WO2018132886A1

WO2018132886A1 - Modified-release composition for readjusting the human biological clock and use of a modified-release composition for readjusting the human biological clock

Info

Publication number: WO2018132886A1
Application number: PCT/BR2018/050008
Authority: WO
Inventors: Rodrigo DOS SANTOS CARNEIRO; Vanessa SILVA MORAIS
Original assignee: Dos Santos Carneiro Rodrigo
Priority date: 2017-01-23
Filing date: 2018-01-16
Publication date: 2018-07-26
Also published as: BR102017003855A2; BR102017003855B1

Abstract

The present invention relates to the combination of one or more calming or sleep-inducing substances with one or more stimulating substances in the same composition, for individuals who have difficulty falling asleep and then lack willingness to wake up. The present composition therefore aims to readjust the human biological clock by inducing sleep and stimulating waking up by means of the same capsule, which should be ingested before going to bed. The calming substance is the first substance to be released and absorbed by the stomach. In turn, the stimulating substance is released hours later by means of a delayed-release capsule, and is absorbed by the intestines.

Description

MODIFIED RELEASE COMPOSITION TO REQUIRE HUMAN BIOLOGICAL WATCH AND USE OF A MODIFIED RELEASE COMPOSITION TO REHATE HUMAN BIOLOGICAL WATCH

FIELD OF INVENTION

The present invention relates to a modified release composition comprising the combination of one or more soothing or sleep-inducing substances associated with one or more stimulating substances, said soothing (or sleep-inducing) substances and said substances. stimulants in the same formulation, and being said composition intended for individuals who have difficulty sleeping and subsequently to achieve a peaceful awakening.

BACKGROUND OF THE INVENTION

A very large portion of the world's population suffers from some sleep disorder, either to initiate sleep, maintain it and / or wake up at the desired time.

Thus, there is a wide range of medicines, herbal remedies, and supplements designed for one of these problems, but neither combat both problems at the same time.

Thus, there is a large and considerable number of individuals suffering from the difficulties of initiating sleep and then more difficulty in awakening, eventually failing to have a good night's sleep.

From this need, alternatives were envisioned, such as following all sleep hygiene rituals, wearing ear and visual earplugs, listening to appropriate sleep songs, sounds with different waves, taking care of ambient light, cutting the spectrum. blue of your electronics, avoid exercise and stimulating foods and drinks at night, meditating and even using mobile phone apps that monitor sleep and promise to wake you up at a great time when you are almost awake.

Additionally, some medications such as Rivotril ^® as well as hormones such as melatonin have been tested.

The results obtained were diverse, and the combination of rituals with controlled drugs proved to be the most efficient for the onset of sleep.

However, the desired tranquil, natural awakening and within the average 8 hours of sleep that an adult needs is not achieved.

[009] Thus, it was still sought to eliminate a certain conventionalism that current society imposes on people who cannot wake up on time and, as a result, arrive late in their morning commitments.

[010] There was an abundance of literature and medications that help induce sleep, but there was nothing that could be eaten before bed and that, automatically and even before the individual woke up, began to assist him in awakening.

[011] Some substances are widely known as stimulants, such as caffeine, guarana, taurine, adrenaline, ginseng, among others.

[012] Other substances are also commonly used for sleep aids.

Interesting to point out that nanotechnology is already available to make this release controlled at the molecular level, even powered by the doctor, but are very advanced technologies and used in the treatment of more serious diseases such as cancer.

[014] A number of compositions containing soothing or sleep-inducing substances, such as Passiflorine ^® and Ritmoneuran ^® , are currently available on the market. However, a possible side effect of these substances is the occurrence of daytime sleepiness, which is harmful to the individual.

In this context, it is possible to cite US6458384, which deals with a composition comprising two pharmacologically active substances, said substances having different release profiles and promoting different effects.

[016] The present invention differs from US6458384 in that it does not contemplate the physical separation of the immediate release substance from the controlled release substance and there is a high possibility of interaction between them.

[017] Also, in US6458384, absorption of the second substance also occurs in the stomach, not protecting the stomach from the acid effect and discomfort of the various hours of absorption.

Interestingly, the main difference is that the present invention effectively separates the immediate release substance from the physically controlled release substance.

Consequently, the possibility of interaction between them is minimized and the absorption of the second This substance does not occur in the stomach (as suggested by US6458384), but in the colon. This provides protection of the stomach against the acid effect and discomfort that several hours of absorption may cause.

Thus, as disclosed by the present invention, it is advantageous that having physical separation would avoid the necessary coating treatment as US6458384 uses, thus preserving the substances closest to their natural state.

Unlike what is intended with the present formulation, US6458384 intends for the substances to be integrated, which can be properly verified in the examples of formulations which are described throughout said document.

Accordingly, US6458384 deals with biological function broadly, not focusing on sleeping and waking as the present invention. The document cited repeatedly mentions that the objective is to alleviate the unwanted final phase of the first substance, but does not focus on the second substance as a possible solution for awakening.

Another divergent point from US6458384 in relation to the present invention concerns the ingestion of the substances separately, ie the substances need to be separated into two capsules (or other means) in order to achieve what is desired in US6458384, unlike the present invention, in which a formulation in a single capsule is proposed.

Also, it is possible to cite the international document WO2006133543, which deals with a supplement dietary supplement provided in two parts, one part being provided during the day, comprising stimulating substance; and the other part at night, soothing or sleep-inducing substance.

[025] Such an invention contemplates two lengths, as opposed to the intended formulation, which has a single capsule.

[026] Thus, there is a need for the individual not to forget to consume one of these pills, as well as not facilitating awakening, as awakening is essential for the individual to ingest the stimulant substance.

[027] Thus, there is the possibility of the individual forgetting to consume the stimulating part during the day, presenting drowsiness due to the consumption of the other soothing or sleep-inducing part.

[028] Therefore, it is a clear advantage of the present invention not to impair the cognitive abilities of the individual throughout the day.

Accordingly, the present invention solves the technical problem described above by means of a composition comprising at least one soothing or sleep-inducing substance, and at least one delayed release stimulating substance, providing a tranquil awakening and preventing the occurrence of daytime sleepiness.

DESCRIPTION OF THE INVENTION

[030] The present invention relates to a composition comprising the combination of one or more soothing or sleep inducing substances together with one or more stimulating substances in the same formulation. Thus, in order for the formulation claimed by the present invention to reach this large population that finds problem sleeping and awakening, this separation was sought in the capsule itself, which led to the use of two capsules, one of which is within on the other.

[032] The present composition is presented as a modified release pharmaceutical form, specifically consisting of delayed or delayed release form, which comprises a standard outer gelatin capsule and an inner capsule composed of hydrophilic delayed release polymers.

The outer capsule comprises one or more soothing or sleep-inducing substances. The inner capsule, on the other hand, comprises one or more stimulant substances.

[034] The inner capsule, in turn, has a special coating to absorb within hours of ingestion (eg 6 hours) and will contain the stimulant. This inner capsule will be surrounded by another larger, rapidly absorbing capsule which contains the sedative (as shown in Figure 4).

[035] Thus, the formulation may be ingested minutes before bed, promoting a sleep induction and a smooth awakening approximately 6 to 8 hours later, according to the rate of metabolism of each and also taking into account. resistance to substances (FIGURE 5).

[036] The present invention deals with the first formulation involving antagonistic active substances that interact in specific biological functions and which are released at different times, absorbed into tracts. different and physically separated from each other.

[037] The purpose of the claimed invention is to assist individuals who have difficulty sleeping and trouble or trouble waking up quietly.

[038] Thus, the invention enables sleep to be induced after ingestion of the composition and still provides a pleasant wake up after about 6 to 8 hours by stimulating substances which are absorbed and end up favoring more wakefulness. consistent and at the desired time (FIGURE 8).

[039] The present composition comprises two groups of substances with antagonistic functions, these substances being absorbed at different times by the human organism.

[040] Thus, it is the purpose of the present application to readjust the human biological clock by inducing sleep and subsequently stimulating awakening using a single capsule, which must be taken before bed.

[041] The soothing substance present in this capsule is the first to be released and absorbed by the gastrointestinal tract.

Preferably, Passiflora incarnata or Valerian is the first (sleep-inducing) substance to be released and absorbed by the stomach.

[043] The stimulant, in turn, is released hours later by means of a delayed release capsule.

Preferably, caffeine or Guarana is the substance released late (hours later), being absorbed in the intestine and promoting the awakening of the individual.

[045] In this sense, it is interesting to point out that several sleep-inducing substances already widely studied that can be used in the formulation of lawsuit, such as Passiflora incarnata and Valerian; while stimulating substances which may be used in the composition of the present invention are caffeine and taurine.

In order to demonstrate the advantages achieved by its composition, the combination of Passiflora and caffeine was merely illustrative and not restrictive.

[047] The next step was to establish a way for these antagonistic substances to have different and controlled moments of absorption by the human organism.

[048] Thus, the composition claimed here comprises:

(a) one or more soothing or sleep-inducing substances;

(b) one or more stimulating substances; and

(c) appropriate excipients and carrier.

Possible suitable excipients for the present invention are:

About the capsules:

[050] The outer capsule containing passiflora is a standard hard gelatin capsule. The internal capsule comprising caffeine is a delayed or delayed hard gelatin capsule. About the caffeine stimulant:

[051] Preferred excipients are modified microcrystalline cellulose Cellulomax ^® , calcium carbonate, stearic acid, silicon dioxide, silicon dioxide antiumectants, maltodextrin carrier, corn starch, antiumectant.

Further, it is preferred that the lubricant be magnesium stearate.

[053] Croscarmellose sodium is used as a stabilizer.

[054] Controlled release matrix forming agents may be: hydroxypropyl methylcellulose (HPMC), Aerosil ^® , Carbopol ^® , Methocel ^® and Microcel ^® .

About the soothing "Passiflora":

Preferred excipients are microcrystalline cellulose, magnesium stearate, silicon dioxide.

[056] The effect of late release may be reduced if excess sugar is taken before bedtime and intense physical activity before bedtime.

BRIEF DESCRIPTION OF THE FIGURES

[057] FIGURE 1 illustrates the phase 1 (T1) release of the first substance in a short time, inducing sleep. Phase 2 (T2) represents the necessary and pre-established time for the second substance to await its release. Phase 3 (T3) is the effective release of the second substance, increasing one's overall metabolism, ending its effect on Phase 4 (T4). The desired effect is that of sedation in Phase 1, becoming lighter during Phase 2 and a stimulation in Phase 3 and 4, which then determines a more active awakening. [058] FIGURE 2 illustrates the release of assets in% per minute.

[059] FIGURE 3 illustrates the release of assets in% per minute.

FIGURE 4 illustrates the structure of the inner capsule containing the coated stimulant for differentiated absorption after ingestion. Said inner capsule will be surrounded by another larger, rapidly absorbing capsule containing the sedative substance.

[061] FIGURE 5 illustrates the times when the

Passiflora takes effect, the desired sleep and the moment when caffeine is absorbed and arouses the individual.

[062] FIGURE 6 illustrates the daily sleep information obtained from patients during the test period.

[063] FIGURE 7 illustrates daily information on sleep heart rate obtained from patients during the test period, as well as weekly sleep history.

[064] FIGURE 8 illustrates the absorption sites of each of the substances of the invention.

EXAMPLES AND TESTS

[065] Examples of compositions will be provided hereinafter, which are purely exemplary, and are not intended to limit or restrict the subject matter of the present application.

EXAMPLE 1

A possible composition for readjusting the human biological clock comprises:

Component Weight in composition

Passionflower Incarnate 150mg to 200mg Excipient qsp Gelatin capsule .... 2 (350mg) or 1 (450mg)

Caffeine 100mg to 200mg

Size 4 Extended Release Capsule

Excipient q.s.p

(100mg) or 3 (200mg)

EXAMPLE 2

[067] Another possible composition for readjusting the human biological clock comprises:

Component Weight in composition

Valerian 300mg to 500mg

Gelatin capsule .... 0 (650mg) or 00

Excipient q.s.p

(950mg)

Caffeine 100mg to 200mg

Size 4 Extended Release Capsule

Excipient q.s.p

(100mg) or 3 (200mg)

[068] Tests have been performed

analyzed the following parameters:

• hours of total sleep of the individual;

• Hours of light sleep of the individual;

• REM sleep hours of the individual;

• Hours the individual was awake at night;

• How many times the individual woke up at night;

• Heart rate of the individual during sleep;

• Time when the individual slept; and

• Time when the individual woke up.

[069] Thus, the tests were done in three stages, each of which was 21 days long. These steps are as follows:

1. Without ingesting the formulation 2. Ingesting placebo

3. Ingesting the formulation

[070] The equipment used was the UP3 monitor

Black Twist Jawbone. NS21B539600E4EF037. Firmware 1.3.20, along with Jawbone UP Application Version 4.28.0.81.

[071] The information collected is illustrated in Figures 6 and 7, and was recorded by the monitor on 01/06/2017.

EXAMPLE 3

Other possible compositions for readjusting the human biological clock include:

1) Caffeine 100mg + Passiflora

- Step 1: Internal

Caffeine 100mg

HPMC 140mg

Capsule # 3 - Color: Colorless

- Step 2: External

Passionflower 200mg

Magnesium Stearate 30mg

Microcrystalline Cellulose 30,35mg

Capsule No. 0 - Color: White / White

2) Caffeine 150mg + Passiflora

- Step 1: Internal

Caffeine 150mg

HPMC 120mg

Capsule # 2 - Color: Colorless

- Step 2: External

Passionflower 200mg

Magnesium Stearate 30mg

Microcrystalline Cellulose 30,35mg Capsule No. 0 - Color: White / White

Preferably, the proportion of caffeine HPMC should be 50% for the expected release effect to occur between 5-8h.

Claims

1. MODIFIED RELEASE COMPOSITION TO REHAKE HUMAN BIOLOGICAL WATCH, characterized by comprising:

(a) one or more soothing or sleep-inducing substances;

(b) one or more stimulating substances; and

(c) appropriate excipients and vehicle,

wherein the release of (b) is controlled through the hydrophilic polymer capsule, and

wherein substances (a) and (b) are physically separated into different capsules.

Composition according to Claim 1, characterized in that said one or more soothing or sleep-inducing substances may be: Passiflora incarnata or Valerian, preferably Passiflora incarnata.

Composition according to Claim 1 or 2, characterized in that it comprises from 150 to 200 mg of Passiflora incarnata.

Composition according to any one of Claims 1 to 3, characterized in that the Passiflora incarnata is in the rapid release outer capsule.

Composition according to any one of Claims 1 to 4, characterized in that said one or more stimulating substances may be: caffeine or guarana, preferably caffeine.

Composition according to any one of Claims 1 to 5, characterized in that it comprises from 100 to 200 mg of caffeine.

7. COMPOSITION according to any of the following Claims 1 to 6, characterized in that the caffeine is in the delayed or delayed internal release capsule.

Composition according to any one of Claims 1 to 5, characterized in that said caffeine capsule excipients may be at least one of: modified microcrystalline cellulose Cellulomax ^® , calcium carbonate, stearic acid, silicon dioxide, anti-dioxide silicon, maltodextrin carrier, cornstarch, antiumectant; the lubricant being magnesium stearate; the stabilizer being croscarmellose sodium; controlled release matrix forming agents are at least one of: hydroxypropyl methylcellulose (HPMC), Aerosil ^® , Carbopol ^® , Methocel ^® and Microcel ^® .

Composition according to any one of Claims 1 to 5, characterized in that said Passiflora capsule excipients may be at least one of: microcrystalline cellulose, magnesium stearate, silicon dioxide.

USE OF THE MODIFIED RELEASE COMPOSITION TO IMPROVE HUMAN BIOLOGICAL WATCH, as defined in any one of claims 1 to 9, characterized in that it is intended for the manufacture of a supplement to assist the individual in inducing sleep and subsequent quiet awakening.