WO2023241390A1

WO2023241390A1 - Compositions and uses thereof

Info

Publication number: WO2023241390A1
Application number: PCT/CN2023/098264
Authority: WO
Inventors: Gregg WARD; Mengjin LIU; Yi Jin; Jinhui Hu
Original assignee: Nutricia Early Life Nutrition Shanghai Co Ltd
Current assignee: Nutricia Early Life Nutrition Shanghai Co Ltd
Priority date: 2022-06-16
Filing date: 2023-06-05
Publication date: 2023-12-21
Anticipated expiration: 2024-12-16
Also published as: EP4539687A4; CN119584873A; AU2023293647A1; JP2025520453A; EP4539687A1

Abstract

The compositions for preventing or treating insomnia, improving sleep quality, improving skin appearance, reducing halitosis and increasing relaxation towards sleep, improving sleep quality. In particular, the compositions comprise a probiotic bacteria selected from the group comprising: Lacticaseibacillus ssp., Bifidobacterium ssp., or combinations thereof; and optionally a prebiotic fibre.

Description

COMPOSITIONS AND USES THEREOF

Field of the invention

The present invention relates to compositions for preventing or treating insomnia, improving skin appearance, reducing halitosis and increasing relaxation towards sleep, improving sleep quality.

Background of the invention

The amount of sleep hours varies per person. For most adults, seven to eight hours per night is considered necessary. As aging occurs, internal sleep clock starts to lose consistency. Older adults thus tend to become tired earlier in the evening and wake up earlier in the morning, resulting in less sleep overall and increasing the risk of cognitive decline. Elderly people experiencing Alzheimer’s , dementia, or other neu-rodegenerative diseases experience even more severe changes in sleep drive.

An increasing part of the adult population will, at some point in life, experience short-term, acute insomnia which lasts for days or weeks. This is usually the result of a stressful or a traumatic event. However, some people suffer from long-term, chronic insomnia, wherein insomnia itself may be the primary problem, or it may be associ-ated with other medical conditions or medications.

Data shows that more than 300 million Chinese people experience poor sleep quality, sleep disorders or insomnia. Individuals suffering from poor sleep quality or insomnia often still feel tired after waking up, and experience negative impacts on energy lev-el, mood and overall health, work performance and quality of life.

The large group of individuals suffering from poor sleep quality and/or insomnia has driven the consumption of sleep-aid products. In recent years, various types of sleep monitoring and support softwares have been launched in major APP stores. Moreo-ver, latex pillows, sleep aids, aromatherapy lamps, melatonin, sleep gummies, and other products are commonly sought for to help the sleep.

CN104187613 discloses a nutritional recipe for insomnia comprising Chinese medicines, probiotics, water soluble prebiotic fibres, etc.

CN107496850 discloses a preparation for regulating intestinal microecology with ginseng to calm the verse, and then to help on enhancing sleep.

CN107874251 disclosed a bazhen probiotic composition comprising 1-9 parts of Chinese herbal extract, 0.01-2 parts of food grade probiotics and 0.1-5 parts of prebiotics.

Adults especially aging people suffer more of poor sleep due to various reasons, e.g. pressure from work, depression from lockdown, inter-personal disputes, etc. However, there is a reluctancy to seek for pharmacological treatment. There thus remains the need for improved nutritional interventions to induce relaxation and treat insomnia with an easy and convenient way.

Summary of the invention

In a study with over 200 human adults, the inventors have observed a substantial improvement in the sleep induction and quality, mood and a reduction on psychological stress when subjects were administered a composition comprising a combination of prebiotic soluble fibres and probiotic bacterial strains. Unexpectedly, this improvement was observed within 7 days from the start of consumption of the composition according to the invention.

Accordingly, in one aspect, the present invention relates to a composition for use in preventing and/or treating insomnia in a human subject, the composition comprising:

a. 10³ to 10¹² colony forming units per gram of composition of at least a probiotic bacteria selected from the group comprising: Lacticaseibacil-lus ssp., Bifidobacterium ssp., or combinations thereof; and, optionally,

b. ≥ 11 wt%prebiotic fibre based on the total weight of the composition.

In a second aspect, the present invention relates to a non-therapeutic method of improving sleep quality and/or inducing and/or enhancing pre-sleep relaxation, the method comprising administration of a composition to a human subject in need thereof, wherein the composition comprises:

a. 10³ to 10¹² colony forming units per gram of composition of at least a probiotic bacteria selected from the group comprising: Lacticaseibacil-lus ssp., Bifidobacterium ssp., or combinations thereof; and optionally

b. ≥ 11 wt%prebiotic fibre, based on the total weight of the composition.

Herein, induction and/or enhancement of pre-sleep relaxation is in comparison with a human subject not administered with the composition according to the invention. It can be determined by individual perception as assessed by specialized questionnaire (including digital) , or by psychological and mental care professional.

Moreover, the inventors surprisingly observed remarkable improvements in skin appearance and condition, and reduced halitosis.

In a third aspect, the present invention relates to a non-therapeutic method of reducing halitosis, the method comprising administration of a composition to a human subject in need thereof, wherein the composition comprises:

b. ≥ 11 wt%prebiotic fibre based on the total weight of the composition.

Halitosis reduction is herein defined in comparison with a subject not administered with the composition according to the invention. It can be determined by individual perception as assessed by specialized questionnaire, or by dental care professional. In a fourth aspect, the present invention relates to a non-therapeutic method of improving skin appearance and texture, the method comprising administration of a composition to a human subject in need thereof, wherein the composition comprises:

b. ≥ 11 wt%prebiotic fibre based on the total weight of the composition.

Improvement in skin appearance and texture is herein defined in comparison with a subject not administered with the composition according to the invention. It can be determined by individual perception as assessed by specialized questionnaire, or by skin care professional such as aesthetician.

In a fifth aspect, the present invention relates to a composition comprising:

i. at least 40 wt. %carbohydrates, based on total weight of the composition,

ii. ≥85 wt. %prebiotic soluble fibres, based on total weight of carbohydrates,

iii. 10³ to 10¹² colony forming units per gram of composition of at least a probiotic bacteria selected from the group comprising: Lacticaseibacillus ssp., Bifidobacterium ssp., or combinations thereof

wherein the composition does not comprise lactose.

In all aspects of the invention, the composition is preferably a synbiotic composition.

As defined herein, the composition is an enteral composition, preferably an oral composition.

Detailed description of the invention

"Probiotic" means microbial cell preparations or components of microbial cells with a beneficial effect on the health or well-being of the host. (Salminen S, Ouwehand A. Benno Y. et al "Probiotics: how should they be defined" Trends Food ScL Technol. 1999: 10 107-10) .

“Synbiotic” as used herein refers to a composition comprising a combination of probiotic microorganisms and prebiotic components.

“Prevention” as used herein refers to reduction in the likelihood of developing a certain condition or symptom associated with a condition in subjects in need thereof or particularly at risk of developing said symptoms and conditions. “Treatment” as used herein refers to the reduction, alleviation or complete removal of symptoms associated with certain conditions causing human suffering or discomfort.

“Insomnia” is a common sleep disorder characterized by the difficulty in falling asleep, staying asleep, or causing the affected subject to wake up too early and not be able to get back to sleep, and unsatisfactory proportion of deep or restorative sleep. Induction of pre-sleep relaxation increases quality and duration of sleep, helping to increase the overall sensation of feeling rested after sleep. It can be diagnosed and assessed by general practitioner or medical specialist in sleep and correlate conditions.

As used herein, “sleep quality” refers to quantitative aspects of sleep, such as sleep duration, sleep latency, or number of arousals, as well as subjective aspects, such as depth or restfulness of sleep. Sleep quality can be determined by Pittsburgh Sleep Quality Index (Buysee et al. “The Pittsburgh Sleep Quality Index: a new instrument for psychiatric practice and research” . Psych Res, 28, 193-213.1989) .

Herein, improving sleep quality and/or induction and/or enhancement of pre-sleep relaxation is in comparison to a human taking no nutritional composition comprising a and b (i.e., no composition or taking another composition not comprising a and b) . Accordingly, in comparison to a human taking no nutritional composition comprising a and b (i.e., no composition or taking another composition not comprising a and b) , the improvement in the human taking the nutritional composition comprising a and b increases ≥ 2%, preferably ≥ 5%, more preferably ≥ 50%, even more preferably ≥65%. Specifically, if the improvement to a human taking no nutritional composition comprising a and b (or taking another composition not comprising a and b) is M, and the improvement as compared to the human taking the nutritional composition comprising a and b is N, then: (N-M) /N*100%is the percentage it increases.

“Halitosis” (fetor oris or bad breath) is a condition characterized by oral malodor and is not necessarily linked to oral and dental diseases. Halitosis may be of either intra-oral or extra-oral origin. Extra-oral (non-oral) halitosis may be from gastrointestinal origin. The inventors have surprisingly observed a reduction in halitosis in subjects administered the composition according to the invention. Without wishing to be bound any theory, it is hypothesized that the composition according to the invention prevents dysbiosis in the gastrointestinal tract, thereby removing extra-oral causes of halitosis.

“Skin appearance and texture” refers to the improved perception of skin upon consumption of the composition according to the invention. Particularly, the inventors have surprisingly observed that adults who consumed the composition of the invention claimed a significant improvement on the skin appearance and reduction of large skin pores.

In some jurisdictions, the present invention is defined as a method of preventing and/or treating insomnia in a human subject, the method comprising the administration of a composition to the human subject, the composition comprising:

b. ≥ 11 wt%prebiotic fibre based on the total weight of the composition.

In other jurisdictions, the present invention is defined as the use of a composition in the manufacture of a composition for preventing and/or treating insomnia in a human subject, the composition comprising:

b. ≥ 11 wt%prebiotic fibre based on the total weight of the composition.

In further jurisdictions, the present invention is defined as the non-therapeutic method of preventing and/or treating insomnia in a human subject, the composition comprising:

b. ≥ 11 wt%prebiotic fibre based on the total weight of the composition.

Preferably, prevention and/or treatment is in comparison to a human taking no nutritional composition comprising a and b (i.e., no composition or taking another composition not comprising a and b) . Accordingly, in comparison to a human taking no nutritional composition comprising a and b (i.e., no composition or taking another composition not comprising a and b) , the improvement to preventing and/or treating insomnia (including poor sleep) in the human taking the nutritional composition comprising a and b increases ≥ 2%, preferably ≥ 5%, more preferably ≥ 50%, even more preferably ≥ 65%. Specifically, if the improvement to a human taking no nutritional composition comprising a and b (or taking another composition not comprising a and b) is M, and the improvement as compared to the human taking the nutritional composition comprising a and b is N, then: (N-M) /N*100%is the percentage it increases.

Probiotics

Preferably, the composition comprises 10³ to 10¹² colony forming units per gram of composition of at least a probiotic bacteria, more preferably 10⁴ to 10¹⁰ colony forming units per gram of composition of at least a probiotic bacteria selected from the group comprising: Lacticaseibacillus ssp., Bifidobacterium ssp., or combinations thereof.

In one embodiment, the composition comprises 1-20 wt. %of at least a probiotic bacteria, based on dry weight of the composition, more preferably 3-15 wt. %of at least a probiotic bacteria, based on dry weight of the composition.

In another embodiment, the composition comprises 25-250 mg of at least a probiotic bacteria per gram of the composition, more preferably 50-150 mg of at least a probiotic bacteria per gram of the composition.

The daily dose of the at least one probiotic bacteria in the composition according to the invention in an amount from 10³ to 10¹² colony forming units, preferably 10⁸ to 10¹¹ colony forming units.

In a preferred embodiment of the invention, the composition comprises at least one species of Lacticaseibacillus ssp. Preferably Lacticaseibacillus ssp present in the composition is selected from the group comprising: Lacticaseibacillus paracasei, Lacticaseibacillus acidophillus, Lacticaseibacillus murinus, Lacticaseibacillus reuteri, Lacticaseibacillus rhamnosus, or mixtures thereof. Preferably, the probiotic bacteria comprises Lacticaseibacillus paracasei subsp. paracasei, more preferably Lacticaseibacillus paracaseisubsp. paracasei CRL 431.

The composition may comprise at least one species of Bifidobacterium ssp. Preferred species of Bifidobacterium ssp. Include: Bifidobacterium adolescentis, Bifidobacterium longum subsp. longum, Bifidobacterium subsp. infantis, Bifidobacterium pseudolongum, Bifidobacterium bifidum, Bifidobacterium lactis, Bifidobacterium animalis subsp. lactis, Bifidobacterium breve, and mixtures thereof. In a preferred embodiment, the Bifidobacterium ssp. is Bifidobacterium lactis BB12 (as deposited at Deutsche Sammlung von Mikroorganismen und Zellkulturen GmbH (DSMZ) under deposit number DSM 15954) , commercially available by Christian Hansen company of Denmark under the trade mark Bb12.

In a particularly preferred embodiment of the invention, the composition comprises at least one species of Lactobacillus ssp. and one species of Bifidobacterium ssp. More preferably, the composition comprises a mixture of Lacticaseibacillus paracasei subsp. paracasei CRL 431 and Bifidobacterium lactis BB12.

Prebiotic fibres

The composition comprises carbohydrates, including the prebiotic fibres.

Preferably, the composition comprises ≥ 11 wt%of prebiotic fibres, more preferably ≥30 wt%, even more preferably ≥40 wt%, especially more preferably 60-90 wt%of prebiotic fibre based on total weight of the composition.

Preferably, total carbohydrates are present in an amount ranging from 40 –98 wt. %by weight of total composition, more preferably 50-95 wt. %by weight of total composition.

Carbohydrates used herein include sugars and sugar derivatives, simple and complex sugars, and sugar-rich ingredients. Preferably, the composition comprises sugar-rich ingredients such as honey powder, juice powder, etc. preferably, the composition comprises 1-15wt%, preferably 2-13wt%of honey powder, based on total weight of the composition. The composition may further comprise 1-10wt%juice powder, more preferably 2-8wt%of a juice powder, based on total weight. A preferred juice powder is acerola juice powder.

In a preferred embodiment, the composition does not comprise lactose and milk-derived carbohydrates, preferably the composition does not comprise lactose.

Preferred prebiotics are sialo-oligosaccharides (SOS) , fructo-oligosaccharides (FOS) , galacto-oligosaccharides (GOS) , isomalto-oligosaccharides (IMO) , xylo-oligosaccharides (XOS) , arabino-xylo oligosaccharides (AXOS) , mannan oligosaccharides (MOS) , oligosaccharides of soy, glycosylsucrose (GS) , lactosucrose (LS) , sialyl-lactose (SL) Fucosyl-lactose (FL) , Lacto-N-Neotetraose (LNNT) , lactulose (LA) , palatinose-oligosaccharides (PAO) , malto-oligosaccharides, gums and/or hydrolysates thereof, pectins, starches, and/or hydrolysates thereof.

The prebiotic fibres are preferably soluble prebiotic fibres. “Soluble prebiotic fibres” , herein also referred to non-digestible fibres, are beneficially affect the host by selectively stimulating the growth and/or activity of one or a limited number of bacteria in the colon, and thus improving host health. Such ingredients are non-digestible in the sense that they are not broken down and absorbed in the stomach or small intestine and thus pass intact to the colon where they are selectively fermented by the beneficial bacteria.

Preferred soluble prebiotic fibres are selected from fructooligasaccharides, inulin, galactooligasacharides, β-glucans (preferably yeast or oat β-glucans, more prefera-bly oat β-glucans) , or combinations thereof. In a particularly preferred embodiment, the composition comprises at least one of inulin, fructooligasaccharides and oat β-glucans, more preferably the composition comprises inulin, fructooligasaccharides and oat β-glucans. Commercially available sources include short chain fructo-oligosaccharides such as the product sold under the trade markand inu-lin such as the product sold under the trade mark

In a further aspect, the invention relates to a composition comprising:

i. at least 40 wt. %carbohydrates, based on total composition,

wherein the composition does not comprise lactose.

Preferably, the composition comprises 45-95 wt. %carbohydrates, more preferably 50-80 wt. %, even more preferably at least 70 wt. %carbohydrates based on total composition.

Based on total weight of carbohydrates, the composition preferably comprises at least 90 wt. %prebiotic soluble fibres, more preferably at least 95 wt. %prebiotic sol-uble fibres, even more preferably at least 98 wt. %prebiotic soluble fibres.

In a preferred embodiment, the composition comprises 0-15 wt. %lipids, based on total composition, preferably less than 10 wt. %lipids based on total composition, more preferably less than 5 wt. %lipids based on total composition. In a particularly preferred embodiment, the composition is substantially free of lipids, for instance, no added lipids is present in the composition and only trace amounts present via other ingredients could be detectable.

According to a preferred embodiment, the composition comprises honey powder 1-15wt%, preferably 2-13wt%of honey powder, based on total weight of the composi-tion.

The composition may further comprise 1-10wt%juice powder, more preferably 2-8wt%of a juice powder, based on total weight. A preferred juice powder is acerola juice powder.

Uses and applications

The composition of the invention has been surprisingly found to significantly improve pre-sleep relaxation, reduce psychological stress, improve mood in adults subjected to administration of the composition. Also, skin dullness and pore size were im-proved, as well as a noticeable reduction on halitosis.

Preferably, the human subject is selected from a toddler, adolescent or adult. Ac-cordingly, the composition according to the invention is for administration in a human older than 3 years of age, preferably older than 6 years of age, more preferably older than 12 years of age, more preferably older than 16 years of age.

In a particularly preferred embodiment, the human subject is an adult older than 18 years of age, preferably older than 30 years of age, more preferably older than 45 years of age, even more preferably older than 55 years of age.

The composition is preferably administered to the human subject in a fasting state, preferably a fasting state of at least 8 hours, more preferably 10-14 hours. For ex-ample, the composition can be administered in the morning, e.g. after 8 hours of the last meal or dinner. Preferably, the composition is administered before 7 am in a fasting state.

Preferably, the composition is to be administered once a day. The composition is preferably administered for a period of at least 7 days, more preferably at least 14 days, even more preferably at least 30 days.

The composition of the invention is preferably a powder or a ready-to-drink bever-age, preferably a powder. The powder is preferably reconstituted in water or liquid foods, for instance, warm water. However, the powder is suitable for reconstitution in animal or vegetable milk, beverages, yoghurt, soup, cereals, warm or cold food, and the like. The composition may also be presented as a liquid suspension, a tablet, gum, candy, nutritional supplement, and the like.

The invention is herein described by means of the following illustrative, non-limiting examples.

Examples

Example 1

A synbiotic supplement according to the invention can be prepared by dry-blending. The composition is shown in Table 1.

Table 1

Example 2

Healthy volunteers (n=209) were subjected to a study including administration of the composition according to Example 1 for a period of 14 days. The human volunteers were aged between 40-60 years old (mean of 49 years) wherein 49%were male and 51%were female participants.

Before start of the study, the volunteers were asked to assess different parameters of their health status using a questionnaire. The product according to Example 1 was recommended to be consumed in the morning, thus with a minimum of 8 hours fasting, diluted in water at around 30 ℃. At day 7 and at day 14 day, the volunteers were asked to reassess the healthy status. The percentage of the studied subjects indicating to observe the present of a given parameter is provided in ‘Day 0’ . The percentage of observed improvement is indicated in col. Day 7 and day 14. The results are shown in table 2 below.

Table 2

Claims

An enteral composition for use in preventing and/or treating insomnia or sleep disorders in a human subject,

the composition comprising:

a. 10³ to 10¹² colony forming units per gram of composition of at least a probiotic bacteria selected from the group comprising: Lac-ticaseibacillus ssp., Bifidobacterium ssp., or combinations thereof; and, optionally,

b. ≥ 11 wt%prebiotic fibre based on the total weight of the composi-tion.
The enteral composition according to claim 1, wherein the daily dose of the at least one probiotic bacteria is from 10³ to 10¹² colony forming units, preferably 10⁸ to 10¹¹ colony forming units.
The enteral composition according to any of the preceding claims, where-in the composition does not comprise lactose.
The enteral composition according to any of the preceding claims, where-in the composition comprises at least one species of Lacticaseibacillus ssp, preferably selected from Lacticaseibacillus paracasei, Lacticaseiba-cillus acidophillus, Lacticaseibacillus murinus, Lacticaseibacillus reu-teri, Lacticaseibacillus rhamnosus, or mixtures thereof.
The enteral composition according to any of the preceding claims, wherein Lacticaseibacillus ssp. is Lacticaseibacillus paracasei, preferably Lacticaseibacillus paracasei subsp. paracasei, more preferably Lacticaseibacillusparacasei subsp. paracasei CRL 431.
The enteral composition according to any of the preceding claims, where-in the composition comprises at least one species of Bifidobacterium ssp., preferably selected from Bifidobacterium adolescentis, Bifidobacterium longum subsp. longum, Bifidobacterium subsp. infantis, Bifidobacterium pseudolongum, Bifidobacterium bifidum, Bifidobacterium lactis, Bifidobacterium breve, and mixtures thereof.
The enteral composition according to any of the preceding claims, where-in the Bifidobacterium ssp. is Bifidobacterium lactis, preferably Bifidobacterium lactis BB12.
The enteral composition according to any of the preceding claims, where-in the composition comprises Lactobacillus ssp. and Bifidobacterium ssp.
The enteral composition according to any of the preceding claims, where-in the prebiotic fibre, preferably soluble prebiotic fibres is selected from fructooligasaccharides, inulin, galactooligasacharides, β-glucans, or com-binations thereof.
The enteral composition according to any of the preceding claims, where-in the composition is administered to a human subject in fasting state.
The enteral composition according to any of the preceding claims, where-in fasting is at least 8 hours, preferably 10-14 hours.
The enteral composition according to any of the preceding claims, where-in the human subject is an adult, preferably ≥30 years old adult.
The enteral composition according to any of the preceding claims, where-in the composition is administered once a day.
The enteral composition according to any of the preceding claims, where-in the composition is administered for a period of at least 7 days, prefera-bly at least 14 days.
The enteral composition according to any of the preceding claims, where-in the composition is a powder, preferably a powder to be reconstituted in warm water.
The enteral composition according to any of the preceding claims, where-in comparing a human not taking a nutritional composition comprising a and b, the prevention and/or treatment is improved in ≥ 2%, preferably ≥5%.
Non-therapeutic method of improving sleep quality, and/or inducing and/or enhancing pre-sleep relaxation, the method comprising administra-tion of an enteral composition to a human subject in need thereof, where-in the composition comprises:

a. 10³ to 10¹² colony forming units per gram of composition of at least a probiotic bacteria selected from the group comprising: Lac-ticaseibacillus ssp., Bifidobacterium ssp., or combinations thereof; and

b. ≥ 11 wt%prebiotic fibre based on the total weight of the composi-tion.
The non-therapeutic method of claim 17, wherein improvement and/or enhancement is with respect to a human not taking a nutritional composition comprising a and b, wherein the improvement and/or enhancement is ≥2%, preferably ≥5%.
Non-therapeutic method of reducing halitosis, the method comprising administration of an enteral composition to a human subject in need thereof, wherein the composition comprises:

a. 10³ to 10¹² colony forming units per gram of composition of at least a probiotic bacteria selected from the group comprising: Lac-ticaseibacillus ssp., Bifidobacterium ssp., or combinations thereof; and

b. ≥ 11 wt%prebiotic fibre based on the total weight of the composi-tion.
Non-therapeutic method of improving skin appearance and texture, the method comprising administration of an enteral composition to a human subject in need thereof, wherein the composition comprises:

a. 10³ to 10¹² colony forming units per gram of composition of at least a probiotic bacteria selected from the group comprising: Lac-ticaseibacillus ssp., Bifidobacterium ssp., or combinations thereof; and

b. ≥ 11 wt%prebiotic fibre based on the total weight of the composi-tion.
An enteral composition comprising:

i. at least 40 wt. %carbohydrates, based on total composition,

ii. ≥85 wt. %prebiotic soluble fibres, based on total weight of carbohydrates,

iii. 10³ to 10¹² colony forming units per gram of composition of at least a probiotic bacteria selected from the group comprising: Lacticaseibacillus ssp., Bifidobacterium ssp., or combinations thereof

wherein the composition does not comprise lactose.
Use of a composition as defined in any of claims 1 to 16 in the manufac-ture of an enteral product for preventing and/or treating insomnia or sleep disorders in a human subject, the composition comprising:

a. 10³ to 10¹² colony forming units per gram of composition of at least a probiotic bacteria selected from the group comprising: Lac-ticaseibacillus ssp., Bifidobacterium ssp., or combinations thereof; and, optionally,

b. ≥ 11 wt%prebiotic fibre based on the total weight of the composi-tion.
The use of claim 22 wherein comparing a human not taking the composi-tion comprising a and b, the prevention and/or treatment is improved in ≥2%, preferably ≥ 5%.