WO2007016756A1

WO2007016756A1 - Pharmaceutical compositions containing plant extracts, use of pharmaceutical compositions and method of treatment

Info

Publication number: WO2007016756A1
Application number: PCT/BR2005/000163
Authority: WO
Inventors: Adriana Schulz Dos Santos
Original assignee: Lendar Do Brasil S.A.
Priority date: 2005-08-08
Filing date: 2005-08-08
Publication date: 2007-02-15

Abstract

The present invention deals with a pharmaceutical composition comprising, as the active agent, a combination of four plant extracts (Paullinia cupana, Trichilia catigua, Pychopetalum olacoides, Pfaffia stenophylla), as well as its use to stimulate the central nervous system (CNS), particularly as an adaptogen for the treatment of physical and intellectual weakness of humans, locomotion ataxia, partial paralysis, neuralgia and chronic rheumatism, among others.

Description

"PHARMACEUTICAL COMPOSITIONS CONTAINING PLANT EXTRACTS, USE OF PHARMACEUTICAL COMPOSITIONS AND METHOD OF

TREATMENT" FIELD OF THE INVENTION The present invention deals with a pharmaceutical composition comprising, as the active agent, a combination of four plant extracts, as well as its use to stimulate the central nervous system (CNS), particularly as an adaptogen for the treatment of physical and intellectual weakness of humans, locomotion ataxia, partial paralysis, neuralgia, chronic rheumatism and light stages of anxiety and depression.

BACKGROUND OF THE INVENTION

The human nervous system is able to receive, send, elaborate and store information. The nervous system comprises a central nervous part formed by the cerebrospinal axis, from which stimulation derives and to which sensations arrive. The central nervous system (CNS) is the headquarter of human intelligence, responsible to command the whole organism, be it in the physical or in the psychical sense. It receives information on changes occurring in external means, i. e. it relates the individual to his/her environment and starts and regulates appropriate replies. It is not only affected by external means, but also by internal means, i. e. everything occurring in the different regions of the body.

When changes occur in the medium affecting the nervous system, these are called stimulation. Excessive stimulation, mainly due to modern life or some situations of extreme tiredness, may cause damage to CNS, resulting in stress, physical tiredness, as well as other diseases, such as locomotion ataxia, partial paralysis, neuralgia, chronic rheumatism, light stages of anxiety and depression, among others.

Numerous synthetic medicines have been developed in the last decades, as well as much research is being made to develop new treatments for CNS disorders. However, known treatments provide high side effects to patients, both clinical such as nausea, vomiting, headache and stomach disorders, as well as psychological, such as strong emotional disorders.

Adverse reactions related to benzodiazepinics are: sedation, instability, sleepiness, emotional closing, lack of attention, tiredness, headache, dizziness, muscle weakness, ataxia or double vision, disorientation, depression, nausea, feeding disorders, chronic headache, sleep disorders, agitation, dermatological changes and eye disorders, as well as various gastrointestinal symptoms and autonomic manifestations. As with all benzodiazepinics, paradoxical reactions such as stimulation, agitation, extreme irritation or hallucination may occur.

Adverse reactions related to tricyclic antidepressants are: obscure vision, mastication, suction and tongue movements, uncontrolled movements of legs or arms, confusion, delirium, hallucination, difficult speaking or swelling, nervousness, agitation, muscle rigidity, photosensitivity, convulsive attacks, heartburn, vomiting, nausea, diarrhea, uncommon excitation, sleeping disorders, dry mouth, constipation, sweating, urination disorders, CNS disorders, sleepiness, fatigue, increased appetite, confusion or hallucination, sleep disorders, orthostatic hypotension, sinus tachycardia and anorexia. The development of new therapies which are efficient but also provide reduced toxic side effects to patients is therefore desired.

DISCLORE OF THE INVENTION

The present invention presents a composition comprising, as the active agent, a combination of extracts taken from the plants Paullinia cupana H. B. K., Trichilia catigua Juss, Ptychopealum alacoides Benth and Pfaffia stenaphilla Spreng, efficient to stimulate the central nervous system, particularly used as an adaptogen for the treatment of physical and intellectual weakness of humans, locomotion ataxia, partial paralysis, neuralgia, chronic rheumatism and light stages of anxiety and depression, providing reduced side effects to patients.

Paullinia cupana H. B. K., also known as guarana, is a plant of the family Sapindaceae, native of the Amazon region in Brazil, Venezuela and the Guyanas. Seeds of guarana are constituted of about 3 to about 5% of caffeine, about 8 to about 12% of catekic tannins (such as catedermal acid and catechol), xantinic alkaloids (such as teobromine) and also choline, resine, mucillage and saponosides (such as timbonside). Xantinic alkaloids present in guarana act over the circulation, promoting vessel dilatation by relaxing vessel plain muscles. They have strong effect over cell metabolism. On smooth muscles, caffeine promotes an improvement in the production of lactic acid due to the increased consumption of oxygen, thus resulting in better contraction force (Teske et al, Compendio de Fitoterapia, 3^rd edition, page 317, Brazil, 1997). Furthermore, guarana is traditionally used to treat physical weakness, asthenia, nervous depression, headache, gastrointestinal tract disorders such as flatulence, dyspepsia and diarrhea, besides helping in intellectual activities.

Scientifically designated as Trichilia caigua Juss, of the family Bignoniaceae, catuaba is native of Brazil. Its chemical composition includes aromatic compounds, a bitter substance known as catuabine, tannins, resins, fat and tropanic alkaloids similar to atropin and iombin. Its husk is believed to change vegetative functions, acting over nervous centers and interfering with the conduction of impulses of motor nerves. Muscarinic and adrenergic stimulating activities were verified in rabbits (Teske et al, Compendio de Fitoterapia, 3^rd edition, page 317, Brazil, 1997).

Rychopelatum alacoides Benth, of the family Olacaceae, is a bush native of Amazon, popularly known as marapuama and used as a sexual stimulant. The chemical constitution of marapuama is given by alkaloids, mainly marapuamine, in a quantity of about 0.05%, resins rich in organic acids and tannins, traces of terpenic substances, triterpenic alcohol and sterols, such as beta-sitosterol, lupeol and campestero.

Pfaffia stenophilla Spreng of the family Amaranthaceae is a bush found all over Brazil, popularly known as "Brazilian ginseng", for its similarity to Asian ginseng. Its chemical composition varies, containing vitamins A, B, C, D, E and F, pfafic acid, stigmasterol, sitosterol, allantoin, aminoacid, mucillagens, Ca, P, K and nortriterpenoid saponines, such as beta-ecdisone. Its attributed actions include a general tonic for the organism, immunostimulant, healing and antiinflamatory.

Extracts of these plants may be obtained by methods known by the expert in the art, such as decoction or percolation, and may be in dry or fluid form.

Pharmaceutical compositions of the invention may vary from about 40 mg to about 800 mg, preferably about 400 mg of the active agent as obtained from the extracts of the four plants under the proportion of about 1 :1 :1 :1 in a mixture with pharmaceutically acceptable excipients. Preferably, but not excluding any other way, the compositions of the invention may be orally given, in liquid or solid pharmaceutical forms, including immediate and/or controlled release forms.

Liquid pharmaceutical forms may be given as syrups, solutions, suspension or emulsion and may include, as pharmaceutically acceptable excipients, flavoring, coloring, edulcorating and suspension agents, preservers, stabilizers, antioxidants, chelating agents, buffer agents, solvents, acidifying agents, dispersing agents, viscosity agents and others.

Solid pharmaceutical forms may be given as pellets, caplets, hard or soft gelatin capsules and may include, as pharmaceutically acceptable excipients, sliders, lubricants, agglomeration agents, diluents, disintegrants, agglutinants, wetting agents, adsorbents, solvents, pellicle-forming agents and film-forming agents, among others.

Pharmaceutically acceptable carriers to make the present invention may include all those known in the art, with no limitation. A reference work for the inclusion of adjuvants to the composition of said pharmaceutical forms is the book Remington's Pharmaceutical Sciences, from the U. S. publisher Mack Publishing.

The preferential pharmaceutical composition is given in the form of caplet and contains silica dioxide as excipient. The present invention also includes the use of pharmaceutical compositions to prepare an efficient medicine as adaptogen, acting as a tonic and CNS stimulator, which can also be used for the treatment and prevention of physical and intellectual weakness of humans, locomotion ataxia, partial paralysis, neuralgia, chronic rheumatism and light stages of anxiety and depression.

Adaptogen means herewithin the active agent able to favor the adaptation of a human organism when exposed to various factors of physical overload or stress.

Another object of the present invention is the method to stimulate and strengthen the CNS comprising the administration to a patient in need of a pharmaceutical composition of the present invention at least once a day, preferably twice a day, in the morning.

Furthermore, the present invention contemplates the method to treat and prevent human physical and intellectual weakness, locomotion ataxia, partial paralysis, neuralgia, chronic rheumatism and light stages of anxiety and depression comprising the administration to a patient in need of a pharmaceutical composition of the present invention at least once a day, preferably twice a day, in the morning.

As the skilled man in the art may see, the present invention allows numerous variations from the information as supplied herewithin, not however going beyond the content of the attached claims. Below please find merely illustrative examples of a few aspects of an embodiment of the invention, not imposing any limits to its extension beyond the ones included in the attached claims.

As we can see in the assays, in light stages of anxiety and depression, treatment with the pharmaceutical composition of the invention brings benefits in comparison to traditional medicines, such as stimulants.

Furthermore, the pharmaceutical composition provides a reduction in toxicity risks by overdose, i. e. serious toxic reactions, which are frequently harmful and possibly deadly, due to accidental overdose of a given drug by error of the physician, pharmaceutical or the patient himself, or even intentional error in cases of homicide and suicide.

The less risk of toxicity by overdose is frequently the reason why physicians prefer one medicine over another one when both products are equally efficient, especially for the treatment of younger children (2 to 12 years old). Therefore, the pharmaceutical composition as presented herewithin is especially suited to treat younger children.

We will show below that side effects were also significantly minimum or non-existing, also keeping an acceptable rate of pharmacological action, which makes the pharmaceutical compositions of the present invention become efficient for all treatments as already disclosed herewithin.

EXAMPLES EXAMPLE 1 COMPOSITION OF THE INVENTION ADMINISTERED AS A CAPLET

EXAMPLE 3 PHARMACOLOGICAL ACTION OF THE COMPOSITIONS OF THE PRESENT INVENTION

The examples that follow show the efficacy of the composition of the present invention, as well as the results in the reduction of side effects in comparison to a standard drug.

The standard drug as used was anfepramone, presenting a range of side effects and counter indications, not being indicated for children younger than 12 years old or elder people. Among known side effects, vertigo, chronic headache, sleeplessness, nervousness, irritability, depressive manifestations, tasting dysfunction, dry mouth, nausea, vomiting, diarrhea or constipation, hypertension, tachicardia, arrhythmia, precordial pain and hypotension, sexual dysfunction, urination dysfunction and gynecomastia, urticaria and exanthem. In cases of long-lasting use, pharmaceutical dependence and serious alterations were reported, such as less concentration, weakness and changes in personality. The most severe manifestations were psychotic dysfunctions similar to schizophrenia. The pharmacological activity of the composition of Example 1 was evaluated over the following behavior models: a) forced swimming assay; b) open field assay; c) Rota Rod assay; and e) barbituric sleeping assay. Results are shown in the attached drawings. EXAMPLE 3A

FORCED SWIMMING ASSAY

Male Wistar rats weighing 150 to 200 g and male albino Swiss mice weighing 25 to 30 g were used. The animals were kept in groups of 7 (n =

7) in polyethylene cases with water and food ad libitum in a room with a 12-hour day/night cycle and controlled temperature (25 ± 20 ⁰C). About 24 hours before the experiments, the animals fasted, only keeping free access to water.

Animals were orally treated with a composition of the invention thirty minutes before the experiments under the doses of 20 mg/kg and 100 mg/kg. The drug used as standard was anfepramone under the dosage of 10 mg/kg. For all experiments, a control group was used and received just 0.5 ml of distilled water.

In forced swimming assays, none of the animals evaluated in the test dipped, and this aspect was therefore not discussed. The treatment with anfepramone (10 mg/kg) significantly reduced the time to immobility, presenting 61.88% inhibition over the control. The treatments with the composition of the invention also caused a reduction in immobility time, which followed a dosage- response relation. The 20 mg/kg dosage reduced in 33.63% the time to immobility and the 100 mg/kg dosage reduced it in 49.66%. Results are shown in the attached Figure 1. EXAMPLE 3B

OPEN FIELD ASSAY

Animals were put and analysed for five minutes in an open field.

This consists in a white-covered box (100 cm x 100 cm x 50 cm) illuminated with fluorescent lamps located 50 cm above the center. Its floor was divided by parallel and perpendicularly located blue bands in a 20 cm quadrant. Five objects were put in the central frames to evaluate explorative activity. Evaluated standards were deambulation (number of run frames), vertical exploration (the animal is solely supported by its end legs, supported on the wall or not) and horizontal exploration (number of touches on the objects).

The evaluation of deambulation (number of run frames) showed an improvement caused by the treatments made with the composition of the invention under the doses of 20 and 100 mg/kg, as shown by Figure 2.

Horizontal exploration was also not influenced by the treatment with the composition of the present invention, under the used doses, as shown by Figure

3. The number of vertical explorations, known as "rearings", increased with the treatment with the composition of the present invention, under the dose of 100 mg/kg, in comparison to the control group. The improvement observed with the treatment with anfepramone was considered as significant for p < 0.01 , as shown by Figure 4.

EXAMPLE 3C ROTA ROD ASSAY

Male Wistar rats (n = 7) were selected and trained 24 hours before the experiment, and those ones which could not stay for 300 seconds in the set were rejected (Rota Rod, Mod. 7750, Ugo Basile, Italy), with 4-40 rpm acceleration, in three attempts. Animals receiving the treatment with the composition of the present invention under the dosage of 20 mg/kg had their latency time reduced, similar to the treatment with anfepramone with 10 mg/kg. Results are shown by Figure 5.

EXAMPLE 3D BARBITURIC SLEEP ASSAY

To induce sleep, sodium thiopental was used intraperitoneal^ under the dosage of 20 mg/kg in groups of rats (n = 8), 30 minutes after the administration of assay drugs. The animals were then observed by registering the time required to awake them, considering as 100% the time of the control group. The animals were considered as awaken when they were able to stand up supported on their four feet. The groups of animals receiving the treatments with the composition of the invention under the doses of 20 and 100 mg/kg produced dosage-response effect, but for both doses the time of sleep was similar to the control group. On the other hand, in the group treated with anfepramone (10 mg/kg), the time of sleep was inhibited in 65%, in comparison to the control group. Results are shown by Figure 6.

The composition of Example 1 , as it can be seen from the graph of Figure 6, provided enough response dosage for stimulating action.

EXAMPLE 4 TOXICOLOGICAL ACTION ASSAYS

EXAMPLE 4A LD50 DETERMINATION

With the oral administration of doses (50, 100, 200, 400 and 2000 mg/kg) in mice, LD50 could not be established, since these doses did not cause any death within the 7-day observation period and, in the first 72 hours after the administration, the animals did not show any sign of intoxication, such as reduced deambulation, diarrhea, hair erection etc. after the treatment with a composition of Example 1.

EXAMPLE 4B EVALUATION OF TOXICITY IN ACUTE (ORAL. 15 DAYS) AND SUBCHRONIC (30 DAYS) TREATMENT STAGE WITH A COMPOSITION OF THE PRESENT INVENTION

In the evaluation of acute oral toxicity in rabbits (15 days), despite the groups treated with a composition of the present invention presenting less weight development than the controls, there were no statistically significant differences of said standard in the different groups (male and female). Results are shown by Figure 7. In the subchronic toxicity assay, no significant difference was observed between the weight development of the animals treated with the composition of the invention and the control groups. However, the development of rats, in both groups treated with a composition of the present invention and control were lower than rats up to the end of the treatment period. Results are shown by Figure 8. Concerning diuresis, we can observe that the verified variations were similar in all groups, as shown by Figure 9. The variation in urine volume may have occurred due to the isolation of animals in metabolic cages, as well as their daily handling, causing stress and influencing diuresis. As for the consumption of water and food, there was practically similar variation in all experimental groups as presented by Figures 10 and 11.

EXAMPLE 4C

TOXICOLOGICAL STUDY

The average weight of organs is within normal standards for the animal species (rats). Differences found in groups treated with a composition of the present invention over the control group (white) were not statistically significant as shown by the table below. TABLE 1 -WEIGHT OF THE ORGANS OF ORALLY TREATED (50 MG/KG) RAT ANIMALS

(MALES AND FEMALES) WITH A COMPOSITION OF THE PRESENT INVENTION AND

CONTROL GROUP (5 ML/KG) FOR 30 DAYS

Control Group Treat. Group Control Group Treat. Group Male Male Female Female

Kidneys 1.225 ± 0.046 1.112 + 0.03 0.921 ± 0.03 0.899 ± 0.016

Liver 10.828 ± 0.53 10.1 ± 0.275 8.161 ± 0.466 7.408 ± 0.302

Stomach 1.718 ± 0.124 1.663 ± 0.097 1.380 ± 0.054 1.472 ± 0.061

Lung 1.848 ± 0.135 1.656 ± 0.121 1.567 ± 0.091 1.945 ± 0.188

Heart 1.041 ± 0.060 1.051 ± 0.090 0.933 ± 0.031 0.775 ± 0.035

Intestine 0.722 ± 0.061 0.778 ± 0.110 0.840 ± 0.049 0.803 ± 0.103

Spleen 1.442 ± 0.131 1.198 ± 0.164 1.004 ± 0.139 0.788 ± 0.030

Each value represents the average ± EPM of n = 10/group. Values are expressed in g. EXAMPLE 4D EVALUATION OF BIOCHEMICAL AND HEMATOLOGICAL STANDARDS AFTER ACUTE (15

DAYS) AND SUBCHRONIC (30 DAYS) TREATMENTS WITH A COMPOSITION OF THE

PRESENT INVENTION

Biochemical and hematological standards were evaluated at the end of the treatment, 16^th day for the acute treatment and 31^st day for the subchronic treatment with the composition of the present invention. In the groups treated with a composition of the present invention for 15 and 30 days concerning hematological data, no occurrences of change in the rates of analysed blood variants were verified to show any damage at such levels caused by the treatment with the assay product. We can forecast that the occurrence of eosinophil as observed in rabbits may be related to a direct reaction to the product, as for aspirin, in which there is sensitivity to said pharmaceutical product (Wallach et al, The Effects of Antihistamines in Modified Behavioral Despair Test, Commun. Psychopharmacol. 3: 35-39, 1979). For all other standards, there was no significant difference for p < 0.05, as per Mann- Whitney's "U" assay. Results are shown by the tables below. TABLE 2 - HEMATOLOGICAL STANDARDS OF ORALLY TREATED (50 MG/KG) RABBIT ANIMALS (MALES AND FEMALES) WITH A COMPOSITION OF THE PRESENT INVENTION

Each value represents the average ± EPM (n = 3/group). * p < 0.05, Mann-Whitney's "U" assay.

TABLE 3 - HEMATOLOGICAL STANDARDS OF ORALLY TREATED (50 MG/KG) RAT

ANIMALS (MALES AND FEMALES) WITH A COMPOSITION OF THE PRESENT INVENTION

20

AND CONTROL GROUP (5 ML/KG) FOR 30 DAYS

Each value represents the average ± EPM (n = 10/group). p < 0.05, Mann-Whitney's "U" assay. TABLE 4 - BIOCHEMICAL STANDARDS OF ORALLY TREATED (50 MG/KG) RABBIT

ANIMALS (MALES AND FEMALES) WITH A COMPOSITION OF THE PRESENT INVENTION

AND CONTROL GROUP WITH WATER (5 ML/KG) FOR 15 DAYS

Each value represents the average ± EPM (n = 3/group).

TABLE 5 - BIOCHEMICAL STANDARDS OF ORALLY TREATED (50 MG/KG) RAT ANIMALS (MALES AND FEMALES) WITH A COMPOSITION OF THE PRESENT INVENTION AND

Each value represents the average ± EPM (n = 10/group).

EXAMPLE 4D HISTOPATHOLOGIC ASSAY OF ORGANS OF ANIMALS TREATED FOR 30 DAYS WITH A

COMPOSITION OF THE PRESENT INVENTION ANALYSIS OVER TREATED GROUPS FOR 30 DAYS (RATS) All assayed tests, including kidneys, lungs, heart, intestine, stomach and liver, were within normal standards. Some histological discoveries were found, such as the presence of hemorrhage, autolysis, consequences which are perfectly expected due to the surgical form of collection of organs as well as failures and technical variations such as cutting artifacts, insufficient attachment etc. RESULTS OF PHARMACOLOGICAL ACTION ASSAYS

With the obtained results, we may suggest that the oral treatment with the composition of the present invention under the dose of five times as indicated for human use has been shown as safe concerning the occurrence of toxicological side effects in the used animal species. Small variations observed in hematological and biochemical analysis did not present any organic compromise, since in histopathological analysis (macroscopic and microscopic), all analysed organs were within normal standards.

Claims

1. Pharmaceutical composition which comprises, as the active agent, a mixture of extracts from the plants Paullinia cupana h. b. k., Trichilia catigua Juss, Ptychopetalum alacoides Benth and Pfaffia stenophilla Sprena under the proportion of about 1 :1 :1 :1.

2. Pharmaceutical composition of claim 1 , which comprises about 40 mg to about 800 mg of the active agent.

3. Pharmaceutical composition of claim 2, which comprises about 400 mg of the active agent.

4. Pharmaceutical composition of any of claims 1 to 3, which is presented in liquid or solid form.

5. Pharmaceutical composition of claim 4, wherein liquid forms comprise syrups, solutions, suspensions or emulsions.

6. Pharmaceutical composition of claim 5, wherein the liquid form includes as pharmaceutically acceptable excipients flavoring, coloring, edulcorating, suspension agents, preservers, stabilizers, antioxidants, chelating agents, buffer agents, solvents, acidifiers, dispersing agents, viscosity agents or their combinations.

7. Pharmaceutical composition of claim 4, wherein solid forms include pellets, tablets, hard or soft gelatin caplets of immediate and/or delayed release.

8. Pharmaceutical composition of claim 5, wherein solid forms include, as pharmaceutically acceptable excipients, sliders, lubricants, agglomeration agents, diluents, disintegrants, agglutinants, wetting agents, adsorbents, solvents, pellicle-forming agents and film-forming agents or their combinations.

9. Pharmaceutical composition of claim 1 , wherein the extract of Paullinia cupana h. b. k. comprises caffeine and/or xantinic alkaloids, the extract of Trichilia catigua Juss comprises tropanic alkaloids, the extract of Ptychopetalum alacoides Benth comprises marapuamine and the extract of Pfaffia stenophilla Spreng comprises nortriterpenoid saponines.

10. Use of a pharmaceutical composition of any of claims 1 to 9 to prepare an efficient medicine as adaptogen, acting as a tonic and CNS stimulator, useful for the treatment and prevention of physical and intellectual weakness of humans, locomotion ataxia, partial paralysis, neuralgia, chronic rheumatism and light stages of anxiety and depression.

11. Method to stimulate and strengthen the central nervous system comprising the administration to a patient in need of a pharmaceutical composition of any of claims 1 to 9 at least once a day.

12. Method to treat and prevent human physical and intellectual weakness, locomotion ataxia, partial paralysis, neuralgia, chronic rheumatism and light stages of anxiety and depression comprising the administration to a patient in need of a pharmaceutical composition of any of claims 1 to 9 at least once a day.