ES2457718B1 - Melatonin orodispersible pharmaceutical composition - Google Patents

Abstract

Mechatonin orodispersible pharmaceutical composition # The present invention relates to solid orodispersible pharmaceutical compositions for oral administration of melatonin, without simultaneous fluid intake and without swallowing problems, which use crospovidone as a major binder and allow high doses of melatonin to be included and other active ingredients such as vitamin E and tryptophan in small tablets made by direct compression.

Description

DESCRIPTION

Melatonin orodispersible pharmaceutical composition.

SECTOR OF THE TECHNIQUE 5

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.

 10

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 20 (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 infarction, 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). 25

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.

 30

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 meet is to have an 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.

 40

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 easiest 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, freeze-drying technique and that 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 tablets 60 orodispersible 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. 65

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 5 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

 10

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 15 (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. twenty

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

OBJECT OF THE INVENTION 25

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.

 30

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 know 35 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 in the blood) or that improve the supply of the original compound to a biological compartment (for example, the brain or lymphatic system) with respect to the original species.

 Four. Five

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

 5

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 posology, 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. twenty

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 25 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

 35

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. 40

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. Four. Five

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. fifty

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.

 55

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 60% 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%.

 65

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 a diluent, the composition will contain mannitol, since its use together with crospovidone allows rapid disintegration and is 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. 10

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 that is between 10 and 60 Newton, preferably between 30 and 56.4 Newton.

EMBODIMENTS OF THE INVENTION

 twenty

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.

 25

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. 30

 Constituents

 Amount (mg)

 Melatonin

 3

 Mannitol

 100

 Crospovidone

 42

 Magnesium stearate

 3

 Aerosil®

 2

 Total Weight

 150

Characteristics of the tablets:

Average hardness: 30.4 Newton 35

Temperature: 37 ºC

Disintegration: 21 sec

Friability: <1%

Size: Height: 1.66 mm, diameter: 10.12 mm

 40

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

 Four. Five

Characteristics of the tablets:

Average hardness: 33.2 Newton

Temperature: 37ºC

Disintegration: 21 sec

Friability: <1% 50

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.

 5

 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

Disintegration: 25 sec 10

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 seconds. fifteen

 Constituents

 Amount (mg)

 Melatonin

 60

 Mannitol

 67

 Crospovidone

 twenty

 Magnesium stearate

 2

 Aerosil®

 one

 Total Weight

 150

Characteristics of the tablets:

Average hardness: 33.1 N 20

Temperature: 37 ºC

Disintegration: 20 seconds

Friability: 0.91%

Size: Height: 1.85 mm, diameter: 10.07 mm

 25

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.

 30

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 40

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. Again, magnesium stearate and aerosil® are included. The diluent and binder used are the same as those used for melatonin orodispersible tablets. 5

 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

Temperature: 37ºC 10

Disintegration: 33 sec

Friability: <1%

Size: Height: 1.86 mm, diameter: 10.11 mm

 fifteen

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. twenty

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 the release of the neurotransmitter serotonin will be favored. The
anxiety, the
insomnia and the
Stress benefit from a better balance 25 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.

 30

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

Characteristics of the tablets: 35

Average hardness: 56.4 Newton

Temperature: 37ºC

Disintegration: 20 sec

Friability: <1% 40

Size: Height: 2.51mm, diameter: 10.06mm

Claims (12)

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 5 100% 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%. 10 3. Solid orodispersible pharmaceutical composition comprising melatonin according to any of the preceding claims further comprising vitamin E 4. 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 which further comprises 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. twenty 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. 25 11. 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 orodispersible solid 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 stress , insomnia stress Y stress . 30