KR20150132877A - Compositions comprising arabinogalactan and polyphenols from larch trees - Google Patents

Abstract

The present invention discloses a composition comprising arabinogalactan and polyphenol from lepidoptera for use in the prophylactic treatment of upper respiratory tract infections.

Description

Technical Field [0001] The present invention relates to a composition comprising arabinogalactan and polyphenol from a tree,

The subject matter of the present invention is a composition comprising arabinogalactan and polyphenol from mulberry trees for use in the prophylactic treatment of upper respiratory tract infections.

Every year, millions of people suffer from upper respiratory tract infections (URIs or URTIs), which are mainly caused by viral infections. Approximately 30-40% of the cases are caused by renovirus infection. Other viruses include coronavirus, parainfluenza virus, adenovirus, and enterovirus. Another source of infection is bacterial attack, partly as a secondary infection. URI is associated with the above-mentioned nose, sinus, pharynx or larynx and is usually associated with tonsillitis (inflammation of the tonsil), otitis media, rhinitis (inflammation of the nasal mucosa), sinusitis or sinusitis (Inflammation of the sinuses including the sphenoid sinus and sphenoid sinus), nasopharyngitis (nasopharyngitis or cold causing inflammation of the nostrils, pharynx, hypopharynx, uvula and tonsil), pharyngitis (inflammation of the pharynx, hypopharynx, Diseases such as gastritis (inflammation of the upper part of the larynx and inflammation of the area above the vocal cords), laryngitis-inflammation of the larynx, laryngeal bronchitis (inflammation of the larynx, of the bronchus and of the area under the vocal cords) and bronchitis . More than 200 lino viruses are known to cause URIs. Depending on the region, the typical risk range for URIs ranges from less than 10 cases per person per year in the most industrialized countries to less than a hundred cases per person in some African and Asian countries each year. In Central America, Africa and Asia, the overall risk is approximately 100 manifestations. In some areas, predominantly in the East African coast and Central Asia, the risk can reach approximately 200 or more levels of expression each year.

Viruses and germs that cause URIs spread from person to person, primarily through air shedding by sneezing or coughing from an infected person. In some cases, viruses and germs can spread when a person touches an infected surface (such as a door handle, a countertop, or a telephone) and then touches the body part, including the mucous membranes such as the nose, mouth, or eyes. Thus, these diseases are most easily spread in crowded conditions like schools. Most people are fully recovered, but URI-mediated bully days cause huge damage to the economy every year. In rare cases, even high-risk groups such as people with other medical conditions (eg, diabetes or cancer) or people with weak immune systems, the elderly, or very young children may even die as a result of URIs. The peak time of cold is fall, midwinter, and early spring school and kindergarten. In industrialized western countries with high levels of medical and hygiene, children have a cold of about eight times a year, adults have roughly four colds each year, and the elderly have about two colds each year. The total number of URI expressions will be slightly higher. People infected with influenza or cold virus become carriers 24 hours after the virus enters the body (often before the symptoms appear). Adults remain infectious for about 6 days (the virus can spread to others), and the child remains infectious until 10 days.

Typical preventative measures for URIs include simply general handwashing, general behavior such as shrouding, coughing or sneezing, and vaccination, but immunizations should be given to children under six months of age, to egg or chicken protein allergies, People with allergies to any given ingredient, an allergic reaction to the flu vaccine, or acute illness are not recommended.

Therefore, there is a need to provide an additional preventive measure against URI, preferably a rhinovirus infection and more preferably a cold.

For example, arabinogalactan from Echinacea or Leucopoda has been reported to stimulate the immune system regardless of the actual disease outcome (Yale et al., Arch. Intern. Med. 2004, 164, 1237-1241 and Turner et al., AAC, 2000, 44, 1708-1709).

There is a current level of skill indicating that the arabinogalactan extract from the lobster can effectively reduce the risk of getting a URI, preferably a rhinovirus-induced disease or more preferably a cold in the actual patient I never do that.

Arabinogalactan (also referred to as arabinogalactan, arabinogalactan, galactoatavinin, arachidic fiber, or giltwood gum; CAS: [9036-66-2]) contains galactose units and arabinose units Is a highly branched polysaccharide having a molecular weight of 15,000 to 60,000 Daltons, consisting of a ratio of approximately 6: 1 (Scheme 1). For convenience, the botanical source is from Larix laricina (L.) or Larix occidentalis (L.). Arabinogalactan from the myrtle tree usually contains a certain amount of polyphenols. Typically, the polyphenol is present in an amount of about 1 to 4% by weight, more preferably about 2% by weight. Arabidopsis thaliana has been approved as a direct food additive by the US Food and Drug Administration (FDA) as GRAS (a substance generally considered safe). Commercially available forms of arabinogalactan are ResistAid (R), an extract from the bark of the tree bark and / or wood (chip or sawdust) (Larix spp.).

[Scheme 1]

The chemical structure of arabinogalactan in resist AID (TM)

constitutional formula:

It is an object of the present invention to provide an additional preventive measure against URI, preferably a rhinovirus infection and more preferably a cold.

Surprisingly, the technical problems presented above are solved by using a composition containing arabinogalactan to increase the adaptive immune response in a patient as defined in the claims.

We could first prove that the daily administration of arabinogalactan and polyphenol-containing compositions from the lobsters can be used effectively in the prophylactic treatment of upper respiratory tract infections.

"Patient" according to the claims is a vertebrate animal, preferably a mammal and a bird, more preferably a human, a pig, a poultry, a beef cattle, a dog, a cat, a goat and a horse, most preferably a human.

It should be understood that "arabinogalactan" according to the present invention relates to any compound consisting of a ratio of galactose units and arabinose units of about 100: 1 to 1: 1, preferably 6: 1. Specifically, the arabinogalactan according to the present invention is preferably characterized by having a backbone of 2 (1 → 3) -bonded β-D-galactopyranosyl units, wherein the units are C-6 Position. Most of these side chains are? -L-arabinofuranosyl units as well as galactobiose units containing (1? 6)? -D- linkages. However, the scope of the present invention also encompasses the use of arabinogalactan, for example arabinogalactan-proteins (AGP) as disclosed in Classen et al., Carbohydrate Research, 2000, 327, 497-504, When covalently bonded to various amounts of the protein of the present invention, arabinogalactan derivatives. Other derivatives include arabinogalactan in quaternized or lipidated form.

According to the present invention, arabinogalactan and polyphenol, preferably from alder tree, can be obtained from Leucophora (Larix subspecies), in particular Larix larixina (eastern lobster) or Larix oxydendellis It comes from.

A composition comprising arabinogalactan and polyphenol from mulberry trees for use in the prophylactic treatment of infections is obtained from the Patent Office.

Further compositions for the use of prophylactic treatment of diseases caused by rhinovirus, comprising arabinogalactan and polyphenol from the mulberry tree, are obtained further.

The claimed galactopyranosyl is also a composition comprising arabinogalactan and polyphenol from lobsters for use in the prophylactic treatment of the cold.

In accordance with the above-mentioned diseases, we also seek further patent applications for use in the prophylactic long-term treatment of diseases selected from the group consisting of upper respiratory infections, diseases caused by rhinovirus and colds.

The composition according to any one of claims 1 to 3 has prophylactic effects in increasing tolerance to diseases selected from the above infection, diseases caused by rhinovirus and colds.

In a preferred embodiment of the above-described composition, the composition comprising arabinogalactan and polyphenol from the mulberry tree is administered by the infectious agent, a rhinovirus, in order to reduce the number of disease events compared to the untreated patient Can be used in the treatment of patients with an increased risk of developing a disease selected from the diseases and colds caused.

Patients with an increased risk of catching a cold in the sense of the present invention are, for example, people in highly contagious areas, persons with insufficient sleep, or people with weak immune systems. More specifically, the patient with such increased risk is, for example, an elderly person aged 65 years or older, a person living in a nursing home or a long-term care facility, a patient with lung disease (e.g. asthma, chronic obstructive pulmonary disease) (Eg, angina pectoris, congestive heart failure), diabetes, other metabolic diseases, kidney problems, patients with blood disorders (eg, anemia), patients with pathological obesity or generally having a weak immune system Patients who have been diagnosed (eg, have received steroid medication, have cancer, or have HIV), and those at high risk of complications, those who are traveling in areas with additional URIs, 6 to 23 months, or 6 Children aged between 18 and 18 years of age with long-term medication, healthy children between two and four years of age, and additional healthcare workers such as doctors, nurses, and pharmacists. In animals, the increased risk arises from large or intensive livestock facilities. People who work or live near these animals are also potentially affected if the virus can be transmitted from animals to humans and vice versa.

In another preferred embodiment of the above-described composition, the composition comprising arabinogalactan and polyphenol from the mulberry tree is applied to the topical infections, to the linovirus, to reduce the number of disease events, ≪ RTI ID = 0.0 > and / or < / RTI > susceptibility to selected diseases of the disease.

Patients with increased susceptibility to URI are people from the above group who already have one or more other diseases and / or have a suboptimal health status.

In general, people with increased risk and / or increased risk of catching a cold, preferably a child, such as children, for example infants, infants, , Students, people with sleep disorders or sleep deprivation, people who are stressed, the elderly, and those with poor nutritional status will have three or more colds within six months without treatment.

The compositions of the present invention should be administered daily, including arabinogalactan from polygonatum and polyphenols, for example Resistea (R), commercially available from Lonza (Switzerland).

For convenience, the administration of the composition starts before the cold preliminarily during spring and / or autumn, preferably 30 days before the cold preliminarily, more preferably 60 days before the cold preliminarily. In general, preferably, the composition of the invention is administered as a prolonged administration for at least 30 days, more preferably at least 60 days, and even more preferably at least 12 weeks.

Compositions of the invention are conveniently administered in liquid or solid form. The composition may be mixed with food, feed and any type of beverage.

To achieve a prophylactic effect, the compositions of the present invention should be administered in an amount of from about 0.5 g to 15 g per patient per day, more preferably from 1.0 g to 7 g. Exceeding 15 g daily does not adversely affect the health of the patient, especially the human. Preferably, the treatment is carried out with 1.5 g to 4.5 g daily, most preferably 1.5 g daily or more. In another preferred embodiment, the daily dose, more preferably about 1.5 g, of each dose of the composition is administered no more than three times daily.

We also seek the use of a composition comprising arabinogalactan and polyphenol from the mulberry tree to prevent the development of a cold.

In addition, a method of using the composition for the manufacture of a medicament, preferably a medicament for the prevention of diseases selected from the group consisting of infections caused by the infections, diseases caused by the rhinovirus, and a cold is obtained.

We also seek patent applications for the use of compositions comprising arabinogalactan and polyphenol from the mulberry tree for the manufacture of nutritional products. The nutritional product may be a food, a food additive, a food supplements, a feed, a feed additive and a feed supplement suitable for directly or indirectly for use in a method for treating human or animal body, respectively, ≪ / RTI > The nutritional product may also be in the form of tablets, capsules, tablets, liquids (such as provided in ampoules / vials), dry powders, and the like as functional beverages, functional foods such as nutritional bars, breakfast cereals, Blends or premixes.

Finally, prophylactic treatment of diseases selected from the group consisting of infections caused by rhinovirus, diseases caused by rhinovirus, and colds, characterized in that arabinogalactan and polyphenol compositions are administered from lawn as described above. How to get the patent office also.

Example:

The invention is further illustrated by the following non-limiting examples and study results.

Example 1: Double-blind study

1.1 Research Purpose

The purpose of this double-blind randomized placebo-controlled multicenter clinical study performed by Analize & Realize (a & r, Berlin, Germany) was to increase the sensitivity of patients with increased sensitivity to upper respiratory infections, And the prophylactic effect of

The primary endpoint was a reduction in the number of cold embryos in a comparison between the Resides AID (registered trademark) and placebo studies.

The secondary end point was the decrease in expression duration and expression intensity.

Safety and additional parameters included a comprehensive assessment of efficacy and tolerance assessed by both investigators and patients and an assessment of adverse events, safety experimental parameters, specific experimental parameters (leukocyte differentiation), and eating habits.

1.2 Research patients

A full analysis set (FAS) group consisted of 199 patients, of which 12 patients were excluded from the per protocol (PP) group and 187 patients were generated. All patients were healthy at the beginning and at the end of the study, as confirmed by physical examination as well as blood analysis.

1.3. Research design

Clinical studies have led to their application to patients with increased susceptibility to upper respiratory infections.

During the 12-week study period, 101/97 patients (FAS / PP) had to take the investigational study product (RESIDEID®), and an additional 98/90 patients (FAS / PP) (Maltodextrin). The patients were instructed to dissolve the contents of the sachet containing the irradiated product (4.5 g of powder) in approximately 100 to 150 ml of liquid and take the prepared drink at breakfast. All other eating habits remained unchanged.

Three basic visits were made: visit 1 (= baseline), control visit 6 weeks, and end visit 12 weeks. In addition, an episode visit was made at the beginning and at the fifth day of each cold episode. The exact date of the cold expression was recorded in the CRF.

One or more cold episodes could occur between control visit and end visit as well as between visit 1 and control visit. During expression, the patients recorded and evaluated their cold symptoms in the patient's diary for a period of 14 days. At the second visit of each visit, the investigators checked the journal.

At the end of the study (termination visit), the investigators and patients assessed the overall efficacy and tolerability of the investigational product. At the beginning and end of the study, the patients recorded their dietary habits in the dietary log. In addition, safety experiment parameters as well as specific experimental parameters (white blood cell differentiation) were evaluated.

The investigators distributed the investigational product, including the reserve amount for an additional 8 day period, to the patients at visit 1 and control visit, respectively. Unused sachets were returned to the investigators at the time of the control visit and the closing visit for conformity assessment.

1.4 Analysis

The primary endpoint was defined as a decrease in cold-expressed numbers after a 12-week study period in the verum group compared to placebo. Thus, the primary parameter was the number of cold expressions (Number CE).

Thus, the statistical null hypothesis H0 means a statement that there is no difference between the mean cold expressions of the two groups, and thus can be expressed as:

H0 = NumberCE (Berum) = NumberCE (Placebo)

The null hypothesis should be verified against the hypothesis HA,

HA: NumberCE (berum) ≠ NumberCE (placebo)

And

HA: NumberCE (berum) <NumberCE (placebo) (one-way black).

The non-parametric only - Whitney U test had to be used so that the hypothesis could be proved by the rank sum. All tests had to be performed at a significance level (I-type error) of 5.0% (double-blind) or 2.5% (one-way test).

Secondary endpoints (reduction in duration and intensity of individual cold embryos) and safety and additional parameters (efficacy and tolerance, number of AEs, comprehensive evaluation of experimental parameters and dietary habits) should be evaluated by non-parametric procedures. Only Whitney U tests should be used for group-to-group comparisons, and Wilcoxon test should be used for intra-group (pre / post) comparisons. In addition, the Friedman test should be used for comparison of dependent samples, and the Chi2 test should be used for the evaluation of the proportional value. For small sample sizes (eg subgroups), you should use the correct test. The parametric procedure supplements the above analysis if the magnitude of the observed values justifies testing of this kind.

This should be discussed if there is a mismatch between the non-parameter and the parameter, rather than checking the condition of the normal distribution value.

All primary and secondary endpoints as well as safety and other variables were assessed narratively in addition to the inquiry test. For quantitative data (continuous data), statistical properties (number, mean, standard deviation, median, extremum and quartile) are provided. In the case of ranking type data (discontinuous data), frequency distribution was performed. All nominal data (categorical data) are also summarized using checks. Where appropriate, the values of the metric data were merged into ranking classes according to clinical criteria and their frequency distribution was measured. The data collected during the repeat visit were checked using the multivariate analysis method with repeated measures.

Experimental parameters should be evaluated as metric type parameters; In addition, deviations from the reference range should be sought.

All tests should be performed at a significance level (I-type error) of one-sided tests of 5.0% (double-sided) or 2.5% at 80% verification. The 95% confidence interval should be measured.

All p-values from the statistical test associated with the exploration analysis exceeding the primary endpoint test should be described in tentative terms.

All statistical analyzes should be performed on the entire analysis group (FAS). At least for the primary endpoint, additional analysis should be performed in the valid case analysis set (VCAS). All of the results of the two groups should be compared and any differences discussed.

The FAS group consists of all patients who received more than one dose of the investigational product (for therapeutic purposes). The VCAS group consists of all patients from the FAS group who completed a clinical investigation according to a clinical investigation plan (CIP) without major protocol infringement. Assignment to the FAS and VCAS groups should be performed prior to disclosure of the data. Where appropriate, the analysis of any subgroups may be carried out on the basis of additional criteria and the rules described for the planned statistical analysis apply.

For the evaluation of expression, the observed values should be independent (expression from different patients) and dependent (expression of the same patient). Thus, parameters related to expression can be analyzed on the basis of the number of infected patients (regardless of the number of expressions per patient) or the number of expressions (regardless of whether the patient has more than one expression); Each criterion of the analysis should be described.

1.5 Results

Overall, 191 cold episodes were documented in detail on the CRF, with a total of 132 patients (66.3% of 199 patients) having a cold. Of these, the three expressions were considered invalid since the influenza vaccination (similar to cold symptoms) preceded.

Thus, a total of 188 expressions involving 130 patients (65.3%) were analyzed.

There was a difference between the study groups as to the number of patients suffering from cold manifestations: V-group 58.4% (59 out of 101) vs. P-group 72.4% (71 out of 98); pChi = 0.038.

A total of 191 expressions involving 132 patients were analyzed, taking into account all the expressions (including flu vaccination). There was a difference between the study groups as to the number of patients with cold episodes: 60.3% (61 of 101) versus 72.4% (71 of 98) of the V-group versus P-group; pChi = 0.072.

1.6 Effectiveness end point

As a result of taking Resisaid (registered trademark), the average number of cold expressions decreased (PP group-Berum: 0.85 + 0.82 vs. placebo: 1.10 + 0.85; Pu = 0.040). The total number of expressions showed statistically significant difference in the Reside AID (R) group compared to the placebo group (PP group -Berum: 82 [n = 97] vs. placebo: 99 [n = 90]).

Percentage of patients with one or more manifestations was significantly higher in placebo compared to the active group (PP group vs. Berum: 59.8% vs. placebo: 74.4%, PChi = 0.033).

1.7 Conclusion and Discussion

This randomized, double-blind, placebo-controlled concurrent-group study showed that consumption of Resice AID (TM) was associated with a significant reduction in cold-expressed numbers compared to placebo. Only about 25% of untreated patients did not have a cold, while about 40% of treated patients did not have a cold. Thus, the number of patients who did not develop a cold increased to 63%. Supplementation of the arabinogalactan formulations reduced the number of cold expressions by 23%, suggesting the potential of Resisteid (R) regulating the immune response to invading pathogens. This study has proven an excellent safety profile of Resist Aid (R).

1.8 Safety

During the study period of 12 weeks, a total of three basic visits were made: visit 1 (start study), control visit (at 6 weeks), and end visit (at 12 weeks). In addition, an expression visit was scheduled at the beginning and 5 days of each cold episode. The number of expression visits per patient varied with the number of expressions developed during the study.

During the presentation, the patients recorded and evaluated their cold symptoms in the patient's diary for a period of 14 days. At the end of the visit, investigators and patients assessed the overall efficacy and tolerability of the investigational product. At the beginning and end of the study, patients recorded their dietary habits in diary logbooks and evaluated safety experimental parameters / specific experimental parameters (leukocyte differentiation). The use of analgesics and antibiotics was recorded in the CRF and patient logbooks. Any expression of antibiotics treated was not included in the evaluation of the relevant parameters.

1.9 Abbreviations

CRF Case report form

FAS Whole analysis group

GRAS Substances generally considered safe

P Placebo

pChi Chi2 black p value

PP Per protocol (completed study)

Pu Bay - Whitney U test p value

URI or URTI The above-

V Berum; visit

VCAS Effective case analysis group

Example 2: Simplified Test Study

Ten healthy patients were instructed to dissolve 1.5 g of the contents of the sheath of the irradiated product in approximately 50 ml of liquid and to take the prepared beverage once daily on a daily basis. Although the sample group was small, a reduction in cold expression could also be observed in light of the placebo group of Example 1.

Claims (15)

A composition comprising arabinogalactan and polyphenol from lobsters for use in the prophylactic treatment of upper respiratory infections. A composition comprising arabinogalactan and polyphenol from lobsters for use in the prophylactic treatment of diseases caused by the rhinovirus. A composition comprising arabinogalactan and polyphenol from teaspoons for use in the prophylactic treatment of cold. 4. The method according to any one of claims 1 to 3,
For the prophylactic long-term treatment of a disease selected from the group consisting of infections, diseases caused by rhinovirus, and the cold. 5. The method according to any one of claims 1 to 4,
A composition having prophylactic effects in increasing tolerance to selected infections, diseases caused by rhinovirus, and colds. 6. The method according to any one of claims 1 to 5,
A composition for treating a patient having an increased risk of developing a disease selected from the group consisting of an infectious disease, a disease caused by a rhinovirus, and a cold, in order to reduce the number of disease events compared to an untreated patient. 7. The method according to any one of claims 1 to 6,
A composition for treating a patient having increased susceptibility to a selected disease selected from the group consisting of an infectious disease, a disease caused by a rhinovirus, and a cold, in order to reduce the number of disease events compared to an untreated patient. 8. The method according to any one of claims 1 to 7,
Wherein the administration is daily applied. 9. The method according to any one of claims 1 to 8,
Wherein the administration is started before the cold climax of spring and / or autumn, preferably 30 days before cold climax, more preferably 60 days before cold climax. 10. The method according to any one of claims 1 to 9,
Liquid or solid. 11. The method according to any one of claims 1 to 10,
Wherein the composition is administered in an amount of from 0.5 g to 15 g per patient per day, more preferably from 1.0 g to 7 g. A method of using a composition comprising arabinogalactan and polyphenol according to any one of claims 1 to 11 for preventing the occurrence of a cold. Use of a composition according to any one of claims 1 to 12 for the manufacture of a medicament. Use of a composition according to any one of claims 1 to 12 for the manufacture of a nutritional product. A method for the prophylactic treatment of a disease selected from the group consisting of the infections, diseases caused by the rhinovirus, and the cold, which comprises administering the composition according to any one of claims 1 to 14.