용성 단일중합체성 PVP류, 및 비닐피롤리돈/비닐 아세테이트 및 비닐피롤리돈/디메틸아미노-에틸메타크릴레이트와 같은 공중합체류를 포함한다. 가교-결합된 단일중합체는 불용성이고 일반적으로 제약업계에서 폴리비닐폴리피롤리돈, 크로스포비돈 및 PVP라는 명칭들로 알려져 있다.The formulations of the present invention may also include additional ingredients such as nucleation-preventing agents and / or penetration enhancers. As used herein, "anti-nucleation agent" means any substance included in the formulation to prevent crystallization of the pharmaceutical active from a non-aqueous excipient. Suitably, the anti-nucleation agent should be present in an amount from about 1% to about 10% of the formulation by weight. In a preferred embodiment, the anti-nucleation agent comprises about 5% of the formulation by weight. Suitable anti-nucleation agents useful in the present invention are polyvinylpyrrolidone (PVP). The term "polyvinylpyrrolidone" or "PVP" refers to vinylpyrrolidone (also called N-vinylpyrrolidone, N-vinyl-2-pyrrolidone and N-vinyl-2-pyrrolidone) It means a polymer, which is a homopolymer or a copolymer containing as a monomer. PVP polymers include soluble and insoluble homopolymeric PVPs and copolymers such as vinylpyrrolidone / vinyl acetate and vinylpyrrolidone / dimethylamino-ethylmethacrylate. Cross-linked homopolymers are insoluble and are generally known in the pharmaceutical art by the names polyvinylpolypyrrolidone, crospovidone and PVP.
본 발명에서의 용도를 위해 적합한 PVP는 본 발명이 속하는 기술 분야에서 PVP K-30으로 알려져 있다. 적합하게는, PVP K-30은 중량 기준으로 제제의 약 1% 내지 10%의 양으로 포함된다.Suitable PVPs for use in the present invention are known in the art as PVP K-30. Suitably, PVP K-30 is included in an amount of about 1% to 10% of the formulation by weight.
일구체예에서, VP/VA 공중합체는 핵형성-방지제로서 작용할 수 있고, 이 경우, 추가적인 핵형성-방지제는 불필요할 수 있다.In one embodiment, the VP / VA copolymer can act as a nucleation-preventing agent, in which case additional nucleation-preventing agents may be unnecessary.
본 발명의 제제들은 또한 약학적 활성제들의 피부를 통한 전달을 촉진하는 것으로 알려진 작용제들을 포함할 수 있다. 이와 같은 작용제들은 침투 또는 투과 증강제들, 촉진제들, 보조제들 및 흡수 촉진제들을 의미하며, 총괄적으로 본 명세서에서 "침투 증강제류(penetration enhancers)"로 지칭된다. 침투 증강제류는 적합하게는 제제의 약 0.01% 내지 약 5.0%의 양으로 제공된다.The formulations of the present invention may also include agents known to facilitate delivery of the pharmaceutical actives through the skin. Such agents refer to penetration or permeation enhancers, accelerators, auxiliaries and absorption promoters, collectively referred to herein as "penetration enhancers." Penetration enhancers are suitably provided in amounts of about 0.01% to about 5.0% of the formulation.
본 발명에서의 사용에 적합한 침투 증강제류의 예들은 에탄올 및 이소프로필, 부틸 및 벤질 알코올류와 같은 일가 알코올류(monohydric alcohols), 또는 에틸렌 글리콜, 디에틸렌 글리콜, 또는 프로필렌 글리콜, 디프로필렌 글리콜 및 트리메틸렌 글리콜과 같은 이가 알코올류(dihydric alcohols), 또는 글리세린, 솔비톨, 및 폴리에틸렌 글리콜과 같은 다가 알코올류(polyhydric alcohols), 폴리옥시에틸렌(4) 라우릴 에테르, 폴리옥시에틸렌(2) 올레일 에테르 및 폴리옥시에틸렌(10) 올레일 에테르 및 폴리옥시에틸렌 알킬 에테르류를 포함하는, (세틸, 라우릴, 올레일 및 스테아릴과 같은) 지방족 알코올류의 폴리에틸렌 글리콜 에테르류; 올리브유 및 피마자유, 스쿠알렌, 및 라놀린과 같은 식물성, 동물성 및 어류 지방류 및 오일류; 프로필 올리에이트(propyl oleate), 데실 올리에이트, 이소프로필 팔미테이트, 글리콜 팔미테이트, 글리콜 라우레이트, 도데실 미리스테이트(dodecyl myristate), 이소프로필 미리스테이트 및 글리콜 스테아레이트와 같은 지방산 에스테르류; 올레일 알코올 및 그 유도체류와 같은 지방산 알코올류; 올레아미드 및 그 유도체류와 같은 지방산 아미드류; 우레아 및 알란토인과 같은 우레아 유도체류; 디메틸라우릴아미드, 도데실피롤리돈, 이소솔비톨, 살리실산과 같은 극성 용매류; 아미노산류 및 라우릴 술페이트 염류 및 솔비톨과 TWEEN 20이라는 상품명으로 판매되고 있는 폴리솔베이트(polysorbate) 20 및 21, 40, 60, 61, 65, 80, 81 및 85와 같은 다른 폴리솔베이트류와 같은 솔비톨 무수물의 에스테르류와 같은 보다 고분자량의 지방족 계면활성제류이다. 다른 증강제류는 올레산 및 리놀레산류, 아스코르브산, 판테놀, 부틸화된 히드록시톨루엔, 토코페롤, 토코페롤 아세테이트, 토코페릴 리놀리에이트를 포함한다. 본 발명에서 유용한 특별히 적합한 침투 증강제류는 멘톨, 디메틸이소솔비드(dimethylisosorbide), 글리세릴모노-올리에이트 및 미리스틸 락테이트를 포함한다.Examples of penetration enhancers suitable for use in the present invention are monohydric alcohols such as ethanol and isopropyl, butyl and benzyl alcohols, or ethylene glycol, diethylene glycol, or propylene glycol, dipropylene glycol and tri Dihydric alcohols such as methylene glycol, or polyhydric alcohols such as glycerin, sorbitol, and polyethylene glycol, polyoxyethylene (4) lauryl ether, polyoxyethylene (2) oleyl ether and Polyethylene glycol ethers of aliphatic alcohols (such as cetyl, lauryl, oleyl and stearyl), including polyoxyethylene (10) oleyl ethers and polyoxyethylene alkyl ethers; Vegetable, animal and fish fats and oils such as olive oil and castor oil, squalene, and lanolin; Fatty acid esters such as propyl oleate, decyl oleate, isopropyl palmitate, glycol palmitate, glycol laurate, dodecyl myristate, isopropyl myristate and glycol stearate; Fatty acid alcohols such as oleyl alcohol and derivatives thereof; Fatty acid amides such as oleamide and derivatives thereof; Urea derivatives such as urea and allantoin; Polar solvents such as dimethyllaurylamide, dodecylpyrrolidone, isosorbitol, salicylic acid; Amino acids and lauryl sulfate salts and sorbitol and other polysorbates such as polysorbate 20 and 21, 40, 60, 61, 65, 80, 81 and 85, sold under the trade name TWEEN 20; Higher molecular weight aliphatic surfactants such as esters of sorbitol anhydride. Other enhancers include oleic and linoleic acids, ascorbic acid, panthenol, butylated hydroxytoluene, tocopherol, tocopherol acetate, tocopheryl linoleate. Particularly suitable penetration enhancers useful in the present invention include menthol, dimethylisosorbide, glyceryl mono-oleate and myristyl lactate.
일구체예에서, 비-수성 부형제는 침투 증강제로 작용할 수 있고, 이 경우, 추가적인 침투 증강제는 불필요할 수 있다.In one embodiment, the non-aqueous excipient may act as a penetration enhancer, in which case additional penetration enhancers may be unnecessary.
본 발명의 제제들은 일반적으로 다음과 같이 제조된다. VP/VA 공중합체를 먼저 비-수성 부형제에 용해시키고, 이어서 약학적 활성제를 첨가한다. 필요하다면, 약학적 활성제가 용해될 때까지 용액을 초음파 처리한다. 본 발명이 속하는 기술 분야의 당업자들이 이해하는 바와 같이, 활성제를 용해시키는 추가적인 또는 대체적인 수단이 사용될 수 있다.The formulations of the present invention are generally prepared as follows. The VP / VA copolymer is first dissolved in non-aqueous excipients and then the pharmaceutical active is added. If necessary, the solution is sonicated until the pharmaceutically active agent is dissolved. As will be appreciated by those skilled in the art, additional or alternative means of dissolving the active agent may be used.
본 발명은 또한 경피용 스프레이 제제들을 투여하는 방법을 포함한다. 본 명세서에서 사용되는 "투여하는(administering)"이라는 용어는 제제와 대상자의 해부학상 부위 또는 표면 영역과의 물리적 접촉을 초래하는, 대상자의 조직에 제제를 적용하는 임의의 방식(mode)을 의미하도록 의도된다. "대상자(subject)"라는 용어는 모든 온혈 포유류, 바람직하게는 사람을 포함하도록 의도된다.The present invention also includes methods of administering transdermal spray formulations. As used herein, the term "administering" is intended to mean any mode of applying the agent to a tissue of a subject that results in physical contact of the agent with an anatomical site or surface area of the subject. It is intended. The term "subject" is intended to include all warm-blooded mammals, preferably humans.
본 명세서에서 약학적 활성제에 대해 사용되는, "약학적 유효량(therapeutically effective amount)"이라는 용어는 의도된 용도의 기간동안 국소적으로 적용되었을 때, 원하는 국소 또는 전신 효과를 가져오기에 충분한 활성제의 양을 의미하도록 의도된다. 일부 구체예들에서, 필름은 피부 상에 약 24시간 동안 유지되도록 허용된다. 통상적으로, 약학적 활성제는 제어된 방출 방식으로 전달된다.The term “therapeutically effective amount”, as used herein for a pharmaceutical active, refers to an amount of active agent sufficient to produce the desired local or systemic effect when applied topically for a period of intended use. It is intended to mean. In certain embodiments, the film is allowed to remain on the skin for about 24 hours. Typically, the pharmaceutically active agent is delivered in a controlled release manner.
특정한 활성제류에 대하여, 약학적 유효량들이 문헌에 공지되어 있거나, 또는 본 발명이 속하는 기술 분야에서 공지된 방법들에 의해 결정될 수 있다. 통상적으로, 유효량들은 선택된 활성제류 및 적용 부위에 따라 약 0.1 mg 내지 약 2,100 mg 사이의 범위에 있다. 활성제의 양에 대한 유일한 상한(upper limit)은 조성물은 결정들이 실질적으로 없는 상태로 유지되어야 하고 활성제를 용해시키기 위해 요구되는 용매의 양은 제제의 패치-형성 특성들을 억제해서는 안 된다는 것이다.For certain actives, pharmaceutically effective amounts are known in the literature or can be determined by methods known in the art. Typically, effective amounts range from about 0.1 mg to about 2,100 mg depending on the active agent selected and the site of application. The only upper limit to the amount of active agent is that the composition should remain substantially free of crystals and that the amount of solvent required to dissolve the active agent should not inhibit the patch-forming properties of the formulation.
본 발명이 속하는 기술분야의 당업자들이 이해하는 바와 같이, 치료적 투여량(therapeutic dosage) 및 투여 단위량들(dosage unit amounts)은 체외 플럭스 데이터(in vitro flux data)에 의해 추정될 수 있다. 단위 면적, 즉 제곱 센티미터 또는 세제곱 센티미터당 활성제의 양 및 농도는 원하는 치료 효과를 달성하기 위해서 독립적으로 변할 수 있다. 피부 상에 남는 필름 패치의 두께도 변할 수 있다. 일부 구체예들에서, 계량된 용량 스프레이 장치(metered dose spray apparatus)가 제제를 적용하기 위해 사용될 수 있다. 고정된 거리에서 사용될 때, 계량된 용량 스프레이 장치는 피부 상에 균일한 얇은 필름의 형성을 가능하게 한다. 특정 구체예들에서, 계량된 용량 스프레이 장치는 비-에어로졸 스프레이 장치일 수 있다.As will be appreciated by those skilled in the art, therapeutic dosages and dosage unit amounts can be estimated by in vitro flux data. The amount and concentration of active agent per unit area, ie square centimeters or cubic centimeters, can be varied independently to achieve the desired therapeutic effect. The thickness of the film patch remaining on the skin can also vary. In certain embodiments, a metered dose spray apparatus can be used to apply the formulation. When used at a fixed distance, the metered dose spray device enables the formation of a uniform thin film on the skin. In certain embodiments, the metered dose spray device can be a non-aerosol spray device.
본 발명은 또한 본 발명에 따른 경피용 제제를 이를 필요로 하는 대상자의 피부 상에 분무하는 단계를 포함하는 약학적 활성 필름(pharmaceutically active film)을 형성하는 방법을 제공한다. 본 명세서에서 사용되는 바와 같이, "필름(film)"이라는 용어는 적용 및 후속 건조 후 피부 상에 형성되는, 약학적 활성제를 포함하는 폴리머 필름을 의미한다. 전술된 바와 같이, 피부를 접촉한 직후 비-수성 부형제가 휘발되면 필름이 형성된다. 바람직하게는, 필름 코팅은 약 60초 또는 그 미만 내에 형성된다.The present invention also provides a method of forming a pharmaceutically active film comprising spraying a transdermal formulation according to the invention onto the skin of a subject in need thereof. As used herein, the term "film" refers to a polymer film comprising a pharmaceutically active agent, formed on the skin after application and subsequent drying. As described above, a film is formed when the non-aqueous excipient is volatilized immediately after contact with the skin. Preferably, the film coating is formed in about 60 seconds or less.
다음의 실시예는 본 발명의 추가적인 이해를 돕기 위해 제공된다. 사용되는 특정 물질들 및 조건들은 본 발명을 설명하기 위해서 의도된 것이며 본 발명의 정당한 범위를 제한하지 않는다.The following examples are provided to aid further understanding of the present invention. The specific materials and conditions used are intended to illustrate the invention and do not limit the legitimate scope of the invention.
테스토스테론의 Testosterone 경피용Transdermal 스프레이를 위한 제제 Formulation for Spray
테스토스테론을 활성제로 포함하는 경피용 스프레이 제제를 먼저 VP/VA를 에탄올/아세톤에 용해시키고 활성제를 첨가하고 용해시킨 후, 나머지 성분들을 첨가하여 제조하였다. 결과물인 제제는 다음 성분들을 다음 양들로 포함했다:A transdermal spray formulation containing testosterone as an active agent was prepared by first dissolving VP / VA in ethanol / acetone, adding the active agent and dissolving it, and then adding the remaining ingredients. The resulting formulation contained the following ingredients in the following amounts:
본 발명이 일부 특정성을 가지고 기술되고 예시되었으나, 본 발명이 속하는 기술 분야의 당업자들은 본 명세서에 기술된 범위 내에서 이루어질 수 있는 변형들, 추가들 및 생략들을 포함한 다양한 수정들을 이해할 것이다. 따라서, 이와 같은 수정들도 본 발명에 속하는 것으로 의도된다.Although the present invention has been described and illustrated with some specificity, those skilled in the art will understand various modifications, including variations, additions and omissions, which may be made within the scope described herein. Accordingly, such modifications are also intended to belong to the present invention.
본 명세서에서 인용된 모든 특허들, 문헌들 및 참조들은 이에 의해 참조로서 본 명세서에 포함된다. 본 명세서의 개시와 포함된 특허들, 문헌들 및 참조들이 상충되는 경우, 본 명세서의 개시가 제어하며 본 발명의 범위는 첨부된 청구항들에 법적으로 부여될 수 있는 가장 넓은 해석에 의해서만 한정되어야 한다.All patents, documents, and references cited herein are hereby incorporated by reference. In the event of a conflict between the disclosure of this specification and the patents, documents and references contained therein, the disclosure is controlled and the scope of the invention should be limited only by the broadest interpretation that may be legally granted in the appended claims. .
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| CA2719512A1 (en) | 2010-11-01 | 2012-05-01 | Stiefel Research Australia Pty Ltd | Polymeric topical compositions |
| CN102018671B (en) * | 2011-01-05 | 2012-07-25 | 浙江大学 | Estradiol transdermal spray and preparation method thereof |
| US20150065449A1 (en) * | 2011-08-12 | 2015-03-05 | Florida State University Research Foundation, Inc. | Treating Amyloidoses With A Vitamin B12 Composition Including Melatonin, Resveratrol, and EGCG |
| GB201200062D0 (en) | 2012-01-04 | 2012-02-15 | Innotesto Bvba | Estradiol oromucosal liquid compositions |
| TWI516281B (en) * | 2014-07-16 | 2016-01-11 | 健維生技有限公司 | Improved method of producing testosterone formulation and testosterone formulation produced thereby |
| US20170296484A1 (en) | 2015-11-23 | 2017-10-19 | Grace Therapeutics Llc | Topical Film-Forming Spray |
| WO2019140087A1 (en) * | 2018-01-10 | 2019-07-18 | Celista Pharmaceuticals Llc | Testosterone transdermal spray with film |
| WO2020010205A1 (en) * | 2018-07-05 | 2020-01-09 | Celista Pharmaceuticals Llc | Testosterone and estradiol transdermal spray |
| CN112206222A (en) * | 2018-11-09 | 2021-01-12 | 北京德默高科医药技术有限公司 | Multi-layer transdermal drug delivery system containing ibuprofen structural analogs |
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| FR2732223B1 (en) * | 1995-03-30 | 1997-06-13 | Sanofi Sa | PHARMACEUTICAL COMPOSITION FOR TRANSDERMAL ADMINISTRATION |
| FR2739031B1 (en) * | 1995-09-27 | 1997-11-21 | Lhd Lab Hygiene Dietetique | TRANSDERMAL MATRIX SYSTEM FOR ADMINISTRATION OF AN ESTROGEN AND / OR A PROGESTIVE BASED ON STYRENE-ISOPRENE-STYRENE COPOLYMER, PREPARATION METHOD AND THERAPEUTIC USE |
| IT1299566B1 (en) * | 1998-07-17 | 2000-03-16 | Ifi Istituto Farmacoterapico I | TRANSDERMAL PATCH AND PHARMACEUTICAL COMPOSITIONS INCLUDING R (-) - NORAPROPYLAPOMORPHINE HYDROCHLORIDE AND / OR S (+) - NORAPROPYLAPOMORPHINE |
| ATE252380T1 (en) * | 1999-02-05 | 2003-11-15 | Cipla Ltd | TOPICAL SPRAYS CONTAINING A FILM-FORMING COMPOSITION |
| US6962691B1 (en) * | 1999-05-20 | 2005-11-08 | U & I Pharmaceuticals Ltd. | Topical spray compositions |
| US6274167B1 (en) * | 2000-09-14 | 2001-08-14 | Vincent Margiotta | Topical anesthetic patch |
| US6528040B1 (en) * | 2001-01-18 | 2003-03-04 | Maurine Pearson | EMU oil-based formulations for use as an analgesic, anesthetic and antipruritic |
| DE10211832A1 (en) * | 2002-03-16 | 2003-10-02 | Lohmann Therapie Syst Lts | Hormone-containing transdermal therapeutic system with a drug reservoir based on vinyl acetate-vinylpyrrolidone copolymer with improved cohesion |
-
2004
- 2004-10-21 AU AU2004285335A patent/AU2004285335B2/en not_active Ceased
- 2004-10-21 ZA ZA200604036A patent/ZA200604036B/en unknown
- 2004-10-21 NZ NZ547376A patent/NZ547376A/en not_active IP Right Cessation
- 2004-10-21 KR KR1020067008565A patent/KR20070000397A/en not_active Application Discontinuation
- 2004-10-21 CA CA002543245A patent/CA2543245A1/en not_active Abandoned
- 2004-10-21 RU RU2006117527/15A patent/RU2006117527A/en not_active Application Discontinuation
- 2004-10-21 JP JP2006536176A patent/JP2007509122A/en active Pending
- 2004-10-21 WO PCT/GB2004/004487 patent/WO2005041943A1/en active Application Filing
- 2004-10-21 EP EP04769002A patent/EP1686969A1/en not_active Withdrawn
- 2004-10-21 AP AP2006003628A patent/AP2006003628A0/en unknown
- 2004-10-21 MX MXPA06004460A patent/MXPA06004460A/en unknown
- 2004-10-21 US US10/576,908 patent/US20070219171A1/en not_active Abandoned
- 2004-10-21 BR BRPI0415725-7A patent/BRPI0415725A/en not_active Application Discontinuation
- 2004-10-21 CN CNB2004800382138A patent/CN100431531C/en not_active Expired - Fee Related
- 2004-10-22 PE PE2004001017A patent/PE20050443A1/en not_active Application Discontinuation
- 2004-10-22 PA PA20048615501A patent/PA8615501A1/en unknown
- 2004-10-22 AR ARP040103859A patent/AR046146A1/en unknown
- 2004-10-22 SV SV2004001916A patent/SV2006001916A/en not_active Application Discontinuation
- 2004-10-22 TW TW093132292A patent/TW200524635A/en unknown
- 2004-10-22 SM SM200400022A patent/SM200400022B/en unknown
-
2006
- 2006-04-23 IL IL175094A patent/IL175094A0/en unknown
- 2006-05-18 NO NO20062234A patent/NO20062234L/en not_active Application Discontinuation
- 2006-05-23 MA MA29045A patent/MA28167A1/en unknown
-
2007
- 2007-05-04 HK HK07104732.8A patent/HK1098351A1/en not_active IP Right Cessation
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