阅读说明：本技术 用于治疗或预防更年期障碍的组合物 (Composition for treating or preventing climacteric disorder ) 是由 丹·马克森 约翰·英博尔 A·卡尔松 于 2018-05-23 设计创作，主要内容包括：本文件涉及包含至少一种非离子纤维素醚的药物组合物,其中,所述组合物具有35000cP或更高的粘度、约10mOsmol/kg至约300mOsmol/kg的渗透压摩尔浓度,和约3至约4的pH。该组合物可用于治疗和/或预防更年期障碍,其中,所述更年期障碍选自由以下组成的组：性交期间和/或之后的阴道干燥、阴道刺激、阴道瘙痒、排尿困难、性交困难,和/或阴道出血,以及它们的任意组合。(This document relates to a pharmaceutical composition comprising at least one nonionic cellulose ether, wherein the composition has a viscosity of 35000cP or greater, an osmolality of from about 10 to about 300mOsmol/kg, and a pH of from about 3 to about 4. The composition can be used for treating and/or preventing climacteric disorders, wherein the climacteric disorders are selected from the group consisting of: vaginal dryness during and/or after sexual intercourse, vaginal irritation, vaginal itching, difficulty urinating, difficulty intercourse, and/or vaginal bleeding, and any combination thereof.)

1. A composition comprising at least one nonionic cellulose ether, wherein said composition has a viscosity of about 35000cP or greater, an osmolality of about 10 to about 300mOsmol/kg, and a pH of about 3 to about 4.

2. A composition according to claim 1, wherein the composition has a viscosity of at least about 38000, about 40000, about 45000, about 47000, about 50000, about 52000, or about 55000 cP.

3. The composition of claim 1 or 2, wherein the composition has a viscosity of about 35000cP to about 100000cP, about 38000cP to about 100000cP, about 40000cP to about 100000cP, about 45000cP to about 100000cP, about 47000cP to about 100000cP, about 50000cP to about 100000cP, about 52000cP to about 100000cP, or about 55000cP to about 100000 cP.

4. A composition according to any of the preceding claims, wherein the composition has a viscosity of at least about 38000cP, about 40000cP, about 42000cP, about 45000cP, about 50000cP, about 52000cP, or about 55000cP after storage at room temperature for about 6 months.

5. The composition of any one of the preceding claims, wherein the osmolality is from about 10 to about 200mOsmol/kg, such as from about 20 to about 100mOsmol/kg, or from about 30 to about 50 mOsmol/kg.

6. The composition of any one of the preceding claims, wherein the composition has a pH of about 3 to about 3.8, such as a pH of about 3 to about 3.5, or a pH of about 3 to about 3.3.

7. Composition according to any one of the preceding claims, wherein the pH of the composition is adjusted by adding a pH adjusting agent, such as a buffer, e.g. a lactate buffer or a citrate buffer, to the composition.

8. The composition according to any one of the preceding claims, further comprising a preservative, such as benzoic acid.

9. The composition of any one of the preceding claims, wherein the at least one nonionic cellulose ether is selected from the group consisting of: methylcellulose (MC), Hydroxypropylcellulose (HPC), Hydroxypropylmethylcellulose (HPMC), Hydroxyethylethylcellulose (HEEC), and Hydroxyethylmethylcellulose (HEMC), and any combination thereof.

10. The composition of any one of the preceding claims, wherein the at least one nonionic cellulose ether is hydroxypropyl methylcellulose (HPMC).

11. The composition of any one of claims 1-10, wherein the composition does not comprise an active pharmaceutical agent.

12. The composition of any one of claims 1-10, wherein the composition further comprises an active pharmaceutical agent.

13. A composition according to any one of claims 1 to 12 for use in the treatment and/or prevention of a climacteric disorder, wherein the climacteric disorder is selected from the group consisting of: vaginal dryness during and/or after sexual intercourse, vaginal irritation, vaginal itching, difficulty urinating, difficulty intercourse, and/or vaginal bleeding, and any combination thereof.

14. A method for the treatment and/or prevention of a climacteric disorder selected from the group consisting of: vaginal dryness, vaginal irritation, vaginal itching, dysuria, dyspareunia, and/or vaginal bleeding during and/or after sexual intercourse, and any combination thereof, wherein the method comprises administering to a subject in need thereof a pharmaceutically effective amount of a composition as defined in any one of claims 1 to 12.

15. Use of a nonionic cellulose ether for the preparation of a composition as defined in any one of claims 1 to 12 for the treatment and/or prevention of a climacteric disorder, wherein the climacteric disorder is selected from the group consisting of: vaginal dryness during and/or after sexual intercourse, vaginal irritation, vaginal itching, difficulty urinating, difficulty intercourse, and/or vaginal bleeding, and any combination thereof.

16. A kit of parts comprising:

(i) a composition as defined in any one of claims 1 to 12;

(ii) a dispenser for the composition; and

(iii) optional instructions for use.

Technical Field

This document relates to a composition for the treatment and/or prevention of conditions associated with climacteric disorders, such as vaginal dryness, vaginal irritation, vaginal itching, dysuria, dyspareunia, and/or vaginal bleeding during and/or after sexual intercourse. The composition is a gel comprising a nonionic cellulose ether, and the treatment involves vaginal administration of the gel.

Background

During and after menopause, women may experience several different climacteric disorders, such as vaginal dryness during and/or after sexual intercourse, vaginal irritation, vaginal itching, difficulty urinating, difficulty intercourse, and/or vaginal bleeding, and any combination thereof. Today, such disorders are often treated with hormone replacement therapy, such as administration of estrogens in different forms and formulations. However, such hormone replacement therapy may be associated with side effects, such as increased risk of stroke, blood clots, and cancer.

Cellulose ethers are named and based on cellulose, which is a renewable material and the most common organic compound in nature. A wide variety of ionic and nonionic cellulose ethers are available on the market, such as sodium carboxymethylcellulose, hydroxyethylethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxyethylmethylcellulose and hydroxypropylmethylcellulose.

Cellulose ethers are used as additives in a variety of applications such as food, paints, petroleum recovery, paper, cosmetics, pharmaceuticals, adhesives, printing, agriculture, ceramics, textiles, detergents, and building materials. Cellulose ethers improve the product quality in these applications and are used as thickeners, water-retaining agents, suspending agents, protective colloids, film formers or thermoplastics in different products such as dispersion paints, drilling muds, ice creams, tablet coatings, wallpaper pastes and tile adhesives.

Nonionic cellulose ethers, such as methylcellulose, hydroxypropyl methylcellulose (also known as hypromellose), and methyl hydroxyethyl cellulose, are widely used in the pharmaceutical industry for their ability to thicken, bind and retain water, as well as to emulsify and suspend particles and to form films. Further information on nonionic cellulose ethers can be found, for example, in WO 92/09307.

It is an object of the present invention to overcome or at least alleviate some of the problems associated with the prior art.

Disclosure of Invention

This document relates to a pharmaceutical composition comprising at least one nonionic cellulose ether, wherein the composition has a viscosity of 35000cP or greater, an osmolality of from about 10 to about 300mOsmol/kg, and a pH of from about 3 to about 4. The pharmaceutical composition may or may not contain one or more active pharmaceutical ingredients.

This document also relates to such a pharmaceutical composition for the treatment and/or prevention of a climacteric disorder, wherein the climacteric disorder is selected from the group consisting of: vaginal dryness during and/or after sexual intercourse, vaginal irritation, vaginal itching, difficulty urinating, difficulty intercourse, and/or vaginal bleeding, and any combination thereof.

The present document further relates to a method for the treatment and/or prevention of a climacteric disorder selected from the group consisting of vaginal dryness, vaginal irritation, vaginal itching, dysuria, dyspareunia, and/or vaginal bleeding during and/or after sexual intercourse, and any combination thereof, wherein the method comprises administering a pharmaceutically effective amount of a pharmaceutical composition as defined herein.

This document also relates to the use of a nonionic cellulose ether for the preparation of a pharmaceutical composition as defined herein for the treatment and/or prevention of a climacteric disorder, wherein the climacteric disorder is selected from the group consisting of: vaginal dryness during and/or after sexual intercourse, vaginal irritation, vaginal itching, difficulty urinating, difficulty intercourse, and/or vaginal bleeding, and any combination thereof.

The present document also relates to a kit of parts comprising:

(i) a pharmaceutical composition as defined herein;

(ii) a dispenser for said pharmaceutical composition, and

(iii) optional instructions for use.

Detailed Description

Other features and advantages of the invention will become apparent from the following detailed description, the accompanying drawings, the embodiments, and the appended claims.

Definition of

A "pH adjusting agent" is any agent capable of adjusting and/or maintaining the pH of the pharmaceutical composition, such as a liquid agent, e.g., an aqueous liquid, wherein the pH is maintained approximately within the selected ranges exemplified herein. Such a pH adjusting agent may for example be a buffer, such as a citrate buffer, a lactate buffer or a phosphate buffer. A "buffer" is an ionic compound, usually a salt of a weak acid or weak base, added to a solution to resist changes in its acidity or basicity, thereby stabilizing its pH. The buffer is a solution containing this compound. Other examples of pH adjusters are organic and inorganic acids and bases, such as acetic acid, citric acid, phosphoric acid, hydrochloric acid, and sodium hydroxide.

The cellulose ethers used in the compositions disclosed herein are nonionic, wherein alkyl and/or hydroxyalkyl groups are attached to anhydroglucose units via an ether linkage to form a hydroxyalkyl alkylcellulose, wherein the alkyl groups have from 1 to 4 carbon atoms.

Representative cellulose ethers for use in the pharmaceutical composition according to the invention are Methylcellulose (MC), Hydroxyethylmethylcellulose (HEMC), Hydroxypropylmethylcellulose (HPMC), Hydroxyethylethylcellulose (HEEC) and Hydroxypropylcellulose (HPC). These polymers have non-polar (e.g., methyl) or slightly polar (e.g., hydroxyethyl) substituents that, in combination with the hydrophilic cellulose backbone, provide amphiphilic polymers.

Unless otherwise indicated, the viscosity of the pharmaceutical compositions disclosed herein is measured at 20 ℃ according to the European pharmacopoeia 7.0, 2.2.10, for example using a spindle viscometer Brookfield DV-I Prime, spindle number SC4-28, at 1rpm (revolutions per minute). The torque value should be more than or equal to 10 percent so as to ensure that the result is stable and reliable. If the torque value is < 10%, the Brookfield instrument will display a warning light. The instrument was checked periodically for correct performance using reference standards (oils of different viscosities) supplied by Brookfield. Viscosity is in cP (centipoise).

"composition" in the context of this document refers to a composition suitable for medical use. The composition may also be referred to as a "medical composition" or a "pharmaceutical composition".

"most annoying symptoms" (MBS) are defined in the context of this document as the symptoms of climacteric disorders that are annoying to women, wherein the climacteric disorder is selected from the group consisting of: vaginal dryness during and/or after sexual intercourse, vaginal irritation, vaginal itching, difficulty urinating, difficulty intercourse, and/or vaginal bleeding.

"osmolality" refers to the concentration of an osmotic solution in terms of osmoles or milliosmoles per 1kg of solvent.

Room temperature refers to a temperature of about 20 c to 25 c.

Detailed Description

This document is based on the surprising finding that: a composition comprising at least one nonionic cellulose ether, and having a viscosity of about 35000cP or greater, effective for the treatment and/or prevention of a climacteric disorder selected from the group consisting of: vaginal dryness during and/or after sexual intercourse, vaginal irritation, vaginal itching, difficulty urinating, difficulty intercourse, and/or vaginal bleeding, and any combination thereof.

This document relates to a pharmaceutical composition comprising at least one nonionic cellulose ether, wherein the composition has a viscosity of about 35000cP (1cP (centipoise) ═ 1mPa s) or greater, an osmolality of about 10 to about 300mOsmol/kg (milliosmole), and a pH of about 3 to about 4 at room temperature. The pharmaceutical composition may or may not contain one or more active pharmaceutical agents.

The composition can have a viscosity of at least about 38000cP, about 40000cP, about 45000cP, about 47000cP, about 50000cP, about 52000cP, or about 55000 cP. For example, the viscosity of the composition can be about 35000cP to about 100000cP, about 38000cP to about 100000cP, about 40000cP to about 100000cP, about 45000cP to about 100000cP, about 47000cP to about 100000cP, about 50000cP to about 100000cP, about 52000cP to about 100000cP, or about 55000 to about 100000 cP.

The viscosity as defined in this document is determined as described above according to the european pharmacopoeia (ph. eur.)2.2.10 measured at 20 ℃. Unless otherwise indicated, the viscosity values referred to herein are measured at a speed of 1 rpm. The viscosity of the composition may be at least about 38000cP, about 40000cP, about 45000cP, about 47000cP, about 50000cP, about 52000cP, or about 55000cP after about 6 months of storage at room temperature. The storage stability of the composition in terms of viscosity may be influenced by the storage conditions. For example, refrigerating and/or storing the composition in a glass container can reduce the amount of viscosity reduction during storage.

The composition can have an osmolality of about 10 to about 300mOsmol/kg, such as about 10 to about 200mOsmol/kg, about 20 to about 100mOsmol/kg, about 30 to about 50 mOsmol/kg.

The pH of the compositions disclosed herein is typically in the range of about 3 to about 4, for example about 3 to about 3.8, for example about 3 to about 3.5, or about 3 to 3.3. The pH may be adjusted by adding a pH adjuster to the composition. The pH adjusting agent may be, for example, a buffer, such as a lactate or citrate buffer, or an acid or base, such as hydrochloric acid or sodium hydroxide. The buffer may be added to the composition at a concentration of about 20mM to about 100mM, for example about 25mM to about 100mM, or about 25mM to about 50mM, about 25mM to about 75mM, or about 50mM to about 70mM, in an aqueous solution. It should be noted that these values are not exact, which means that they may vary by a small amount around the values provided. The concentration of the buffer will vary depending on the pH desired and the buffer used in the pharmaceutical composition.

The composition may further comprise a preservative, such as benzoic acid. When benzoic acid is used as a preservative, it may be added in an amount of about 0.5-1.5, for example about 0.6, 0.7, 0.8, 0.9, 1.0, 1.1, 1.2, 1.3, or 1.4mg/g of pharmaceutical composition.

The nonionic cellulose ether may be selected from the group consisting of: methylcellulose (MC), hydroxypropyl methylcellulose (HPMC), hydroxypropyl cellulose (HPC), hydroxyethyl ethylcellulose (HEEC), and hydroxyethyl methylcellulose (HEMC), and any combination of one or more thereof.

The amount of nonionic cellulose ether used in the pharmaceutical composition is selected so as to obtain the desired viscosity. As known to those skilled in the art of drug development, the chain length of the nonionic cellulose ether is one parameter that affects the resulting viscosity, and when a certain concentration of the nonionic cellulose ether is used, a shorter chain length nonionic cellulose ether provides a lower final viscosity than when the same concentration of a longer chain length nonionic cellulose ether is used. It is also known to those skilled in the art of drug development that the chain length of each batch of nonionic cellulose ether always varies, and that this variation may be small or large. However, it is the average chain length that affects viscosity.

Typically, the composition comprises from about 1% to about 5% (w/w) of the nonionic cellulose ether, for example about 1.5%, 2%, 2.5%, 3%, 3.5%, 4% or 4.5% (w/w) of the nonionic cellulose ether. For example, the composition can comprise from about 2.5% to about 3.5% (w/w) nonionic cellulose ether. However, as mentioned above, due to the variation in chain length between different batches of nonionic cellulose ethers, the actual amount of nonionic cellulose ether must be adjusted to achieve the desired viscosity. However, this is a routine procedure for those skilled in the art of drug development.

It has surprisingly been found that a composition comprising at least one nonionic cellulose ether, wherein said composition has a viscosity of about 35000cP or more, preferably an osmolality of about 10 to about 300mOsmol/kg, and a pH of about 3 to about 4, has a therapeutic effect on menopausal disorders, even though the composition is free of active pharmaceutical ingredients.

Without wishing to be bound by theory, this may be due to the hypotonic nature of the composition due to its low osmolality, as its hypotonic nature enables the composition to deliver water to the vaginal mucosa.

Furthermore, the composition disclosed herein has a high viscosity, which is beneficial when administering the composition to the vaginal mucosa, as it is easier to handle, and also allows the gel to remain in the vagina after administration.

Furthermore, the compositions defined herein have good mucoadhesive properties.

Generally, mucoadhesive compositions interact with the mucus layer and mucin molecules that coat the mucosal epithelial surface and increase the residence time of the composition at the site of administration.

Mucoadhesion describes the attractive force between the composition and the mucus or mucosa.

There are two main stages of the mucoadhesion process: a contact phase and a consolidation phase. The contact phase includes the incipient wetness that occurs between the composition and the mucosa. This can be achieved mechanically by bonding the two surfaces together.

The consolidation stage affects the residence time of the composition on the surface, which is controlled primarily by the non-covalent attractive interaction between the two surfaces, and also by the osmolality difference between the composition and the mucosa.

A composition with a low osmolality, i.e. a hypotonic composition, will cause water to flow from the composition to the mucosa.

Furthermore, the compositions defined herein without active pharmaceutical ingredients are non-cytotoxic. Furthermore, since the composition comprises such few ingredients, the risk of adverse reactions thereto is reduced.

The composition may or may not contain active pharmaceutical ingredients such as drugs administered primarily intravaginally including, but not limited to, vaginally administered estrogens and progestogens (a group of hormones including progesterone), antibacterial and antifungal agents for the treatment of bacterial vaginosis and yeast infections, respectively, and oxytocin.

When the composition does not comprise a pharmaceutically active ingredient, the composition may in particular not comprise oxytocin.

The composition may further comprise oxytocin and/or one or more amino acid sequences according to SEQ ID NO: 2, and a pharmaceutically acceptable salt of oxytocin or a fragment and/or variant thereof. Oxytocin and/or one or more polypeptides according to SEQ ID NO: 2, such that a dose of about 50IU to about 600IU, e.g., about 100IU, 200IU, 250IU, 300IU, 350IU, or 400IU, is administered. One International Unit (IU) of oxytocin corresponds to about 1.67 micrograms of pure peptide. Thus, 1g of the composition of oxytocin gel (400IU) corresponds to about 0.67mg/g (European pharmacopoeia 9.2). However, the composition may not otherwise comprise any oxytocin or oxytocin according to SEQ ID NO: 2 (or a pharmaceutically acceptable salt of oxytocin or a fragment and/or variant thereof).

When reference is made herein to "oxytocin", "oxytocin peptide" and/or "oxytocin molecule", this includes oxytocin (SEQ ID NO: 1) and/or one or more of its amino acid sequences according to the general formula SEQ ID NO: 2, or any other variant and/or fragment mentioned herein, and analogs and/or homologs thereof. Whenever a fragment, variant or homologue of an oxytocin molecule/peptide is envisaged, it will be understood that such a variant, fragment or homologue comprises a biological activity comparable to that of the oxytocin molecule (SEQ ID NO: 1) itself. As an example, the substance may be demonstrated to have oxytocin activity by performing an assay showing the actual substance activity, for example by performing a double-blind cross-randomization protocol as described in WO0178758 (example 1).

SEQ ID NO: 2 is defined in this document as:

X₁-X₂-X₃-X₄-Asn-Cys-X₅-X₆-X₇-X₈-NH₂

wherein the content of the first and second substances,

X₁selected from the group consisting of Cys and blank;

X₂selected from the group consisting of Tyr, Phe, and blank;

X₃selected from the group consisting of Ile, Val, Hoph, Phe, Cha, and blank;

X₄selected from the group consisting of Gln, Ser, Thr, Cit, Arg, and Daba;

X₅selected from the group consisting of Pro and blank;

X₆selected from the group consisting of Ile, Leu, blank, Val, Hos, Daba, Thr, Arg, and Cit;

X₇selected from the group consisting of Gly, blank and Ala;

X₈selected from the group consisting of Gly and blank; provided that SEQ ID NO: 2 does not include vasopressin.

The compositions disclosed herein can be prepared by mixing one or more nonionic cellulose ethers with water and optionally one or more pH adjusting agents and/or one or more preservatives.

The compositions described herein can be, for example, compositions comprising or consisting of hydroxypropyl methylcellulose, lactic acid, and benzoic acid, the compositions having a viscosity of about 35000cP or more, an osmolality of about 10 to about 300, e.g., about 10 to about 200, about 20 to about 100, about 30 to about 50mOsmol/kg, and a pH of about 3 to about 4. The concentrations of lactic acid and benzoic acid, as well as the pH of the composition, may be as described elsewhere herein.

The compositions described herein may be administered vaginally. Typically, about 0.5ml to about 1.5ml, e.g., about 1ml, of the composition is administered once a day, although the composition may be administered two or more times a day. The composition is preferably administered while sleeping.

This document also relates to a composition as defined herein for use in the treatment and/or prevention of a climacteric disorder, wherein said climacteric disorder is selected from the group consisting of: vaginal dryness during and/or after sexual intercourse, vaginal irritation, vaginal itching, difficulty urinating, difficulty intercourse, and/or vaginal bleeding, and any combination thereof.

This document also relates to a method for the treatment and/or prevention of a climacteric disorder selected from the group consisting of: vaginal dryness, vaginal irritation, vaginal itching, dysuria, dyspareunia, and/or vaginal bleeding during and/or after sexual intercourse, and any combination thereof, wherein the method comprises administering to a subject in need thereof a pharmaceutically effective amount of a composition described herein.

The present document further relates to the use of a nonionic cellulose ether for the preparation of a pharmaceutical composition as defined herein for the treatment and/or prevention of a climacteric disorder, wherein the climacteric disorder is selected from the group consisting of: vaginal dryness during and/or after sexual intercourse, vaginal irritation, vaginal itching, difficulty urinating, difficulty intercourse, and/or vaginal bleeding, and any combination thereof.

Also disclosed herein is a kit of parts comprising:

(i) the composition as defined herein is a composition which,

(ii) a dispenser for said composition, and

(iii) optional instructions for use.

This document also relates to hydroxypropyl methylcellulose for use in the treatment and/or prevention of a climacteric disorder selected from the group consisting of: vaginal dryness during and/or after sexual intercourse, vaginal irritation, vaginal itching, difficulty urinating, difficulty intercourse, and/or vaginal bleeding, and any combination thereof. This document also relates to the use of hydroxypropyl methylcellulose in the preparation of a pharmaceutical composition for the treatment and/or prevention of a climacteric disorder, wherein the climacteric disorder is selected from the group consisting of: vaginal dryness during and/or after sexual intercourse, vaginal irritation, vaginal itching, difficulty urinating, difficulty intercourse, and/or vaginal bleeding, and any combination thereof. This document also relates to a method for the treatment and/or prevention of a climacteric disorder selected from the group consisting of: vaginal dryness, vaginal irritation, vaginal itching, dysuria, dyspareunia, and/or vaginal bleeding during and/or after sexual intercourse, and any combination thereof, wherein the method comprises administering to a subject in need thereof a pharmaceutically effective amount of hydroxypropyl methylcellulose.

The invention will be further described in the following examples, which do not limit the scope of the invention described in the claims.

Experimental part

Overview

The equipment used for mixing was a Unimix SRT 15. The hypromellose used was Benecel K15 mphar.