ES2457718A1 - Orodispersible pharmaceutical composition of melatonin - Google Patents

Abstract

The invention relates to solid orodispersible pharmaceutical compositions for orally administering melatonin, without having to simultaneously drink liquid and without problems of deglutition, which use crospovidone as the main agglutinant and allow high doses of melatonin and other active substances such as vitamin E and tryptophan to be included in smaller tablets produced by means of direct compression.

Description

Melatonin orodispersible pharmaceutical composition.

SECTOR OF THE TECHNIQUE

The present invention is part of the pharmaceutical sector and refers to orodispersible compositions comprising melatonin. In particular, it refers to orodispersible tablets comprising melatonin manufactured by direct compression.

STATE OF THE TECHNIQUE

Melatonin (N-acetyl-5-methoxytryptamine), is a hormone derived from 5-hydroxytryptamine that is mainly secreted in the pineal gland and the retina of vertebrates during the hours of darkness. Its importance lies in its ability to regulate numerous physiological processes related to biological rhythms and neuroendocrine function.

Melatonin is useful for the treatment of different pathologies, including Parkinson's disease (Molina-Carballo et al., 1997. J Pineal Res 23 (2): 97-105) or circadian rhythm disorders. It is also useful for the regulation of the inflammatory response, the treatment of systemic inflammatory response syndrome (SIRS), the treatment of multiple organic dysfunction syndrome (MODS), the treatment of sepsis in neonates, the treatment of sepsis in adults , the treatment of myocardial infarctions, the treatment of mitochondrial damage, the treatment of pulmonary edema, the treatment of a renal or hepatic failure, or the treatment of the oxidative stress situation, and particularly during abdominal surgery (ES201130791), or for the treatment and prevention of mucositis (ES201101158).

Therefore, in view of the results and scientific evidence on the effect, efficacy and safety of the administration of melatonin, it is necessary to produce compositions that admit high concentrations of melatonin and facilitate its administration.

In the sense of the present invention, orodispersible tablet is understood as a tablet that can be broken down in the mouth, in the absence of any chewing action, in less than 180 seconds, preferably in less than 60 seconds, upon contact with the saliva forming An easy to swallow suspension.

Another requirement that these pharmaceutical forms have to fulfill is that of having adequate mechanical resistance, both for handling and for secondary conditioning and preservation. They must also have good organoleptic characteristics for greater acceptance by the patient. Unpleasant flavors are usually masked by incorporating sugars into the formula, which give good flavor and adequate viscosity when mixed with saliva, or flavorings.

Many people have difficulty swallowing conventional tablets, often of negligible size, for example children and the elderly. Problems related to the ingestion of medications (choking, passing through another duct, suffocation from throat obstruction) are often the cause of poor acceptance of the dosage, even of a suspension of treatment. The orodispersible tablets allow to solve these problems since, among other advantages, they allow their administration to patients with swallowing difficulties and have a high acceptance by the patient. In addition to using these tablets improves the bioavailability of the active substance, a very interesting aspect in the administration of melatonin.

Regarding the development of orodispersible tablets, we can find various procedures. Among them, direct compression is the simplest and most economical procedure because a smaller number of processing steps is required compared to other techniques such as wet or dry granulation, roller compaction, lyophilization technique and of crosslinked polysaccharides. Most of the active substances cannot be compressed directly due to a lack of flow, cohesive properties and lubrication. Therefore, to be able to manufacture tablets satisfactorily it is necessary to mix them with other directly compressible ingredients.

For the preparation of this type of tablets and using this technique of obtaining (direct compression) it is necessary to use superdisintegrating excipients, to facilitate the disintegration of these galenic forms and also the addition of sugars to improve the organoleptic characteristics of the orodispersible tablets . The difficulties encountered in the manufacture of such tablets lie in the fact that it is very difficult to obtain tablets that have constant physical characteristics, reproducible and compatible with the typical handling needs of the tablets. Mixtures of excipients normally used in galenic lead to high hardness tablets, totally misfit for rapid disintegration in the oral cavity.

One of the limitations that stand out for this type of orodispersible compositions is that the active ingredient must be of small weight so that the disintegration is very rapid.

Crospovidone is an insoluble and chemically inert substance. It is a synthetic polymer formed by linear groups Etinil and Pyrrolidone. In pharmacy it is usually applied as an anti-diarrheal since it is capable of forming a protective layer on the gastrointestinal mucosa, which prevents the action of the irritating substances on it, avoiding through this mechanism accelerated peristalsis of the intestine and, as a consequence, the diarrheal phenomenon

In Galenic, crospovidone is not usually used as a binder, since it is characterized by being a good disintegrant and is always used in combination with other binder excipients.

There are orodispersible melatonin tablets on the market such as Sleep Forte®, with 5 mg of melatonin, whose composition comprises microcrystalline cellulose (binder), povidone (disintegrant), magnesium stearate (lubricant), talcum (lubricant and diluent), isomalt (sweetener) and croscarmellose sodium (diluent) or Somnio® Flash, orodispersible tablets with 1.9 mg of melatonin, whose most complex formulation comprises microcrystalline cellulose (binder), corn starch (disintegrant), polyvinyl polypyrrolidone (disintegrant / binder), Pyridoxine hydrochloride (vitamin B6), mannitol (sweetener) and aromas, together with a coating agent comprising sodium salts of fatty acids.

The inventors do not know melatonin orodispersible tablets using crospovidone as a major binder or sole binder.

OBJECT OF THE INVENTION

The present invention aims at a solid orodispersible pharmaceutical form for oral administration of melatonin, as well as a derivative, a salt, a prodrug or a solvate of melatonin, without simultaneous drinking from a glass of water and without swallowing problems.

The term "prodrug" as used in this application is defined herein as meaning a

chemical compound that has undergone a chemical derivation such as a substitution or addition of an additional chemical group to change (for pharmaceutical use) any of its physicochemical properties, such as solubility or bioavailability, for example ester, ether or amide derivatives of an active compound that provide the active compound itself upon administration to a subject. Those skilled in the art are familiar with examples of well-known methods of producing a prodrug of a given active compound and can be found for example in Krogsgaard-Larsen et al., Textbook of Drug design and Discovery, Taylor & Francis (April 2002).

Particularly favored prodrugs are those that increase the bioavailability of the compounds of this invention when such compounds are administered to a patient (for example, allowing a compound administered orally to be more easily absorbed into the blood) or that improve the supply of the compound. original to a biological compartment (for example, the brain or lymphatic system) with respect to the original species.

The term "solvate" according to this invention is to be understood as meaning any form of melatonin according to

the invention having another molecule (most likely a polar diluent) attached by means of a non-covalent bond. Examples of such solvates include hydrates and alcoholates, for example methanolates.

It is possible to synthesize pharmaceutically acceptable salts from melatonin by conventional chemical methods, generally by reacting it with an appropriate acid in water or in an organic diluent or in a mixture of both. Generally, non-aqueous media such as ether, ethyl acetate, ethanol, isopropanol or acetonitrile are preferred. Examples of the acid addition salts include mineral acid addition salts such as, for example, hydrochloride, hydrobromide, iohydrate, sulfate, nitrate, phosphate, and organic acid addition salts such as, for example, acetate, maleate. , fumarate, citrate, oxalate, succinate, tartrate, malate, mandelate, methanesulfonate and p-toluenesulfonate.

The preparation of salts, solvates and prodrugs can be carried out by methods known in the art. It will be appreciated that non-pharmaceutically acceptable salts, solvates or prodrugs are also within the scope of the invention since they may be useful in the preparation of pharmaceutically acceptable salts, solvates or prodrugs.

Various melatonin derivatives are known in the state of the art, which are also included in the present invention.

In particular, the object of the present invention is to manufacture orodispersible tablets with high concentrations of melatonin, reaching up to 40% by weight of melatonin with respect to the total weight of the tablet, using crospovidone as the sole binder or as a major binder, understanding as such, that Assume more than 50% of the weight of all the binders used.

A preferred embodiment of the invention relates to an orodispersible solid pharmaceutical form which further comprises mannitol as diluent and flavoring.

A preferred embodiment of the invention relates to an orodispersible solid pharmaceutical form which further comprises vitamin E.

Another preferred embodiment of the invention is an orodispersible solid pharmaceutical form which further comprises tryptophan.

These last two formulations favor the dosage, since in a single dose, with one tablet, the proposed assets are administered simultaneously, melatonin with vitamin E on the one hand and on the other melatonin with tryptophan.

A second aspect of the invention relates to the use of the composition of the invention in the manufacture of a medicament.

A third aspect of the invention relates to the composition of the invention for use as a medicament.

Thus, the present invention solves some of the problems described above. On the one hand, it allows its pediatric use to be very small, easily manipulated tablets that disintegrate in a few seconds in the mouth. On the other hand, not only do they allow to remedy the known drawbacks of conventional galenic forms for swallowing, but it is also possible to obtain tablets with high doses of active ingredient, overcoming other limitations presented by such compositions.

From an industrial point of view, the present invention simplifies the production process by using direct compression methods, using a small number of excipients to obtain the tablets and not needing water in the process.

EXPLANATION OF THE INVENTION

The authors have discovered that crospovidone, commonly used as a disintegrant or superdisintegrant, is surprisingly effective used as a binding agent in these melatonin tablets, allowing the manufacture of orodispersible tablets comprising melatonin by direct compression in the absence of other binders. In the tablets object of the invention, crospovidone is an excipient that plays the role of binder and disintegrant at the same time.

The invention relates to an orodispersible solid form of melatonin containing crospovidone as the sole binder or as the majority binder. Preferably, mannitol will be used as a diluent since the use of mannitol together with crospovidone allows rapid disintegration and tablets of acceptable taste and pleasant texture are also obtained.

The invention allows to obtain a melatonin formulation, without using water in the manufacturing process, in the form of tablets with low friability and hardness compatible with that obtained by usual handling techniques, with values ranging between 30-33.2 Newton, if the only active substance is melatonin, and between 10 and 60 Newton, if other active ingredients are also included.

On the other hand, this excipient allows to obtain tablets with a very small size, reaching 150 mg tablets with dimensions of 1.66 mm high and 10.12 mm in diameter. These reduced dimensions facilitate the administration of high doses of melatonin even to young children.

The pharmaceutical compositions according to the invention are preferably characterized in that they contain, with respect to the total weight of the composition,

•

Between 2% and 40% by weight of melatonin.

•

Between 10% and 30% by weight of binder excipients which in turn comprise between 50% and 100% by weight of crospovidone.

Preferably, the only binder used will be crospovidone, whereby the compositions will contain between 10% and 30% by weight of crospovidone, more preferably between 13% and 28%.

The composition according to the invention may also contain, for manufacturing reasons, one or more lubricants, preferably magnesium stearate and anhydrous colloidal silica (Aerosil®), in different proportions, as well as aromas, dyes and sweeteners normally used.

As diluent, the composition will contain mannitol, since its use together with crospovidone allows rapid disintegration and they are also organoleptically acceptable without the need for additional sweeteners or flavorings.

In addition, together with melatonin, these tablets may also include high doses of other active substances, such as vitamin E and tryptophan.

The present invention allows to obtain compositions with more than 10% by weight of vitamin E with respect to the total weight of the composition and more than 70% by weight of tryptophan with respect to the total weight of the composition.

The pharmaceutical composition is presented as a tablet. These tablets are manufactured by direct compression and have a hardness between 10 and 60 Newton, preferably between 30 and 56.4 Newton.

EMBODIMENTS OF THE INVENTION

Example 1. Melatonin orodispersible tablets:

Four types of orodispersible tablets with melatonin have been manufactured in different doses, identified by the letters A, B, C and D, whose compositions are given below.

The tablets were prepared by mixing the constituents and subsequently performing a direct compression. Tablet A. For its manufacture it has used a pressure of 1.5 Ton for a compression time of 20 seconds.

Constituents

Amount (mg)

Melatonin

3

Mannitol

100

Crospovidone

42

Magnesium stearate

3

Aerosil®

2

Total Weight

150

Characteristics of the tablets:

35 Average hardness: 30.4 Newton Temperature: 37 ºC Disintegration: 21 sec Friability: <1% Size: Height: 1.66 mm, diameter: 10.12 mm

Tablet B: For its manufacture it has used a pressure of 1.5 Ton for a compression time of 30 seconds.

Constituents

Amount (mg)

Melatonin

5

Mannitol

100

Crospovidone

40

Magnesium stearate

3

Aerosil®

2

Total Weight

150

Characteristics of the tablets: Average hardness: 33.2 Newton Temperature: 37ºC Disintegration: 21 sec Friability: <1%

Size: Height: 10.08 mm, diameter: 1.57 mm

Tablet C: For its manufacture it has used a pressure of 1.5 Ton for a compression time of 30 seconds.

Constituents

Amount (mg)

Melatonin

10

Mannitol

95

Crospovidone

40

Magnesium stearate

3

Aerosil®

2

Total Weight

150

Pressure of 1.5 during a compression time of 30 sec

Average hardness: 32.5 Newton

Temperature: 37 ºC 10 Disintegration: 25 sec

Friability: <1%

Size: Height: 10.06 mm, diameter: 1.53 mm

Tablet D: For its manufacture it has used a pressure of 1 Ton for a compression time of 10 15 seconds.

Constituents

Amount (mg)

Melatonin

60

Mannitol

67

Crospovidone

twenty

Magnesium stearate

2

Aerosil®

one

Total Weight

150

Characteristics of the tablets:

20 Average hardness: 33.1 N Temperature: 37 ºC Disintegration: 20 seconds Friability: 0.91% Size: Height: 1.85 mm, diameter: 10.07 mm

Example 2: Preparation of orodispersible tablets with melatonin and Vitamin E

The association of melatonin with Vitamin E (10 IU) is used to treat children with Duchenne disease, in order to enhance the antioxidant effect of melatonin.

Orodispersible tablets with 60 mg of melatonin and tocopherol acetate (Vitamin E) 10UI.

For its manufacture a pressure of 1 Ton has been used for a compression time of 10 seconds, Mg stearate has been suppressed and only aerosil® is included as a lubricant. The diluent and binder used are the same as those used for melatonin orodispersible tablets.

Constituents

Amount (mg)

Melatonin

60

Vitamin E Acetate

18.32

Mannitol

fifty

Crospovidone

49

Aerosil ®

one

Total Weight

178.32

Characteristics of the tablets:

Average hardness: 13.7 Newton

Temperature: 37ºC

Disintegration: 30 sec

Friability: <1%

Size: Height: 2.34 mm, diameter: 10.16 mm

Orodispersible tablets with 10 mg of melatonin and tocopherol acetate (Vitamin E) 10UI. For its manufacture a pressure of 1.5 Ton has been used for a compression time of 30 seconds. From New magnesium stearate and aerosil® are included. The diluent and binder used are the same as those used for melatonin orodispersible tablets.

Constituents

Amount (mg)

Melatonin

10

Vitamin E Acetate

18.32

Mannitol

95

Crospovidone

40

Magnesium Stearate

3

Aerosil ®

2

Total Weight

168.32

Characteristics of the tablets: Average hardness: 18.9 Newton

10 Temperature: 37ºC Disintegration: 33 sec Friability: <1% Size: Height: 1.86 mm, diameter: 10.11 mm

Example 3: Preparation of orodispersible tablets with Melatonin and Tryptophan

Tryptophan is an essential amino acid in human nutrition. It is one of the 20 amino acids included in the genetic code (codon UGG). It is classified among apolar amino acids, also called hydrophobes. It is essential to promote the release of the neurotransmitter serotonin, involved in the regulation of sleep.

By way of example, orodispersible tablets of melatonin (5 mg) and tryptophan (150 mg) have been produced. The formation of the hormone begins with the uptake of the amino acid tryptophan, from the bloodstream, so if hormone and amino acid are co-administered, the synthesis of melatonin and

25 release of the neurotransmitter serotonin. Anxiety, insomnia and stress benefit from a better balance thanks to tryptophan.

In the composition the diluent has been suppressed, given the high proportions of tryptophan that need to be used. Even so, the proposed formulation meets all the requirements of these pharmaceutical forms.

For its manufacture it has used a pressure of 1.5 Ton for a compression time of 30 seconds.

Constituents

Amount (mg)

Melatonin

5

Tryptophan

150

Crospovidone

60

Magnesium Stearate

3

Aerosil ®

2

Total Weight

220

35 Characteristics of the tablets:

Average hardness: 56.4 Newton Newton: Temperature 37 ° C Disintegration: 20 sec

40 Friability: <1% Size: Height: 2.51mm, diameter: 10.06mm

Claims (13)

1. Solid orodispersible pharmaceutical composition comprising melatonin containing, with respect to the total weight of the composition,

•

Between 2% and 40% by weight of melatonin.

•

Between 10% and 30% by weight of binder excipients which in turn comprise between 50% and 100% by weight of crospovidone.

2. Solid orodispersible pharmaceutical composition comprising melatonin according to the preceding claim containing, with respect to the total weight of the composition,

•

Between 2% and 40% by weight of melatonin

•

Between 10% and 30% by weight of crospovidone, preferably between 13% and 28%.

3.

Solid orodispersible pharmaceutical composition comprising melatonin according to any of the preceding claims further comprising vitamin E

Four.

Solid orodispersible pharmaceutical composition comprising melatonin according to the preceding claim comprising, with respect to the total weight of the composition, more than 10% by weight of vitamin E.

5.

Solid orodispersible pharmaceutical composition comprising melatonin according to any one of claims 1 or 2 further comprising tryptophan.

6.

Solid orodispersible pharmaceutical composition comprising melatonin according to the preceding claim comprising, with respect to the total weight of the composition, more than 70% by weight of tryptophan.

7.

Pharmaceutical composition according to any of the preceding claims, characterized in that it is presented as a tablet.

8.

Tablets according to the preceding claim, characterized in that they are obtained by direct compression.

9.

Tablets according to the preceding claim, characterized in that their hardness is between 10 and 60 Newton, preferably between 30 and 56.4 Newton.

10.

Use of the melatonin orodispersible solid pharmaceutical composition according to any of the preceding claims for the manufacture of a medicament.

eleven.

Use of the melatonin orodispersible solid pharmaceutical composition according to claims 3 or 4 for the manufacture of a medicament for the treatment of Duchenne's disease.

12.

Use of the melatonin solid orodispersible pharmaceutical composition according to claims 5 or 6 for the manufacture of a medicament for the treatment of pathologies associated with the production of serotonin, preferably anxiety, insomnia and stress.

SPANISH OFFICE OF THE PATENTS AND BRAND Application no .: 201231477 SPAIN Date of submission of the application: 24.09.2012 Priority Date: REPORT ON THE STATE OF THE TECHNIQUE 51 Int. Cl.: See Additional Sheet RELEVANT DOCUMENTS

Category

56 Documents cited Claims Affected

TO

CN 101143135 A (GUILI XU et al.) 1-12

(summary) 19.03.2008 [online] [retrieved on 06.27.2013]. Recovered from: HCaplus in STN,

Chemical Abstracts Service (Columbus, Ohio, USA), accession number 2008: 361962.

TO

WO 2010062153 A1 (GARCIA PEREZ MIGUEL ANGEL et al.) 03.06.2010, 1-12

page 17, line 18 - page 19, line 20; claims 22-25.

TO

WO 2005082143 A1 (LIFESCAPE BIOSCIENCES INC et al.) 09.09.2005, 1-12

claims 1.11; page 17, line 1 - page 18, line 5.

TO

US 4687763 A (WURTMAN RICHARD J) 18.08.1987, 1-12

column 1, line 44 - column 4, line 20.

TO

WO 2006007910 A1 (SANTHERA PHARMACEUTICALS CH et al.) 26.01.2006,

claims 8-11.

Category of the documents cited X: of particular relevance Y: of particular relevance combined with other / s of the same category A: reflects the state of the art O: refers to unwritten disclosure P: published between the priority date and the date of priority submission of the application E: previous document, but published after the date of submission of the application

This report has been prepared • for all claims • for claims no:

Date of realization of the report 28.06.2013

Examiner N. Vera Gutiérrez Page 1/4

REPORT OF THE STATE OF THE TECHNIQUE Application number: 201231477 CLASSIFICATION OBJECT OF THE APPLICATION A61K31 / 4045 (2006.01) A61K9 / 20 (2006.01) A61K47 / 32 (2006.01) Minimum documentation sought (classification system followed by classification symbols) A61K Electronic databases consulted during the search (name of the database and, if possible, terms of search used) INVENES, EPODOC, REGISTRY, CAS, WPI, EMBASE, MEDLINE, BIOSIS, NPL, XPESP State of the Art Report Page 2/4  WRITTEN OPINION Application number: 201231477 Date of Completion of Written Opinion: 06.28.2013 Statement

Novelty (Art. 6.1 LP 11/1986)

Claims Claims 1-12 IF NOT

Inventive activity (Art. 8.1 LP11 / 1986)

Claims Claims 1-12 IF NOT

The application is considered to comply with the industrial application requirement. This requirement was evaluated during the formal and technical examination phase of the application (Article 31.2 Law 11/1986).  Opinion Base.- This opinion has been made on the basis of the patent application as published. State of the Art Report Page 3/4  WRITTEN OPINION Application number: 201231477  1. Documents considered.- The documents belonging to the state of the art taken into consideration for the realization of this opinion are listed below.

Document

Publication or Identification Number publication date

D01

CN 101143135 A (GUILI XU et al.) 03/19/2008

D02

WO 2010062153 A1 (GARCIA PEREZ MIGUEL ANGEL et al.) 06.03.2010

 2. Statement motivated according to articles 29.6 and 29.7 of the Regulations for the execution of Law 11/1986, of March 20, on Patents on novelty and inventive activity; quotes and explanations in support of this statement The invention relates to an orodispersible solid pharmaceutical composition comprising melatonin, which contains, with respect to the total weight of the composition, between 2 and 40% by weight of melatonin and between 10 and 30% by weight of binder excipients which in turn they comprise between 50 and 100% by weight of crospovidone. It also refers to compositions that also include vitamin E or tryptophan and its use to manufacture a medicament for the treatment of Duchenne's disease and pathologies associated with the production of serotonin, respectively. Document D01 discloses an orodispersible melatonin tablet for the treatment of insomnia, comprising, in parts by weight: melatonin (3), disintegrant (6-16), effervescent agent (10-22), diluent (40-70), sweetener (3-6) and lubricant (1-3). Among the relationship of possible disintegrants crospovidone is cited. Document D02 discloses pharmaceutical compositions containing melatonin, under different pharmaceutical forms. In one of the described embodiments (page 17, line 18-page 19, line 30), sublingual melatonin tablets are prepared which include as excipients: polyethylene glycol, compressible sugar, lactose, croscarmellose sodium, hydroxypropylcellulose, polyvinylpyrrolidone, Tween 80, magnesium stearate , sweeteners, flavorings and dyes. Documents that disclose solid orodispersible melatonin compositions comprising crospovidone as binder in the proportion described in claim 1 of the application have not been found in the state of the art. Therefore, in view of documents D01 and D02, the invention as defined in claims 1-12 is considered to be new (Article 6.1 L.P.). As mentioned in the application, it seems that the selection of crospovidone as an excipient allows it to be the only binder or the majority binder used in the composition, which would provide a technical advantage over the compositions existing in the state of the art. There are no indications in the cited documents that lead the person skilled in the art to conceive solid orodispersible melatonin compositions with these characteristics. Thus, it is considered that the invention as defined in claims 1-12 of the application implies inventive activity (Article 8.1 L.P.). State of the Art Report Page 4/4