JP2021534081A - Methods and compositions for reducing keratoconjunctivitis sicca - Google Patents

Abstract

Improved methods and compositions for treating dry eye by intranasally administering therapeutically effective amounts of capsicinoid compounds implanted in multiple layers of solid layered crystals of monoglyceride to patients with inadequate tear production. The thing is disclosed. The lipophilic capsaicinoid drug is embedded in multiple layers of solid layered crystals of monoglyceride, which crystallize into a pharmaceutically acceptable vehicle consisting of solutions, suspensions, foams, creams, ointments, and gels. Be incorporated. The resulting capsaicinoid formulation provides a more stable, less irritating to the skin and mucous membranes, increased release and more controlled capsaicinoid compounds.

Description

The present disclosure relates to methods and compositions for alleviating keratoconjunctivitis sicca, which is a dry eye condition.

A condition of keratoconjunctivitis sicca or dry eye can affect as many as 9 million Americans over the age of 50. Discomfort from dry eye can range from a mild burning sensation to constant eyelid scratches. Not only is dry eye painful, the condition predisposes to eye infections and can also cause blurred vision. Dry eye is thought to be due to inability to shed sufficient tears or inflammation of the external eye.

Current attempts to treat dry eye have focused on eye drops, including agents to reduce eye irritation. These drugs are cyclosporine and refitegrast. However, both cyclosporine and refitegrast infusions often cause local irritation with a burning sensation and stinging, blurring vision, causing dysgeusia, diminishing vision, and inadequate effectiveness. As a result, there is a substantial need for new treatments for dry eye that are more effective or less prone to harmful eye reactions.

In October 2007, Applicants filed a US patent application published as US No. 2009/093446, which is incorporated herein by reference and describes a novel method (intranasal) for treating such dry eye. 11 / 868,286) was submitted. However, since the preparation of the capsaicinoid compound used in the method described earlier (Application 11 / 868, 286) has been proved to cause an intolerable nasal irritation reaction to the treated patient, the purpose of the prior invention was intended. Application No. 11 / 868,286 was abandoned in 2010 because it could not be put into proper practice in an operable manner.

Following this, Applicants developed a new formulation of capsaicinoid nasal drops, which, when administered intranasally, is substantially less nasal irritation than previously described or utilized compositions. Or it does not cause nasal irritation at all and the patient is well tolerated. The second unexpected advantage of these formulations is the release of capsicinoid compounds over a longer period of time in increased amounts over a 24-hour period. Recent clinical studies of dry eye (Example 8) have demonstrated that these formulations are highly effective in increasing tear production and are well tolerated.

The present disclosure involves a very novel approach in the development of improved methods for alleviating keratoconjunctivitis sicca. It focuses on what appears to be the neuromodulation of lacrimal gland secretion dysfunction as an important factor in the etiology of keratoconjunctivitis sicca. Dry eye syndrome is a disorder in which the amount and composition of tears changes, and these parameters are affected by defects in the nerve activity of the cranial nerves V (trigeminal nerve) and VII (facial nerve) that innervate the lacrimal glands. The terminal branches of the trigeminal and facial nerves are located in the nasal mucosa. As a result, the nasal route of administration of a compound (capsaicinoid) known to affect the conduction function of these nerves is used to easily and conveniently access the terminal branches of these nerves in the nasal mucosa. .. In doing so, the methods and formulations described herein show the frequent adverse effects (eg, eye irritation, haze, or diminished visual acuity) caused by the introduction of cyclosporine or refitegrast infusion into the eye. It provides a significant improvement method to increase tear production without affecting the above, as well as an improvement over conventional nasal therapeutic formulations as described above. In addition, by affecting the neuromodulation of lacrimal gland secretion, this method resulted in a faster improvement in the patient's eye than the slower anti-inflammatory effects of current therapies.

An improved method and composition for increasing tear production is to intranasally administer therapeutically effective amounts of capsaicinoid compounds implanted in multiple layers of solid layered crystals of monoglyceride to patients with inadequate tear production. including. The use of nasal routes of administration to successfully treat eye conditions was surprising and unexpected. To the best of our knowledge, no nasal preparations have been reported for the successful treatment of eye disorders while minimizing eye irritation.

A method of treating keratoconjunctivitis sicca, also known as dry eye, involves administering to the nasal mucosa an effective amount of a composition containing a lipid microencapsulated capsicinoid compound, resulting in the current treatment of dry eye. There is no localized eye burning sensation, stinging, blurred vision and other adverse symptoms and signs associated with use, and tear production is significantly increased. Capsaicinoid compounds include layered crystals of monoglyceride and pharmaceutically acceptable excipients that can be implanted or encapsulated in vehicles suitable for intranasal administration.

In one embodiment, the method of making a composition for treating keratoconjunctivitis sicca is a step of adding a capsaicinoid compound and a monoglyceride to water to form a mixture, a step of mixing the mixture and heating to at least the melting point of the monoglyceride. Includes steps to cool the mixture to induce monoglyceride crystallization and encapsulation of the capsaicinoid compound in the monoglyceride crystals.

Suitable capsaicinoid compounds include, for example, capsaicin, cibamide, acetylated derivatives of capsaicin and cibamide, or all salts of the capsaicinoids described above.

The compositions disclosed herein are, for example, microencapsulated in solid crystals of monoglyceride and incorporated into a vehicle suitable for nasal administration, as described above at a concentration of about 0.001 to about 5.0% by weight. It is composed of capsaicinoid compounds. The use of such compositions results in significantly reduced nasal irritation compared to the compositions cited in US Application No. 11 / 868,286, as well as a longer and more quantitative and longer term of active capsaicinoids over a 24-hour period. Also provides more release.

Topical formulations suitable for skin or mucosal application consist of monoglyceride-encapsulated capsaicinoids incorporated into vehicles suitable for administration to the nasal mucosa such as solutions, suspensions, creams, ointments, gels or foams.

Surprisingly, the inventor disclosed in US Application No. 11 / 868,286 without the adverse intraocular side effects found in eye drops currently used to treat patients with dry eye. We have found an ameliorating way to increase tear production (lacrimation) without the unwanted nasal irritation induced by the composition. This method consists of intranasal administration of a class of chemicals called capsaicinoids encapsulated in lipid microcapsules, which increases tear production without causing significant irritation to the eyes and the nasal passages themselves.

Suitable capsaicinoid compounds for the formulations described herein include, for example, capsaicin, cibamide, acetylated derivatives of capsaicin and cibamide, or all salts of the capsaicinoids described above. Among the safest and most effective capsaicinoids utilized in this new method are the two previous US patents (US Pat. Nos. 5,063,060 and 7,244) incorporated herein by reference. There is cibamide (cis-8-methyl-N-vanillyl-nonenamide), which is the target chemical substance of No. 446). Surprisingly, in the process of conducting many clinical studies using intranasal capsaicinoids to treat headache and neuralgia pain, as well as nasal congestion, intranasally administered capsaicinoids have no undesired effects on the eyes. It was found to increase tear production in the eye.

This surprising finding is described in US Application No. 11 / 868,286. However, the capsaicinoid composition utilized and referred to in the application causes severe early pain, burning sensation of the nasal mucosa and stinging, and the majority of patients immediately discontinued this treatment before realizing the benefits. ..

To overcome this problem and make the capsicinoid composition less irritating to the nasal mucosa and thus more tolerated, US Application No. 11 / 868,286 is a local anesthetic or a locally effective corticosteroid. Incorporation of any of the costeroids into the composition provided. Nonetheless, the present inventor may, after filing No. 11 / 868,286, minimize the adverse effects of capsaicinoids on the nasal mucosa by incorporating local anesthetics or topical steroids, although they are obtained. We found that the formulation was still irritating and unacceptable to most subjects.

The inventor then investigated several different approaches to reducing the irritation of these capsaicinoid-containing formulations. Only one of these approaches has been successful, which is partly the subject of this application.

In one embodiment, the active compound is encapsulated in solid crystals of monoglyceride. This allows the compound to be effectively used as an acceptable treatment for keratoconjunctivitis and avoids significant irritation of previous formulations. Monoglycerides are a class of glycerides that contain molecules of glycerol bound to esters bound to fatty acids. Fatty acids have 4-28 carbon atom chains, such as 6-21, or 10-15 carbon atoms. The carbon atom chain is linear or branched and can be saturated or unsaturated. While various glycerides of short to medium chain fatty acids can be used to encapsulate capsaicinoid compounds, 1-glyceryl monolaurate and 1-glyceryl monomillistate are the compositions disclosed herein. Is a preferred monoglyceride for. When the fatty acid is bound to a primary alcohol, the resulting compound is 1-monoglyceride, and when bound to a secondary alcohol, the compound is called 2-monoglyceride. In one embodiment, the monoglyceride has a melting point of about 25 ° C to about 65 ° C, eg, about 30 ° C to about 45 ° C, or about 32 ° C to about 35 ° C. In one embodiment, two or more monoglycerides are used in the composition.

In one embodiment, the monoglyceride is a polar lipid in a layered crystalline phase. Monoglycerides are widely used in foods as emulsifiers to prevent the separation of oil and water mixtures. They are also incorporated into some cosmetics to enhance skin hydration and barrier function. However, batches of a particular Pharmaceutical Active Ingredient (API), eg, the capsaicinoid compounds described herein, are dissolved until the monoglyceride dissolves (eg, about 60 ° C to about 100 ° C, or about 65 ° C to about 80 ° C). The individual molecules of the API are lysed by heating with monoglyceride and water, stirring in an inert nitrogen atmosphere (“nitrogen blanket”) for about 15 to about 20 minutes, then cooling the mixture to crystallize the monoglyceride. It can be coated with an envelope of monoglyceride particles. These particulate monoglyceride shells are hydrolyzed in the skin or mucous membranes to release glycerin and fatty acids, which in turn release APIs.

In the premixed and preheated composition, the monoglyceride may be added in an amount of about 10 to about 50% by weight, for example about 15% to about 35% by weight, or about 25% to about 30% by weight. Water can be present in an amount of 50% to 90%, such as about 60% to about 80%, or about 65% to about 75%. The API and other inert ingredients may be added in an amount of about 0.001% to about 10%, eg, about 0.1% to about 7%, or about 1% to about 5%. The monoglyceride can be a weight ratio of about 10,000: 1 to about 30: 1 capsaicinoid compounds, for example, about 5000: 1 to about 100: 1, or about 3000: 1 to about 300: 1.

According to the present disclosure, for example, about 0.01% by weight to about 1% by weight, or about 0.015% by weight to about 0.5% by weight of an acetylated derivative or salt of capsaicin, shibamide, capsaicin and shibamide, and the like. About 0.001% to about 5.0% by weight of the total composition is embedded in multiple layers of solid layered crystals of monoglyceride with a thickness of 40-100 Å, such as 50-90 Å or 60-80 Å, solution, suspension. After being incorporated into formulations such as turbid liquids, lotions, creams, gels, ointments, and foams, it is introduced into the nasal cavity.

The pharmaceutical product can be introduced into the nasal cavity, for example, by dropping or spraying a solution or suspension of a capsaicinoid compound. Patients generally receive the active formulation once or twice daily in the left, right, or both nasal passages.

Other pharmaceutically acceptable excipient components suitable for intranasal delivery formulations for mammals can be added to the composition. These may include, for example, preservatives and emulsifiers such as polyoxyethylene (20) oleyl ether (BRIJ-98) and polyethylene glycol stearate (Myrj 59).

The above compositions and methods produce effective stimuli for increased tear production without adverse eye side effects such as eye sting or blurred vision and intranasal irritation. The compositions described herein indicate the frequency and / or severity of intranasal side effects by incorporating capsaicinoid compounds into lipid microspheres that provide a long-term and more substantial release of capsaicinoids into the nasal mucosa. Reduce.

Examples The examples are provided for explanatory purposes and are not intended to limit the scope of disclosure.

Example 1
Thirty healthy volunteers assigned to three separate 10 subject panels were ethyl alcohol, polysorbate 20, potassium dihydrogen phosphate, EDTA disodium, dibasic sodium phosphate anhydride, benzalkonium chloride. Participated in a multi-dose 14-day tolerability study assessing the topical effect of a shibamide nasal spray consisting of purified water containing butylated hydroxytoluene and various amounts of shibamide. The nasal spray formulation was administered twice daily to the first 10 subject panels, and the cibamide was 0.0075% by weight. The second 10 subjects received the same formulation, but 0.01 wt% cibamide was administered twice daily, and the third 10 subjects received the same formulation. 0.015 wt% shibamide was administered once daily. In each of the two groups receiving twice-daily cibamide, 10 of 10 subjects (100%) were associated with increased tearing (tear production) by 0.015 weight. Nine (90%) of the 10 subjects who received% Shibamide once daily had increased lacrimation.

Example 2
Fifty-five patients with vasomotor rhinitis (non-allergic rhinitis) participated in a double-blind, placebo-controlled, two-week evaluation of symptom relief with 0.01 wt% Shibamide nasal spray or placebo nasal spray (active product). Vehicle) was administered. Thirty-one percent (31 percent) of patients using 0.01% shibamide spray reported increased lacrimation, while 0 percent of placebo patients had such side effects.

Example 3
Thirty-four migraine patients applied 0.025 wt% capsaicin cream to the nasal mucosa to relieve the headache. Seventy-three percent (73 percent) of such patients had some headache relief 4 hours after administration of 0.025% capsaicin cream. Forty-four percent (44 percent) of these patients reported increased lacrimation as a side effect.

Example 4
Use 0.025 wt% nasal drops given once daily for 1 week to 28 patients with transient cluster headache (generally severe vasomotor headache occurring in clusters of 4 to 24 weeks) In the study, 9 of 18 patients (50%) had increased tearing with cibamid nasal drops, whereas 0 of 10 patients (0%) with vehicle controls. ..

Example 5
Of 112 patients with transient cluster headache who received either 0.01 wt% nasal drops or an inert control (10% NaCI) twice daily, 36 patients (51) with sivamid spray. %), 3 patients (7%) in control reported increased lacrimation.

Example 6
Two patients with migraine disorders received 0.025 wt% capsaicin cream intranasally to acutely relieve migraine pain. Both reported lacrimation within 30 minutes of application of capsaicin cream.

Example 7
Five batches of microencapsulated cibamide were prepared as follows according to the techniques described herein.

Batches were produced in a laboratory scale reactor in a nitrogen atmosphere, heating to 70 ° C. provided by a water bath. The ingredients were stirred at high temperature for 15 minutes and then cooled to room temperature. At about 33-36 ° C, crystallization of monoglyceride for encapsulating shibamide occurs.

Microencapsulated shibamide was then added to the solution, cream, suspension, ointment, gel, and foam.

Example 8
Twenty-five patients with keratoconjunctivitis sicca used a 0.01% microencapsulated cibamide solution (Batch 1 of Example 7) as a nasal spray self-administered twice daily for 12 weeks. Patients were evaluated for tear production and disease symptoms, respectively, using Schirmer's test and the Ocular Surface Disease Index (OSDI). Eighteen of the 25 patients (72%) had a significant improvement in Schirmer's test by the end of the study, and 24 of the 25 patients (96%) had an OSDI improvement by the end of the study. No significant nasal irritation has been reported.

Example 9
Monoglycerol (eg, monoglycerol, eg API release from the batch of 0.075% shibamide encapsulated by batch 3) of 7 with a batch of unencapsulated shibamide cream (commercially available Zuacta® cream) and benzyl alcohol, cetyl alcohol, stearic acid. The same vehicle composed of glyceryl acid acid, isopropyl myristate, PEG-100 stearate, purified water, sorbitol solution and white vaseline was compared. A comparison of API (cibamide) releases at 2, 6, and 24 hours is shown in Table 2 below. As can be seen in Table 2, the monoglyceride encapsulated formulation released more than 4-fold amount of cibamide over 24 hours than the non-encapsulated formulation.

The above includes examples of one or more embodiments. Of course, it is not possible to describe all possible modifications and modifications of the above device or methodology for the purposes of explaining the aforementioned embodiments, but those skilled in the art will be able to make more modifications and substitutions of the various embodiments. You can recognize that it is possible. Accordingly, the described embodiments are intended to embrace all such changes, modifications, and modifications within the spirit and scope of the appended claims. Further, where "comprising" is used as an interim word in a claim, as long as the term "includes" is used in either the form for carrying out the invention or in the claims. Such terms are intended to be as inclusive as the term "comprising". As used herein, the term "essentially constructed" means one that does not substantially affect the basic and novel properties of a particular material or step, and material or method. Unless otherwise indicated in the context, all percentages and averages are by weight. If not specified above, the properties described herein may be determined by the applicable ASTM standard, or if the ASTM standard is not present in the property, the most commonly used known to those of skill in the art. You can use the standards that are used. The articles "a," "an," and "the" should be construed to mean "one or more," unless the context indicates the opposite.

Claims (20)

A method of treating keratoconjunctivitis sicca
A method comprising intranasally administering to the nasal mucosa an effective amount of a composition comprising layered crystals of monoglyceride and a capsicinoid compound implanted in a vehicle suitable for intranasal administration. The method of claim 1, wherein the capsaicinoid compound is selected from the group consisting of capsaicin, cibamide, acetylated derivatives of capsaicin and cibamide, and the pharmaceutically acceptable salts described above. The method of claim 1, wherein the capsaicinoid compound is present in the composition in the range of about 0.001% by weight to about 5% by weight. The method according to claim 2, wherein the capsaicinoid compound is present in the composition in the range of about 0.001% by weight to about 5% by weight. The method of claim 1, wherein the vehicle is selected from the group consisting of solutions, suspensions, creams, ointments, gels and foams. The method of claim 1, wherein the monoglyceride comprises a fatty acid having 4 to 28 carbon atom chains. The method of claim 1, wherein the monoglyceride has a melting point of about 25 ° C to about 65 ° C. The method of claim 1, wherein the composition comprises two or more monoglycerides. The method of claim 1, wherein the monoglyceride is selected from the group consisting of 1-glyceryl monolaurate, 1-glyceryl monomillistate, and combinations thereof. The method according to claim 6, wherein the fatty acid is a saturated fatty acid. The method of claim 1, wherein the composition does not cause nasal irritation. A method for producing a composition for treating keratoconjunctivitis sicca.
Steps of adding capsaicinoid compounds and monoglycerides to water to form a mixture,
The step of mixing the mixture and heating to at least the melting point of the monoglyceride,
A method comprising cooling the mixture to induce crystallization of the monoglyceride and encapsulation of the capsaicinoid compound in the monoglyceride crystals. The method for making a composition for treating keratoconjunctivitis according to claim 12, wherein the mixture is heated to about 65 ° C to about 100 ° C. The method for making a composition for treating keratoconjunctivitis according to claim 12, wherein the step is carried out in an inert atmosphere. A composition suitable for intranasal or topical application to the skin or mucous membranes of mammals.
A composition comprising a capsaicinoid compound encapsulated in layered crystals of monoglyceride, and a pharmaceutically acceptable excipient. 15. The composition of claim 15, wherein the monoglyceride comprises a fatty acid having 4 to 28 carbon atom chains. 15. The composition of claim 15, wherein the monoglyceride has a melting point of about 25 ° C to about 65 ° C. 15. The composition of claim 15, wherein the composition comprises two or more monoglycerides. 15. The composition of claim 15, wherein the monoglyceride is selected from the group consisting of 1-glyceryl monolaurate, 1-glyceryl monomillistate, and combinations thereof. The composition according to claim 15, wherein the capsaicinoid compound is present in the composition in the range of about 0.001% by weight to about 5% by weight.