FORM 2
THE PATENT ACT 1970
(39 of 1970)
&
The Patents Rules, 2003
PROVISIONAL SPECIFICATION
(See section 10 and rule 13)
1. TITLE OF THE INVENTION:
"Herbal Composition for reducing ADD/ADHD and method thereof
2. APPLICANT (S)
(a) NAME: NISARGA BIOTECH PVT.LTD. (b)NATIONALITY: Indian Company incorporated under the Indian
Companies ACT, 1956
(c) ADDRESS: 275, Chandan Nagar, Addl. M.I.D.C., Satara-415004, Maharastra, India
3. PREAMBLE TO THE DESCRIPTION
The following specification describes the invention.

Technical field:
The present invention relates to synergistic herbal compositions useful in the treatment of Attention Deficit disorder (ADD) and Attention deficit/hyperactivity disorder (ADHD). More particularly the invention relates to a herbal composition capable of reducing the ADD/ADHD symptoms, which helps to improve memory and cognitive skills in adolescents and adults. The invention further relates to method for treating the same.
Background and prior art:
Attention Deficit Disorder (ADD) and Attention Deficit/Hyperactivity Disorder (ADHD) (severally and collectively hereinafter referred to as "ADHD") are developmental disorders, largely neurological disorders effecting 5% of the world population. The disorder typically presents itself during childhood, and is characterized by a persistent pattern of inattention and/or hyperactivity, as well as forgetfulness, poor impulse control or impulsivity, and distractibility.
Inattentive behavior is often characterized by difficulty focusing on one task, failure to pay attention to details, and making careless mistakes in a variety of tasks. Individuals exhibiting inattentive behavior may appear as if their minds are elsewhere or they are not listening or did not hear what has just been said.
Hyperactive people always seem to be in motion and may suffer from feelings of restlessness and difficulty engaging in sedentary activities. Common signs include excessive unproductive movement, excessive talking, and an inability to sit still. Hyperactive children often roam around the room, and feel compelled to touch everything.
Impatience and a failure to think before acting often characterize impulsivity. Impulsive young children may frequently interrupt others, fail to listen to directions, and have difficulty waiting for their turn.
These problems are reflected in impairment of a person's will or capacity to control his or her own behavior relative to the passage of time and to keep future goals and consequences in mind. ADHD is most commonly diagnosed in children and, over the past


decade, has been increasingly diagnosed in adults. About 60% of children diagnosed with ADHD retain the disorder as adults.
Studies indicate that the disorder is highly heritable and that genetics contribute about three quarters of the total ADHD population. While the majority of ADHD is believed to be genetic in nature, 1/5 of all ADHD cases are thought to be acquired after conception due to brain injury caused by either toxins or physical trauma prenatally or postnatally. Scientists have not yet identified a single underlying cause behind these behavior characteristics. While some have been linked to decreased brain activity, the biological reason for the decreased brain activity is still unknown. Treatment for ADD and ADHD is therefore limited to treating the symptoms of the disorders.
Methods of treatment usually involve some combination of medications, behaviour modifications, life style changes, and counseling.
The most common treatment for ADD and ADHD is the use of mild central nervous system stimulant drugs, such as Ritalin, Cylert, and Dexedrine. However, there are several drawbacks in using these drugs such as frequent short-term side effects include insomnia, loss of appetite, headaches, stomachaches, hyperactivity, drowsiness, blood pressure and pulse changes, and cardiac arrhythmia. In addition to this, the possible consequences of long-term exposure to these drugs in children are not thoroughly investigated. The use of Ritalin in children under six years of age is particularly undesirable since safety and efficacy in this age group has not been established.
As an alternative to the aforementioned conventional treatments, U.S. Pat. No. 5,719,178 discloses a method for treating ADHD comprising taking a quantity of proanthocyanidin sufficient to relieve symptoms of ADHD every approximately 3.5 to 4.0 hours. A heterocyclic antidepressant, preferably desipramine may be taken optionally with the proanthocyanidin in quantities sufficient to attenuate ADHD-related symptoms of lack of cognitive focus. However, a major drawback of this method is that repeated doses are required to alleviate symptoms throughout the day, which is inconvenient as well as difficult especially for school going children.


US6093404 describes a therapeutic composition for treatment of ADD or ADHD comprising in percentage by weight: 3-9% proanthocyanidin, 30-40% yucca root, 15-25% hawthorn berry, 10-20% bilberry, 5-15% silymarin, and 10-15% gingko biloba.
6759053 provides compositions and methods for using the S(+) enantiomer of desmethylselegiline (N-methyl-N-(prop-2-ynyl)-2-am- inophenylpropane), for the treatment of selegiline-responsive diseases and conditions. Diseases and conditions responsive to selegiline include those produced by neuronal degeneration or neuronal trauma and those due to immune system dysfunction. Effective dosages are a daily dose of at least about 0.015 mg/kg of body weight.
The use of 3-[l-[2-(l-acetyl-2,3-dihydro-lH-indol-3-yl)ethyl]-l,2,3,6-tetr- ahydropyridin-4-yl]-6-chloro-lH-indole, any of its enantiomers and pharmaceutically acceptable salts thereof for the preparation of a pharmaceutical composition for the treatment of attention deficit hyperactivity disorder is disclosed in US20040152737.
The pharmaceutical compositions are comprised of a therapeutically effective combination of a nicotine receptor partial agonist and an anti-ADHD agent and a pharmaceutically acceptable carrier and the method of using these compounds is disclosed in US20040220184
WO2003068251 describes a herbal formulation comprising Bacopa monneri; Centella asiatica; Glcyrrhiza glabra; Withania somniferan and Celastrus paniculatus and process for preparing the same for treating attention deficiency disorder in Humans. The herbs are subjected to solvent extraction using hazardous solvents such as hexane, chloroform, methanol and acetone. The herbs are extracted especially Brahmi and Jyotishmati using Hydrocarbon solvents such as Hexane, Chloroform which are considered hazardous to human health. The extraction of the herbs at higher temperature destroys or modifies molecular and chemical structure of temperature sensitive phytochemicals which may contribute to the therapeutic value of the herbs, incase of use of Hydrocarbon solvents such as Hexane and chloroform.
In a conventional solvent extraction process, the separation temperature is always greater than the extraction temperature. This means that when the solvent is recovered, the


obtained extract is subjected to higher temperature, which is likely to destroy many temperature sensitive phyto nutrients and phyto chemicals in the extract.
A combination of hyperforin, 5-hydroxy triptophan, rhodiola rosea, along with Vitamins B, Vitamin C, Vitamin D3, and minerals like selenium and Zinc are sold under the brand name of Amoryn for treating ADHD disorders. The daily dose comprises 1 to 4 capsules per day.
There is a need in the art to provide herbal formulation for oral administration comprising safe and effective extracts of two or more herbs, effective for the treatment of ADHD, and is devoid of any side effects.
Summary of the invention:
Accordingly, in one aspect, the invention discloses herbal composition comprising two or more effective extracts of the herbs selected from Acorus calamus, Azadirchta indica, Bacopa monnieri, Boswellia serrata, Eclipta alba, Embelia ribes, Fumaria indica, Linum usitatissimum, Mucuna pruriens, Nardostachys jatamansi, Nigella sativa, Ocimum sanctum, Phyllanthus niruri, Rosmarinus officinalis, Ricinus communis, Valeriana officianalis and Zingiber officinale useful in the treatment of ADHD.
In another aspect, the invention discloses method of extraction of the herbs used in the invention. The herbs are extracted using a unique method of extraction, so as to ensure that the extractives are safe and effective and contains no harmful extraction solvents.
The supercritical C02 extraction which is used in the present invention with or without entrained ethanol does not leave any hazardous solvent residues. The extraction temperature is maintained between 35°C to 45°C, which ensures the retention of all temperature sensitive ingredients.
The method adopted by the present inventors for extraction (SCO2 extraction with or without entrained ethanol) always has a much lower separation temperature than the extraction temperature. Thus integrity of phyto nutrials and phytochemicals is maintained apart from retaining the temperature sensitive ingredients (Typical temperature for


conventional extraction is 35 to 45 degree c while the separation temperature will be around 25°C to 28°C in the present process)
In a further aspect, the invention describes a method of treating Attention Deficit Disorder (ADD) and Attention Deficit/Hyperactivity Disorder (ADHD) using the compositions of the present invention. The invention also relates to using the formulation/composition for improving cognitive skills and memory.
Detailed description:
In accordance with the above aspects, the invention will now be described in detail in connection with certain preferred and optional embodiments, so that various aspects thereof may be more fully understood and appreciated.
The present invention describes herbal compositions for oral application comprising mixture of extractives of two or more herbs selected from Acorus calamus, Azadirchta indica, Bacopa monnieri, Boswellia serrata, Eclipta alba, Embelia ribes, Fumaria indica, Linum usitatissimum Mucuna pruriens, Nardostachys jatamansi, Nigella sativa, Ocimum sanctum, Phyllanthus niruri, Rosmarinus officinalis, Ricinus communis, Valeriana officianalis and Zingiber officinale useful in the treatment of ADHD and improving memory and cognitive skills.
The herbs are extracted using a unique method of extraction, so as to ensure that the extractives are safe and effective and contains no harmful extraction solvents such as Hexane, Acetone and Chloroform.
The principal characteristics of ADHD are inattention, hyperactivity and impulsivity. Some of the disorders known to be accompanying ADHD are learning disabilities (LD), Tourette syndromes, and oppositional defiant disorder; conduct disorder, anxiety and depression or Bipolar disorder.
There are many herbs reported in Ayurveda and other alternative medicines known to work on brain functions. Therefore, the inventors of the present invention have undertaken screening strategy of many plant extracts using in vitro cell based experimental protocols followed by in vivo experimental studies and found that the


extracts of the following plants are known to work on brain functions. Accordingly, the current invention uses a mixture of extractives of two or more herbs selected from Acorus calamus, Azadirchta indica, Bacopa monnieri, Boswellia serrata, Eclipta alba, Embelia ribes, Fumaria indica, Linum usitatissimum Mucuna pruriens, Nardostachys jatamansi, Nigella sativa, Ocimum sanctum, Phyllanthus niruri, Rosmarinus officinalis, Ricinus communis, Valeriana officianal and Zingiber officinale.
In a preferred embodiment, all the herbal extracts used in the formulation are extracted using Supercritical C02 extraction with or without entrained solvent ethanol, using the below mentioned conditions.
Pressure of extraction: Between 72 kg /cm2 to 550 kg/cm2
Preferred Range: 300 kg/ cm2 to 400 kg/cm2
Entrained ethanol 0-10% (Preferred range 3 to 7%)
All the extracts used are free from any hydrocarbon solvent residues such as Hexane, chloroform, Acetone etc, which are hazardous to human health when ingested even at very low residual levels
The herbs can be extracted using any conventional methods using conventional solvents such as cold pressing method, conventional extruder press method, solvent extraction, distillation "modified atmosphere packing" (MAP).
Supercritical CO2 extraction is s a process that produces a broad spectrum of the herbs lipophilic constituents such as oils, fatty acids along with vital temperature sensitive phytonutrients. The spectrum of the extractives can be widened by using up to 10% of ethanol as an entrained solvent along with pure CO2. The major advantages of using this process of extraction are retention of all the temperature sensitive ingredients present in the herb which contributes toward health benefits. Unlike other solvent extraction method such as Hexane, Chloroform, Acetone, the resulting extract is free of hazardous solvent residues. Similarly, the resultant extract is also free from heavy metals contamination as heavy metals are not soluble in CO2 or alcohol.


In a preferred embodiment, the herbal formulation of the present invention comprises: Jyotishmati oil (Celestris paniculata seed oil) in an amount of about 5 to 50% of the total formulation; Flax seed oil (Linum usiatissium seeds) in an amount of about 30 to 65%; Bacopa monniera extract in an amount of about 0 to 10%; Rosmarinus officinalis extract 0-10%, Ginger extract in an amount of 0 to 4% and natural Vitamin E (a Tocopherols)0 to 2%.
Accordingly, one preferred formulation comprises (1.) Celestris paniculata seed oil -35%; (2.)Linum usiatissium seed oil-54.6%; (3.)
Bacopa monniera extract-5.0%; (4.Rosmarinus officinalis extract 4%, (5.)Ginger extract 1.0%, and (6.)natural vitamin E 0.2%.
All the five ingredients from (1.) to (5.) are extracted with Supercritical C02 extraction with or without entrained solvent ethanol.
In another preferred embodiment, the invention provides the composition in the form of a dietary supplement or a herbal medicine in conventional forms of Soft Gel Capsules, Hard Gel Capsules, Liquid Capsules, with or without carrier, dietary powders, drinks, substantially homogeneous mixture i.e., active ingredients are distributed evenly.
In another preferred embodiment, the present invention provides method of treating using the inventive composition for lowering the symptoms of ADD/ADHD. The compositions of the present invention can be administered in a dosage range of 50 mg to 1000 mg per dose in any of the above mentioned dosage forms. The recommended dose of administration is twice a day.
In one preferred embodiment, the above composition is administered in soft Gelatin Capsules without any use of carrier.
The mode of administration may be 100mg capsule twice a day or 200mg capsule twice a day or 300 mg capsule twice a day depending upon the severity of the symptoms of ADHD/ADD and effective amount required to an individual in need of reducing the


symptoms. One more possible mode is administering 100 mg capsule in multiples of 2 or 3 at a time if capsules of 200 mg and 300 mg are not available.
The effective amount is the amount required to treat/alleviate the severity of symptoms associated with this ailments as decided by the persons of ordinary skill in the art.
The oral administration may be accomplished by ingesting the composition preferably in soft gel form with a glass of water. The other dosage forms like hard gelatin caps, powders, liquid capsules (vegetarians) and as additives to food are also equally good modes of administration, at the same recommended dosage two times a day.
The compositions of the invention is also useful effectively in treating the other ailments such as Associated disorders with ADHD, Learning disabilities, Tourette Syndrome, Oppositional defiant disorder, Conduct disorder, Bipolar disorder, Dymensia, Parkinson, Alzaimer and Hypertensive Disorder / High Blood Pressure, loss of memory, Austin, OCI PDD-NOS, REITS, Aspergers, epilepsy, Dyspraxia, Dyslexia, Cerebellar, Ataxia, Down Syndrome, Schizophrenia and other neurodevelopmental disorders that result in leaning dela and behavioral issues also for improving memory and cognitive skills.
Safety data:
The composition is absolutely safe for use and has no side effects at the given dosage levels. This can be evident from the sub acute toxicity data presented below: The objective of the study was to determine the long term 90 days continuous exposure, oral toxicity of the composition following OECD guidelines protocol.
Group I: In the control group, all the animals appeared normal and showed no
mortality upto the end of the study.
Group II was given a human dose of 200mg/kg, all the animals appeared normal and showed no mortality upto the end of the study. There was no irritation to
GITafter the administration of the drug.
Group II was given human dose of 2000mg/kg, all the animals appeared normal and showed no mortality upto the end of the study. The dosage was administered for a continuous period of 90 days.


Body weight: There was no statistically significant decrease in the body weight gain
in all the study groups when compared with the control group animals. Food consumption: There was no significant difference observed in the amount of the
food compared to the control group.
Haematological data: There was no signioficant difference observed in the parameters like RBC, WBC total and differential, Hb, PVC and prothrombin time in all the test groups compared with control group. There was no difference observed in blood chemoistry as well as in the organ weights. Urine analysis was normal and no mortality observed. No abnormal findings were observed in Histopathological findings for heart, brain, testis/ovaries. The drug related changes were not seen in any of the test groups compared to control group.
Therefore, it can be concluded that the herbal compositions of the present invention is safe for long term use based on the sub acute toxicity findings as per the OECD guidelines.
Pilot trials:
Pilot trials have been carried out for dose determination and efficacy of the formulation on the behavioral disorders in adolescent. The results of the pilot study are discussed below in detail.
The trial has been carried out as open labeled study
Number of subjects-8 students of 9th Std. diagnosed as behavior disorder cases.
Criteria of selection of students
1. DSM criteria(diagnostic and statistics manual)
2. Primary physical and mental checkup
3. SPM subjective performance matrices to asses general intellect.
Criteria assessment 1. DSM criteria-

Score Interpretation
Above 42 Hyper


36-42 High
29-35 Moderate
22-28 Moderate
15-21 moderate
8-14 Mild
0-7 Negligible
2 SPM Criteria

Percentile Rank Interpretation
Above 95 Superior
90-94 High
75-89 Above average
60-74 Average+
40-59 average
25-39 Average-
10 to 24 Below average
Below 9 Poor
Methodology:
Students of the 9th standard having behavior disorders were initially screened on the basis of specially designed questionnaire, which was filled up by respective class teachers. Students of behavior disorders were diagnosed on the basis of criteria of DSM. The subjects were subjected to physical and mental check ups to exclude association of any other illness.
Assessment of intellectual status (IQ) was done on the basis of score of PR obtained by standard psychometric test i,e(SPM) with the help of clinical psychologist. Dose of administration is 125mg capsule (containing 100 mg of composition described in this invention with weight of gelatin cover 25 mg making a grass weight of capsule 125 mg) administered along with milk. The progress in behavior, mental and intellectual status was recorded every fortnightly. Incidence of any adverse reaction like vomiting, nausea, headache, gastric upset were also noted and were withdrawn from the study accordingly. At the end of the trial (after 90 days) improvement and effect of the formulation was assessed on the basis of the score obtained by SPM and DSM.
Observations and results are given below which shows the scores before and after treatment as per DSM IV criteria in table 1


Sr. No B.T (Before Treatment) A.T (After treatment)
Score Remark Score Remark
1. 10 Mild 2 Negligible
2 16 Moderate 9 Mild
3 18 Moderate 9 Mild
4. 23 Moderate 9 Mild
5 29 Moderate 11 Mild
6 20 Moderate 15 Moderate
7 25 Moderate 15 Moderate
8 10 Mild 2 Negligible

Table 2 given below shows the effect of the formulation as per DSM IV criteria
Table 2

No B.T A.T Difference=X
1 10 2 8
2 16 9 7
3 18 9 9
4 23 9 14
5 29 11 18
6 20 10 10
7 25 15 10
8 10 2 8
Total 84
Mean difference: =10.5
SD = 3.702
SE =1.309
tl =8.019
A+7 degree of freedom 15%, Significant limit oft is 2.37.
Therefore (t =8.019, p<0.001 reduction in symptoms of ADHD statistically highly
significant.


Table 3 given below shows the intellectual status before and after treatment as per SPM

Sr. No RawScore PR interpretation Raw score PR Interpretation
1 45 68 Average+ 53 90 high
2 37 23 Below average 39 25 Average-
3 43 50 Average 50 86 Above average
4 36 17 Below average 38 22 Below average
5 34 24 Below average 38 41 Average
6 48 75 Above average 53 90 High
7 42 35 Average- 43 35 Average
8 44 68 Average+ 45 68 Average+
Table 4 shows intellectual status before and after treatment as per SPM

No BT(A) BT(B) Difference X=(B-A) Mean X-X-X-=12.1 (X-X-Y
1 68 90 22 10.9 118.81
2 23 25 2 -10.1 102.01
3 50 86 36 23.9 571.21
4 17 22 5 7.1 50.41
5 24 41 17 5.1 26.01
6 75 90 15 3.1 9.61
7. 35 35 0 12.1 146.41
8 68 68 0 12.1 146.41
total 97 1170.88
X =12
S.D =12.93
S.E =4.57
T7 = 2.65
At t7 degrees of freedom, 5% significant limit oft is 2.37. Hence the mean improvement in general intelligence is significant at 5% level.(t=2.65, P<0.05)
Results in table I and II indicates that there was marked reduction in the post treatment scores of all the 8 students. The analysis of the results on the basis of paired test revealed


that the formulation significantly reduced the scores of symptoms of behavior disorders as stated in DSM IV.
Results of table III and IV
After treatment, the scores of percentile rank (PR) as compared to initial score as per SPM of 8 students suggested some improvement however; raw score of each student is markedly improved.
Statistical analysis as per paired test showed significant improvement (P<0.05) in PR of 8 students after the treatment for 3 months in students suffering from behavior disorder. One student complained of nausea and was withdrawn from the trial after 50 days.
From the above trials, it has been concluded that the herbal formulation of the present invention has positive effect on the subject who is suffering with Attention deficit disorder as the symptoms are relieved significantly. It was also confirmed that the administration of inventive composition for 3 months, significantly improves the cognitive skills of the students suffering from behavior disorders. Thus the inventive formulation has nootropic as well as psychotropic effect on the patients suffering from ADD/ADHD.