JP2016033137A - Composition in treatment of anal fissure and use thereof - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a composition comprising protein extract from at least one hibiscus and/or at least one β-glucan or salts thereof, and provide use of the composition for treating anal fissure.SOLUTION: The present invention provides a composition comprising protein extract from at least one hibiscus and/or at least one β-glucan or salts thereof, and provides use of the composition for treating anal fissure.SELECTED DRAWING: None

Description

  The present invention relates to a composition comprising at least one hibiscus protein extract and / or at least one β-glucan. Furthermore, the present invention relates to the use of said composition for the treatment of anal fissure.

  Anal fissure is an ulceration of the epithelium of the lower anal canal, usually located at the level of the posterior commissure of the duct and concomitant with internal sphincter contracture.

  Rupture of the anal mucosa at the site of the crack causes mild bleeding, which occurs during defecation. The condition of internal sphincter contracture results in anal canal hypertony, which causes pain (the main symptom). Pain is very strong and intense, especially during and after defecation (up to 3-4 hours), which causes the subject to avoid defecation and consequently hardens the stool, thus exacerbating the problem.

  Anal fissure occurs in individuals of various ages, regardless of gender; however, it has been empirically demonstrated that individuals aged 20-40 are at the most risk. Anal fissure is the second most common cause leading to rectal examination after vaginal pathology; in fact, the frequency of anal fissures in anal department outpatient clinics is 9-12%. According to the SICCR (Italian Society of Colorectal Surgery) 2009 annual report, a total of 5199 anal fissure cases were observed and 37% (1924) of patients underwent surgery Yes.

  Although the clinical symptoms of cracks are well known, the causative pathology is still unknown.

  According to mechanics theory, the triggering factors are often represented by trauma from difficult stool and the passage of hard stool. This causes strong and lasting pain, which causes the individual to suppress irritation and postpone, cause further hardening of the stool, and exacerbate the situation.

  Thus, traumatic factors can cause cracking, but this can heal if no other factors intervene. These are firstly the presence of persistent hypertonicity of the internal anal sphincter, and secondly the state of localized ischemia at the level of the anal canal. In fact, the anal canal where the crack is located is supplied with blood by the inferior rectal artery. However, in 85% of individuals with cracks, relative arterial deficiency at the level of posterior commissure of the anal canal can be observed (by angiography). Furthermore, blood flow decreases with increasing anal pressure, and vice versa. Therefore, hypertonia and ischemia are closely related phenomena.

  Anal fissures can be distinguished into acute and chronic types.

  The acute form is a radial injury of the anal canal epithelial surface (ie anal canal epithelial layer) and is characterized by a smooth edge and a rose-coloured background. This is usually accompanied by very serious pain. The acute form tends to form scars, but often recurs or progresses to the chronic form.

  A crack is considered acute if it exists for less than 6 weeks. Spontaneous healing of acute anal fissure occurs in 70% of cases.

  Therapeutic treatment for acute cracks is conservative; in fact, surgery is performed only in the event of therapeutic failure.

  Chronic anal fissure is a deep radial injury of the anal canal epithelium and is characterized by a raised white edge with smooth sphincter fibers visible in the background. This is often accompanied by the presence of abnormally enlarged anal processes, ie small soft processes of the anal canal epithelium. A crack is considered chronic if it exists for more than 6 weeks. Chronic fissures usually heal spontaneously in no more than 20% of cases.

  Considering the fact that chronic anal fissures have a very low rate of healing, a number of conservative or surgical studies have been conducted with the aim of establishing a new and very good therapeutic approach.

  Acute anal fissure can be cured in a conservative manner by eliminating the sphincter of the internal sphincter that causes hypertonia.

  Conservative treatment suggests a diet rich in fiber and a large intake of liquid and thorough local hygiene. Where cracks are associated with constipation, the use of lubricants and / or fibers to soften the stool is recommended.

  The medical therapeutic approach is aimed at reducing hypertonicity of the internal anal sphincter to facilitate healing of the crack.

  Recent studies on the physiopathology of the anal sphincter have demonstrated that nitric oxide inhibits internal anal sphincter tone. Therefore, the so-called “reversible chemical sphincter incision” can be performed by topically applying an ointment based on trinitroglycerin (TNG) that can cause relaxation of the internal anal sphincter.

  Within 2 months after treatment, an average of 58% of cases have been demonstrated to cure, while 11-46.2% of cases have relapses.

  The most frequent complication of this treatment is headache, which occurs on average in 57% of cases and often requires discontinuation of treatment.

  Alternatively, medicinal therapy for fissures suggests injecting botulinum toxin into the smooth internal sphincter for these healing by causing a reduction in anal sphincter tone. Usually, relaxation paralysis occurs several hours after administration of the toxin, which tends to persist for 3-4 months.

  Crack scarring occurs in 2 to 96% of cases within 2 months after treatment, while it recurs in 30% of cases.

  However, in 18% of cases, this treatment causes side effects that are very inconvenient, ie temporary fecal incontinence.

  Further treatment alternatives provide administration of calcium channel blockers. While these reduce the maximum sphincter pressure at rest, they have serious overdose side effects in patients with heart disease and diabetes.

  If a satisfactory response is not obtained using conservative or medicinal treatment procedures, or if the crack recurs or worsens over time, surgical procedures are required; this relates to various techniques that are more or less invasive . A “modern” version of anal cleft (as currently considered obsolete), defined as “mechanical sphincteroclasticity” can be performed. This technique provides for the use of a rubber balloon that is inserted into the anal canal and inflated at a controlled pressure. The internal sphincter is thereby expanded for a few minutes (about 5 minutes) and hypersphincter hypertonia is overcome. Negative events can be the onset of varying degrees of fecal incontinence and persist in a significant percentage (8-35%) of cases.

  The “gold standard” treatment for anal fissure is “lateral internal sphincter incision”. This is defined as “open” when providing a skin incision with sphincter exposure and “closed” when performed percutaneously without sphincter exposure.

  Both techniques can ensure that a high percentage of patients will heal (more than 90% of cases will heal within 2 months after treatment).

  The most serious complication is fecal incontinence, which is temporary in the majority of cases (8.9% to 13.0% of cases) but persists in some cases (0.6% to 6. 9%).

  The surgery can also be adjusted with a “regulated lateral internal sphincter incision”, which is controlled based on the degree of cracking, the length of the sphincter, and / or the degree of muscle hypertonia measured. Enables the presence of the part to be incised. This helps to reduce the number of cases that fail due to the persistence or recurrence of complications associated with cracks and incontinence.

  Given the prevalent nature of this morbidity, most of the time with pain that causes very severe inconvenience, a new therapeutic approach that enables healing of at least anal fissures or at least alleviates these pains is: Remarkably needed. In particular, clinical research in this area allows for conservative new therapies, such as healing of anal fissures as previously described, but makes individuals equally inconvenient, especially from a social psychological perspective There has always been much interest in establishing pharmacological protocols that reduce the need for surgery that often causes incontinence, a non-physiological condition.

  The present invention relates to a composition comprising at least one hibiscus protein extract and at least one β-glucan or salt thereof, as adapted herein and as set forth in the appended claims. .

  Furthermore, the present invention provides at least one hibiscus protein extract and / or at least one β-glucan or a salt thereof for the treatment of anal fissure as described in the appended claims. It relates to the use of the composition comprising.

  In fact, Applicants have found that the application of a composition containing one hibiscus protein extract and / or one β-glucan to the anal fissure is symptomatic caused by the anal fissure from the first application, or It has surprisingly been discovered that asymptomatic diseases can be improved.

  In particular, Applicants have shown that this composition exhibits a reparatory action on the local epithelium, as well as a decrease in internal sphincter hypertonia, and thus defecation by helping the smooth muscle relaxation of the anal canal. It has been found that the pain associated with can be alleviated.

  The first aspect of the invention is preferably at least one hibiscus, i.e. a protein extract of Hibiscus esculentus, also known as okra or Abelmoschus esculentus The present invention relates to a protein extract of a plant belonging to the family Malvaceae that grows in the tropical region.

  Said at least one hibiscus protein extract is preferably at least one protein fraction, more preferably at least one soluble protein fraction derived from hibiscus seeds. is there. In particular, the protein extract is derived from hibiscus seeds, preferably from coarse hibiscus seeds, more preferably from defatted seeds and / or meals.

  Said protein extract or said protein fraction is preferably a protein hydrolyzate obtained from natural proteins. The hydrolyzate can be obtained by enzymatic hydrolysis and / or chemical hydrolysis. Alternatively, the hydrolysis is obtained by biotransformation.

  In the present invention, biotransformation is a method that makes a substance more water-soluble by introducing or exposing a hydrophilic group, for example, by being functionalized by hydrolysis, oxidation, reduction, or bonding. Means.

  According to an embodiment, the hydrolyzate is a mixture of oligopeptides. Preferably, the hydrolyzate is a mixture with a binder, more preferably dextrin. In a preferred embodiment, the ratio of the hydrolyzate to the binder is preferably 1: 1.

  A preferred oligopeptide mixture for the purposes of the present invention is the product marketed under the trademark Myoxinol ™.

  The concentration of said at least one hibiscus protein extract is in the range of 0.1-10%; this is preferably in the range of 0.4-5%.

  The second aspect of the present invention preferably relates to carboxymethyl β-glucan and / or β glucan which is a salt thereof, more preferably sodium carboxymethyl β-glucan.

  The concentration of β-glucan is in the range of 0.004 to 0.4%; this is preferably in the range of 0.02 to 0.08%.

  The ratio of the at least one hibiscus protein extract to the at least one β-glucan is preferably 50 to 10: 1, preferably 35 to 20: 1.

  The compositions of the present invention are preferably characterized by a pH in the range of 5-8; this is more preferably in the range of 5.5-6.5. In order to adjust the pH of the composition of the invention, a pH adjusting agent (we define as a pH adjuster), preferably a basic substance such as triethanolamine, may be used. it can.

  The concentration of the agent is in the range of 0.03 to 1%; this is preferably in the range of 0.1 to 0.6%.

  In a preferred embodiment, the composition of the present invention, preferably formulated as a gel cream (ie, gel emulsion), is preferably characterized by a viscosity in the range of 5000-30000; more preferably 7000-25000 This is a range of (mPas).

  The compositions of the present invention are useful in preparing the compositions and are generally biologically safe and non-toxic, at least one pharmaceutically acceptable excipient, or pharmaceutical use or cosmetic It may further contain a compound acceptable for use.

  The excipient may be at least one modifier, preferably a skin or hair moisturizer, an occlusion modifier, or a softener.

  In particular, the regulator comprises the following: dimethicone or dimethylpolysiloxane, preferably linear glycerin, almond oil (preferably almond oil (Prunus amygdalus dulcis oil), phenyl trimethicone, borage oil (preferably Borago officinalis) ) Seed-derived oil), Mulva sylvetris extract and / or mucus, preferably Mulva sylvetris mucus, panthenol, calendula, preferably Calendula officinalis extract, It is selected from the group consisting of ethylhexylglycerin, caprylyl glycol, aspartic acid, maltodextrin, and glyceryl stearate.

  The concentration of the adjusting agent is in the range of 15 to 35%, preferably 20 to 25%.

  Preferably, the concentration of dimethicone or dimethylpolysiloxane ranges from 2.5 to 10%; more preferably from 3.5 to 7%.

  Preferably, the concentration of glycerin ranges from 2.5 to 10%; more preferably from 3.5 to 7%.

  Preferably, the almond oil concentration is in the range of 2-8%; more preferably 3-6%.

  Preferably, the concentration of phenyltrimethicone is in the range of 1-4%; more preferably 1.5-3%.

  Preferably, the concentration of borage oil ranges from 1 to 4%; more preferably from 1.5 to 3%.

  Preferably, the concentration of the Malva extract is in the range of 1-4%; more preferably 1.5-3%.

  Preferably, the panthenol concentration is in the range of 0.5-2%, more preferably 0.75-1.5%.

  Preferably, the concentration of the calendula extract ranges from 0.1 to 0.4%; more preferably from 0.15 to 0.3%.

  Preferably, the concentration of caprylyl glycol ranges from 0.1 to 0.4%; more preferably from 0.15 to 0.3%.

  Preferably, the concentration of maltodextrin ranges from 0.1 to 0.4%; more preferably from 0.15 to 0.3%.

  Preferably, the concentration of glyceryl stearate ranges from 0.4 to 1.8%; more preferably from 0.5 to 1.2%.

  Preferably, the concentration of ethylhexyl glycerol is in the range of 0.05-0.2%; more preferably 0.75-0.15%.

  Preferably, the concentration of aspartic acid ranges from 0.0002 to 0.001%; more preferably from 0.0003 to 0.0008%.

  Said excipient may further be a surfactant, preferably an emulsifying and / or detersive surfactant. More preferably, the surfactant is selected from the group consisting of cetyl alcohol, cetyl (20) OE or ceteth-20, stearyl (20) OE or steareth-20 and stearic acid PEG-75.

  The concentration of the surfactant is in the range of 1 to 3%, more preferably 1.2 to 2%.

  The concentration of the cetyl alcohol is preferably in the range of 0.5 to 1%; or the concentration of the PEG-75 stearate is preferably in the range of 0.2 to 1%; or the ceteth-20 or The concentration of steareth-20 is preferably in the range of 0.05-0.25%.

  In addition, the excipient may be a preservative, preferably phenoxyethanol; otherwise the excipient is selected from antioxidants, preferably tocopherol and glycyrrhiza glabra dry extract obtain.

  The concentration of the preservative is preferably in the range of 0.3-1%, more preferably 0.5-1%; the concentration of the antioxidant is preferably 0.1-1%, more preferably It is in the range of 0.2 to 0.6%.

  The excipient is further selected from among binders, preferably dextrins; otherwise the excipient is a stabilizer, preferably an emulsion stabilizer, more preferably a cross-linked acrylic copolymer. Otherwise the excipient may be a chelating agent, preferably trisodium ethylenediamine disuccinate. Preferably, the concentration of the binder is in the range of 0.5-2%, more preferably 0.75-1.5%; the concentration of the chelating agent is preferably 0.01-0.08%, More preferably it is in the range of 0.02 to 0.06%; and the concentration of the stabilizer is preferably in the range of 0.15 to 0.6%, more preferably 0.2 to 0.4%. is there.

  The percentages given above for the concentrations of the various components of the composition of the invention are considered as weight / weight percentages and are therefore referenced to 100 g of product.

  The composition of the present invention is produced in a solvent that is water and / or 1,2-hexanediol.

  With the solvent, the composition will be 100% of its final weight.

  A further aspect of the present invention is a cream, gel cream, gel, oil, emulsion, gel emulsion (emulgel) ointment, spray, suppository or stick (such as cocoa butter stick) formulated for topical use. Relates to the composition of the present invention formulated as:

  Alternatively, the compositions of the invention can be formulated for oral use, preferably as a troche, tablet or granule, or for injectable use.

  The compositions can be formulated to release the active ingredients contained therein in a controlled manner, either rapidly or delayed and / or after administration.

  A further aspect of the invention relates to the use of a composition comprising at least one hibiscus extract and at least one β-glucan or a salt thereof as a medicament.

  A further aspect of the invention relates to the use of a composition comprising at least one hibiscus extract and / or at least one β-glucan or a salt thereof for the treatment of anal fissures, preferably acute anal fissures.

  In a preferred embodiment, the composition of the invention is administered topically, preferably at least once a day, more preferably at least twice a day.

  Administration is preferably carried out for a period of at least 1 week, more preferably at least 2 weeks. Best results are obtained with at least 20 days of treatment.

  The compositions of the invention can be administered by themselves or in combination with further agents that are effective or adjuvants in the treatment of fissures.

  Alternatively, the composition can be used in conjunction with a method and / or protocol for treating anal fissure. A preferred example of the method and / or protocol relates to the use of an anal dilator.

  A further aspect of the invention relates to a method of producing a composition comprising at least one hibiscus protein extract and / or at least one β-glucan of the invention.

The method comprises the following steps:
(I) at temperatures ranging from 70 to 90 ° C .; more preferably 75 to 80 ° C., said regulators, preferably occlusion and / or softeners, and / or surfactants, preferably emulsified and / or young. Dissolving the cleaning surfactant;
(Ii) mixing the solvent, the modifier, preferably a humectant, the chelating agent, and / or a stabilizing emulsifier with the dissolved raw material of step (i);
(Iii) adding at least one hibiscus extract to the mixture of step (ii); and (iv) adding at least one β-glucan to the mixture of step (iii).

  The hibiscus extract of step (iii) is solubilized in water, more preferably purified water. Solubilization is preferably achieved at a temperature in the range of 40-60 ° C; more preferably 50-55 ° C.

  The at least one β-glucan of step (iv) is preferably added as a 1-5% aqueous solution (percentage is weight / weight percentage), more preferably as a 1.5-2.5% aqueous solution. The temperature of the mixture to which the at least one β-glucan is added is preferably 35 to 45 ° C, more preferably 32 to 37 ° C.

  Mixing of the components of the composition of the present invention is preferably continued until a semi-processed product is obtained. The semi-finished product can be prepared for use or packaging.

  A further aspect of the invention relates to a kit comprising a composition comprising at least one hibiscus protein extract and / or at least one β-glucan or salt thereof.

  Preferably, the kit composition is formulated as a cream, gel or emulsion gel. More preferably, the kit comprises at least 20 dispensers (eg squeeze tubes) comprising at least one, preferably quasi-dose, of the composition of the invention. The dispenser is preferably disposable, and more preferably comprises an applicator that is preferably incorporated into the dispenser to facilitate application of the composition to the crack to be treated.

  Preferably, the dispenser is dimensioned in a method for delivering a quasi-dose, sufficient, required amount of the composition for application.

EXAMPLE A method for producing a composition of the invention in the form of a gel cream.
The raw material is introduced into the agitator according to the procedure and / or amount provided for the formulation. Prior to mixing with the other ingredients of the formulation, the raw material requiring the dissolution process is dissolved in the lysate to a temperature in the range of 75-80 ° C.

  Then, the temperature of the mixture is lowered to 50-55 ° C., Myoxinol solubilized in high temperature (50-55 ° C.) purified water is added, and β-glucan (2% solution) needs to be dissolved or solubilized. It was continuously added along with other ingredients that were not. These ingredients are added to the mixture at a temperature below 35 ° C. and mixing is continued until a semi-finished product for use / packaging is obtained.

Formulation Examples Examples of compositions of the present invention formulated as a gel / cream and functioning for the purposes of the claimed claims are given in Table 1 below.

Rectal mucosal inflammation test using the composition of the present invention The composition of the present invention in the form of a gel cream was subjected to a rectal mucosal inflammation test. The test was conducted on 6 male white rabbits.

  In particular, three rabbits were treated with 1 ml of gel / cream composition and three rabbits were treated with 1 ml of saline (control). The treatment provides a gel / cream (treatment sample) or saline (control sample) that is introduced directly into the rectum of each animal using a flexible catheter. This treatment was repeated for 5 consecutive days.

  The rectal mucosa of each animal was observed daily to detect the presence of any inflammatory phenomenon such as erythema and / or scab.

  24 hours after the last day of treatment, the animals were sacrificed and samples were taken from the rectal mucosa of the animals for histological examination.

  The microscopic response detected was evaluated based on the data shown in Table 3.

  In the macroscopic examination, the inflammatory response detected in the area of application of the animals treated with the test composition is compared to that detected in the control animals.

  The scores for microscopic evaluation of all animals treated with the test composition are added together and divided by the number of animals to obtain the average inflammatory potential for the treatment group. Similar calculations are performed for the control group.

  A score of 9 in the microscopic evaluation of the control tissue can indicate that the pathology has been affected, or in a control equivalent, it can indicate trauma due to administration. If other animals or control groups in the test show a similarly high score, both situations require a retest. The control group average is subtracted from the test group average to obtain an inflammation index.

  Inflammatory indices are shown in Table 4.

  The results of evaluation with the naked eye are shown in Table 5.

  No abnormalities were detected in the animals due to treatment with the test composition or saline.

  The microscopic results are summarized in Table 6.

  Based on the results shown in Table 6, the composition of the present invention exhibits an inflammatory potential equal to zero. The rectal inflammation index is actually zero.

  In conclusion, the compositions of the present invention are considered non-inflammatory to the rectal mucosa.

Delayed type skin hypersensitivity test using the composition of the present invention-Guinea pig maximization test (GPMT)
The test was performed in white female guinea pigs; in particular, a group of 10 animals (Group 1) was treated with the composition of the invention, while 5 animals formed a control group (Group 2). .

  Group 1 was treated with the composition in the form of a gel / cream, while Group 2 was treated with saline.

  Group 1 is treated with a 1-50: 50 (v: v) intradermal injection (sample 1) of a stable emulsion of Freund's complete adjuvant (FCA) and saline, and the product is treated with FCA and saline. Tests were diluted 50:50 (v: v) with a stable emulsion of water (50%).

  Animals in group 2 were treated with 1-50: 50 (v: v) intradermal injection (sample 2) of a stable emulsion of Freund's complete adjuvant (FCA) and saline. Saline was diluted 50:50 (v: v) with a stable emulsion of FCA and saline (50%).

  The animals used in the study were randomly selected from suitable animals available during the study period. The animals were divided into groups and included up to 5 animals per cage.

24 hours prior to treatment, an area of approximately 50 cm ² on the animal's back was shaved.

  The test consists of an induction period and a challenge period.

  On day 0 of the induction phase, three pairs of intradermal injections each containing 0.1 ml of the above sample were performed on either side of the midline of the subscapular region for all animals.

  On day 6 of the induction period, after intradermal injection, all animals were topically applied with 1 ml of 10% sodium lauryl sulfate via a gentle massage.

  On day 7 of the induction period, after intradermal injection, all animals were applied topically with a 1 ml sample under a sealed bandage. The application was applied randomly with respect to the injection site.

  The bandage was left for 48 hours. Similar treatment was performed for the control group using saline instead of the composition of the present invention.

  For the challenge phase, on day 21, all guinea pigs were tested as described above and treated topically on the right flank under a sealed bandage with 1 ml of the composition to be diluted. The bandage was kept for 24 hours.

  On day 23 (24 hours after removal of the bandage) and day 24 (48 hours after removal of the bandage), the skin response of all animals was evaluated. The intensity of erythema and edema was evaluated according to the Magnusson and Kligman scale as shown in Table 7.

  One or more Magnusson and Kligman scale values in the test group generally sensitize, provided that values less than 1 are observed in control animals.

  If a value of 1 or more is observed in a control animal, the response in the test animal that exceeds the most severe response of the control animal is presumed to be due to sensitization.

  If the response is ambiguous, a re-challenge needs to be performed to confirm the outcome of the first challenge. Test results are expressed as the frequency of positive responses to challenge in test and control animals.

  The results are summarized in Table 8.

  The results demonstrate that no abnormalities are observed in either the animals treated with the composition or the control animals and the percentage of guinea pigs sensitized is therefore equal to zero.

First study on subjects suffering from anal fissure and treated with the composition of the present invention Ten subjects with acute fissure of age 21-72 years (mean age 38.7 years) Treated with the composition. The treatment was continued for one month and was performed by treating the cracks locally with a composition in the form of a gel cream, three times a day.

  Subject did not report any side effects.

  After the month of treatment, pain symptoms were completely relieved in 5 out of 10 subjects, while a significant reduction in pain symptoms was observed in another 4 subjects. Pain was measured using a visual rating scale (VSA) and the average VAS ranged from 9 to 3.25.

  In 6 out of 10 subjects, complete scarring of the fissure was confirmed after 1 month of treatment.

  At the end of the topical treatment, further expansion treatment is required in 7 subjects, and the treated subjects consider the fact that there is a clear improvement in these symptoms, which is more Accepted.

  In a second examination performed after 60 days, complete scarring was observed in 9 out of 10 subjects.

  Only subjects who did not heal completely continued treatment for an additional 20 days and showed complete healing in the next examination (ie 90 days after the start of treatment).

Second study on subjects suffering from fissure and treated with the composition of the invention Ten subjects with acute anal fissure were treated with the composition of the invention in gel cream form.

  Treatment was performed at a dose of 3 g / day for 30 days or 3 g / day for 50 days.

  Subject underwent anoscopic examination as an outpatient to diagnose anal fissure.

  Subjects were described for the treatment based on how gel cream was applied and in the event associated with constipation, stool softeners were administered for 30 or 50 days, respectively (FIBRAID, 1 sachet twice daily).

  A clinical follow-up consisting of examination and anoscopy was performed on days 10-30.

  The first endpoint was resolution of symptoms reported in the first test.

  The second endpoint was the resolution of cracks with the naked eye.

  Subject characteristics and results evaluated in follow-up are summarized in Table 9.

  Constipation was a symptom present in about 70% of subjects.

  Immediate benefits including resolution of symptoms or a clear improvement were observed in 58% of treated subjects as early as 10 days after treatment; at 30 days the percentage increased to 75%.

  In subjects treated within 1 month of symptom onset, gross resolution of the cracks occurred in 10 subjects after 10 days.

  At 30 days, crack resolution was observed in more than 50% of the subjects.

  The total percentage of need for further treatment is 27%, which includes one patient who has failed follow-up at 50 days.

  No adverse events or complications were reported by subjects for various follow-up periods.

Claims (38)

  A composition comprising at least one hibiscus protein extract and at least one β-glucan or a salt thereof.   The composition according to claim 1, wherein the hibiscus is Hibiscus esculentus.   The composition according to claim 1 or 2, wherein the protein extract is derived from the seeds of the hibiscus.   4. The composition of claim 3, wherein the seed is defatted.   The composition according to any one of claims 1 to 4, wherein the protein extract is at least a protein fraction, preferably a soluble protein fraction.   The composition according to any one of claims 1 to 5, wherein the protein extract or the protein fraction is a protein hydrolysate.   The composition according to claim 6, wherein the hydrolyzate is obtained by enzymatic hydrolysis, chemical hydrolysis or biotransformation of the protein extract or the protein fraction.   The composition according to claim 6 or 7, wherein the hydrolyzate is a mixture of oligopeptides.   The composition according to any one of claims 6 to 8, wherein the hydrolyzate is a mixture with a binder, preferably dextrin.   The composition of claim 9, wherein the hydrolyzate is Myoxinol ™.   11. The hibiscus protein extract is present in a concentration in the range of 0.1-10%; preferably in the range of 0.4-5%. Composition.   The composition according to any one of claims 1 to 11, wherein the at least one β-glucan is carboxymethyl-β-glucan or a salt thereof; preferably sodium carboxymethyl-β-glucan.   The composition according to claim 12, wherein the β-glucan is present in a concentration in the range of 0.004 to 0.4%; preferably in the range of 0.02 to 0.08%.   14. A composition according to any one of the preceding claims, wherein the ratio of the at least one protein extract to the at least one beta glucan is 50 to 10: 1, preferably 35 to 20: 1.   15. Composition according to any one of claims 1 to 14, characterized by a pH in the range 5-8, preferably 5.5-6.5.   16. Composition according to any one of the preceding claims, characterized by a viscosity in the range of 5000-30000 mPas, preferably 7000-25000 mPas.   The composition according to any one of claims 1 to 16, further comprising at least one excipient acceptable for pharmaceutical use or cosmetic use.   18. A composition according to claim 17, wherein the excipient is at least one modifier, preferably a skin or hair moisturizer, an occlusion modifier, or a softener.   Said excipients or said regulators are: (Oil derived from Borago officinalis), Malva extract and / or mucus, preferably mucus of Malva sylvetris, panthenol, calendula, preferably Calendula officinalis 19. A composition according to claim 17 or 18 selected from the group consisting of an extract, ethylhexyl glycerin, caprylyl glycol, aspartic acid, maltodextrin, and glyceryl stearate.   20. A composition according to claim 18 or 19, wherein the concentration of the modifier is in the range of 15-35%, preferably 20-25%.   18. A composition according to any one of claims 17 wherein the excipient is further a surfactant, preferably an emulsifying and / or cleaning surfactant.   The composition according to any one of claims 21 to 22, wherein the concentration of the surfactant is in the range of 1 to 3%, more preferably 1.2 to 2%.   The surfactant according to claim 21 or 22, wherein the surfactant is selected from the group consisting of cetyl alcohol, cetyl (20) OE or ceteth-20, stearyl (20) OE or steareth-20 and stearic acid PEG-75. Composition.   Said excipient is further a preservative, preferably phenoxyethanol; otherwise said excipient is further an antioxidant, preferably tocopherol and / or glycyrrhiza glabra dry extract; Otherwise the excipient is further a binder, preferably a dextrin; otherwise the excipient is a stabilizer, preferably an emulsion stabilizer, more preferably a cross-linked acrylic copolymer; Otherwise, the excipient is a chelating agent, preferably trisodium ethylenediamine disuccinate.   The concentration of the preservative is 0.3 to 1.5%, preferably 0.5 to 1, and the concentration of the antioxidant is 0.1 to 1%, preferably 0.2 to 0.6. The concentration of the binder is 0.5 to 2%, preferably 0.75 to 1.5%, and the concentration of the chelating agent is 0.01 to 0.08%, preferably 25. The range of 0.02 to 0.06% and the stabilizer concentration is in the range of 0.15 to 0.6%, preferably 0.2 to 0.4%. Composition.   The composition according to any one of claims 1 to 25, wherein the solvent is water or 1,2-hexanediol.   27. A composition according to any one of claims 1 to 26, formulated as a cream, gel cream, gel, oil, emulsion, gel emulsion (emulgel), ointment, spray, suppository or stick.   28. A composition comprising at least one hibiscus extract and at least one beta glucan or a combination of salts thereof according to any one of claims 1 to 27 for use as a medicament.   29. Composition comprising at least one hibiscus extract and / or at least one β-glucan or a salt thereof according to any one of claims 1 to 28 for use in the treatment of anal fissures. object.   30. Composition according to claim 29, wherein the anal fissure is of the acute and / or chronic type, preferably the acute type.   31. A composition according to claim 29 or 30, for use in the treatment of anal fissure by topical administration for at least 1 week, more preferably at least 20 days, at least once daily, more preferably at least twice daily.   32. A composition according to any one of claims 29 to 31 for use in conjunction with a method and / or protocol for treating anal fissure, preferably a method and / or protocol using an anal dilator. A method for producing the composition according to any one of claims 1 to 28, wherein: (i) at a temperature in the range of 70 to 90 ° C, more preferably 75 to 80 ° C; Dissolving a modifier, preferably an occlusion and / or softener, and / or a surfactant, preferably an emulsifying / detergent surfactant;
(Ii) mixing the solvent, the modifier, preferably a humectant, the chelating agent, and / or a stabilizing emulsifier with the dissolved raw material of step (i);
(Iii) adding at least one hibiscus extract to the mixture of step (ii); and (iv) adding at least one β-glucan to the mixture of step (iii).   34. The extract of said hibiscus of step (iii) is solubilized in water, preferably purified water, at a temperature in the range of 40-60 ° C, preferably 50-55 ° C. the method of.   The at least one β-glucan of step (iv) is added as a 1-5% solution, preferably a 1.5-2.5% solution, at a temperature in the range of 35-45 ° C, preferably 32-37 ° C 35. A method according to claim 33 or 34.   29. A kit comprising a composition according to any one of the preceding claims, preferably comprising at least one dispenser, preferably a disposable dispenser, preferably comprising the composition in quasi-dose.   37. The kit of claim 36, comprising at least 20 dispensers.   38. A kit according to claim 36 or 37, wherein the at least one dispenser comprises an applicator incorporated into the dispenser.