INTRODUCTION:

SMOKING¹:

Smoking is bad for your health. Smoking harms nearly every organ of the body. Cigarette smoking causes 87 percent of lung cancer deaths. It is also responsible for many other cancers and health problems. These include lung disease, heart and blood vessel disease, stroke and cataracts.

Women who smoke have a greater chance of certain pregnancy problems or having a baby die from sudden infant death syndrome (SIDS). Your smoke is also bad for other people-they breathe in your smoke secondhand and can get many of the same problems as smokers do. Quitting smoking can reduce your risk of health problems. The earlier you quit, the greater the benefit.

Fig 1: Skull with a Burning Cigarette by Vincent van Gogh, oil on canvas, 1885

ANTI-SMOKING AGENTS³:

These agents not only reduce craving for tobacco but also reduces the smoking withdrawal symptoms. Varenicline was the first anti-smoking agent which was launched by Pfizer. It was approved by US FDA in 2006 under the brand name Chantix and by European regulators under the brand name of Champix. Chantix is a non-nicotine medicine. It blocks nicotine receptors and prevents nicotine to reach over there. In the present work we plan to use fava beans to quit smoking

PLANT PROFILE OF FAVA BEANS⁴:

Binomial Name: Vicia faba, Vicia faba plants in flower, scientific classification

Kingdom: Plantae, (unranked): Angiosperms, (unranked): Eudicots, (unranked): Rosids, Order: Fabales, Family: Fabaceae

Subfamily: Faboideae, Tribe: Vicieae, Genus: Vicia, Species: V. faba

Fig 2: FAVA BEANS PLANT

FAVA BEANS:

It is a species of flowering plant in the pea and bean family Fabaceae. It is the main source of L-dopa, and when you take this on a regular basis, it will get converted to dopamine in your brain. Fava beans are cheaper and effective for quitting smoking and this organic herb can help you to stop smoking instantly.

Fig 3: FAVA BEAN SEEDS

DRUG PROFILE OF CYTISINE:

Chemical name:

1,5-Metano-8H-pyrido[1,2-a][1,5]diazocin-8-one, 1,2,3,4,5,6-hexahydro-, (1R)-

Generic name:

Baptitoxin; Laburnin; Sophorin

Chemical structure:

Fig 4: Chemical structure of Cytisine.

Properties Of Cytisine:

Molecular weight: 190.246g/mol, Melting point: 152-153°c, Boiling point: 218°c, Half life: 4.8 hrs, Clearance: renal: 43ml/min, Category: smoking cessation.

SOURCE:

Plant species that contain cytisine are found in several genera of the Faboideae subfamily of the Fabaceae family, including Laburnum, Anagyris, Thermopsis, Cytisus, Genista, Retama and Sophora. Cytisine is also present in Gymnocladus of the Caesalpiniodeae subfamily.

NEED FOR THE STUDY:

Tobacco smoking is widespread and is one of the world’s most prevalent modifiable risk factors for morbidity and mortality. About 6 million people die of tobacco use globally every year and India accounts for 1/6th of the total deaths. Tobacco use causes 1 death every 6 seconds. Tobacco epidemic: 2,500 die in India daily. An Indian Council of Medical Research (ICMR) report says that use of tobacco accounts for about 30% of all cancers in India. Mass media campaigns, graphic warnings and alternative crop options for tobacco growers can help stop or reduce the estimated 8-9 lakhs tobacco-attributable deaths per year in India, experts say.

SUSTAINED RELEASE DRUG DELIVERY SYSTEM:

The sustained release dosage form is defined as “any drug or dosage form modification that prolongs the therapeutic activity of the drug”. Once it reaches maximum level, the amount of drug in the body decrease slowly. So it will take longer time to drop below the therapeutic range. The terms sustained or controlled drug release incorporates the element of prolongation of duration of drug action as well as the drug predictability and reproducibility in drug release kinetics. Polymeric sustained drug delivery systems is the one which offer numerous advantages when compared with conventional dosage forms, including improved efficacy, reduced toxicity and improved patient compliance.

The short biological half life of drug (2.5 to 3.3 hrs) also favors development of sustained release⁶ formulations.

The goal of any drug delivery system⁷ is to provide a therapeutic amount of drug to the proper site in the body.

ADVANTAGES OF SUSTAINED RELEASE DOSAGE FORMS:

Improved patient compliance, less frequent dosing (by reducing number of doses), reduced night time dosing, and reduced patient care time, Decreased local and systemic side effects: Reduced Gastrointestinal irritation and other dose related side effects. Improve efficiency in the treatment, Optimized therapy. More uniform blood concentration, Reduction in fluctuation in drug level and hence uniform pharmacological response. Cure or control of condition more promptly Reduction in the incidence and severity of untoward systemic side effects related to high peak plasma drug concentrations Maintenance of the therapeutic action of a drug during overnight no dose period, Employ less total drug. It shows minimum drug accumulation on chronic dose Economy.

Pico technology⁵ was described as involving the alteration of the structure and chemical properties of individual atoms, typically through the manipulation of energy states of electrons within an atom to produce metastable (or otherwise stabilized) states with unusual properties, producing some form of exotic atom.

TREATMENT⁸:

Tablets or Vaccination and animal management techniques are most important in these efforts.

MATRIX SYSTEM:

The matrix system is commonly used for manufacturing dosage forms because it makes manufacturing easy. This system is based on the use of a bend of hydrophilic and hydrophobic polymer to sustain the drug release. The tablets are used for sustained release. The active ingredient is embedded in the matrix insoluble substances.

LITERATURE REVIEW^{9, 10}:

1. Review of the health benefits of Faba bean (Vicia faba L.) polyphenols:

Imma Turco et al.,

The dietary consumption of legumes is associated with a lower ncidence of chronic degenerative diseases. Among legumes, a growing interest is devoted to Faba bean (Vicia faba L.), also known as broad bean. Faba bean nutritional properties have been previously studied and several olyphenols (mainly flavonoids) have been evaluated in broad bean extracts. In our study, the literature on polyphenol content in different varieties of Faba bean and on factors that modulate their levels was reviewed. Also, data on bioaccessibility and bioavailability of the main polyphenols contained in Faba bean were reviewed. The molecular mechanisms, antioxidant, anti-inflammatory and anti-diabetic properties, by which Faba bean polyphenols could be involved in the protection against the development of human diseases are described.

2. Effect of processing variables on the canned quality of fava beans

Basima Sa’di et al.,

The preliminary studies showed that the "hardshell" condition which is characteristic of legumes is an obstacle in the processing of fava beans. This explains why longer blanching times were required in our studies. Based on the soaking and blanching study, it was found that the soaking time was highly significant. Additional observations indicate that as the soaking temperature was increased the soaking time required to reach the 55% level of water uptake decreased. The peroxidase test was another factor considered in the selection of our treatments. A negative peroxidase test is de-sirable to inactivate the enzymes particularly lipoxygenase which causes off flavors.

3. J. Mager et al.,

Metabolic effects of pyrimidines derived from fava bean lycosides on human erythrocytes deficient in glucose-6-phosphate dehydrogenase. Susceptibility to favism, an acute hemolytic crisis following ingestion of fava beans, has been shown to be associated with a genetically determined propensity to drug-induced hemolysis

4. Imma Turco et al.,

Review of the health benefits of Faba bean (Vicia faba L.) polyphenols. The dietary consumption of legumes is associated with a lower incidence of chronic degenerative diseases. Among legumes, a growing interest is devoted to Faba bean (Vicia faba L.), also known as broad bean. Faba bean nutritional properties have been previously studied and several polyphenols (mainly flavonoids) have been evaluated in broad bean extracts.

5. Imma Turco et al.,

Effect of processing variables on canned quality of the fava beans. The preliminary studies showed that the "hardshell" condition which is characteristic of legumes is an obstacle in the processing of fava beans. This explains why longer blanching times were required in our studies.

6. Mohseni Mehran S.M et al.,

The Simultaneous Determination of levodopa and Carbidopa from the Fava Beans. Green Peas and Green Beans by High Performance Liquid Gas Chromatography. The results of this study indicate that faba beans are a good source of natural L-dopa and C-dopa. The quantification of this capacity according to the stage and the plant part could be suitable for applications in the food industry and in plant medicine. The consumption of fava beans can increase the levels of L-dopa and C-dopa in the blood, with a marked improvement in the motor performance of the patients with parkinson disease, without any side effects.

METHOD OF EXTRACTION^{11, 12}:

The air dried aerial parts of plant where cut into a small pieces and where extracted with 99% methanol 3 times at room temperature. The combined extract where concentrated acidified with 5% Hcl and then extracted with diethyl ether 3times the aqueous layer was made alkaline with 25% ammonium hydroxide to pH (9-10) and extracted with chloroform 6times the chloroform extracts were combined and dried over anhydrous sodium sulfate and evaporated to dryness in vacuum to give crude alkaline mixture.

METHOD OF ISOLATION:

Column chromatography was performed on a classic 30cm long x 4cm diameter glass Column packed with 130gm of silica gel 60 (70-230 mesh). The ethyl acetate solution of 1gm of alkaloid fraction was applied to the top of column by use of a pipette. Elution was started with toluene then with solvent mixture with increasing polarities: toluene: acetone: diethyl amine. Finally all145 fractions (obtained by column chromatography) were monitored by analytical TLC (above mentioned solvent mixtures)

DIRECT COMPRESSION:

Direct compression is the simplest form of oral dosage production as it contains the fewest process stages, leading to the shortest process cycle and fastest production times.

The ingredients are weighed, blended and then compacted directly following lubrication.

EVALUATION TESTS:

1. Hardness

2. Thickness

3. Friability

4. Weight Variation Test

5. Drug Content

6. In vitro Dissolution Test

TABLET HARDNESS:

The resistance of tablet for shipping or breakage, under conditions of storage, transportation and handling, before usage, depends on its hardness. the hardness of tablet of each formulation was measured by using pfizer hardness tester.

TABLET THICKNESS:

Thickness of tablets was important for uniformity of tablet size. Thickness was measured by using screw gauze on 3 randomly selected samples.

FRIABILITY:

Friability is the measure of tablet strength. Roche Friabilator was used for testing the friability using the following procedure. Twenty tablets were weighed accurately and placed in the plastic chamber that revolves at 25 rpm for 4 mins dropping the tablets through a distance of six inches with each revolution. After 100 revolutions the tablets were re- weighed and the percentage loss in tablet weight was determined.

Initial wt. of tablets - Final wt. of tablets

% loss =---------------------------------------------------x 100

Initial wt. of tablets

Weight variation test:

Random selection of 20 tablets from each batch should be done and note down the weight of the tablet individually and check for any variation in its weight. According to US Pharmacopeias small variations in the weight is negligible and can be accepted. Below is the acceptable limit of percentage deviation in weight variation.

DRUG CONTENT¹³:

3 tablets from each batch were selected randomly and transferred to a 100 ml volumetric flask were, filled up with 0.1N HCL. Kept it for 48 hours then took 1ml from each of volumetric flask was transferred to the test tubes samples were then filtered, suitable diluted and analyzed spectrophotometrically at a suitable wavelength.

In vitro Dissolution Test¹⁴:

Dissolution is the method by which a solid solute enters a solution. Dissolution was carried out using USP dissolution apparatus II (Rotating paddle apparatus). Dissolution of tablets was carried out in 900ml dissolution medium. The dissolution medium for tablet was phosphate buffer pH 5.8. The temperature of the dissolution medium was maintained at 37^OC ±2^OC. The agitation intensity was 50 rpm.

RESULTS AND DISCUSSION:

TABLE NO 2: Evaluation Tests:

FORMULATION CODE	HARDNESS +SD	THICKNESS +SD	FRIABILITY +SD	WEIGHT VARIATION +SD	DRUG CONTENT +SD
F1	6.2 ±0.21	3.19 ±0.029	0.35 ±0.01	121.1±1.25	94.74 ±0.36
F2	6.3 ±0.28	3.20±0.043	0.34 ±0.03	120.1±1.21	95.52 ±0.23
F3	6.2 ±0.25	3.18 ±0.073	0.36 ±0.05	119.1±1.42	96.66 ±0.53
F4	6.3 ±0.24	3.17 ±0.053	0.32 ±0.04	122.1±1.16	98.53 ±0.34
F5	6.4 ±0.27	3.16 ±0.075	0.36 ±0.02	118.1±1.53	96.16 ±0.16
F6	6.5 ±0.25	3.18 ±0.093	0.34 ±0.08	121.1±1.46	94.43 ±0.82

TABLE NO 3: In Vitro Dissolution Test

Time (h)	% Release of Drug in SD (Standard Deviation)
Time (h)	F1	F2	F3	F4	F5	F6
0.5	2.24 ±0.15	2.23 ±0.30	1.25 ±0.33	2.16 ±0.26	2.05 ±0.38	2.05 ±0.31
1	7.48 ±0.51	6.46 ±0.36	4.43 ±0.73	5.39 ±0.36	3.36 ±0.37	4.34 ±0.73
1.5	10.49 ±0.46	8.23 ±0.37	8.25 ±0.92	8.30 ±1.08	9.23 ±0.73	6.08 ±0.92
2	14.24 ±0.13	11.49 ±0.55	13.12 ±0.37	12.88 ±1.28	12.13 ±0.75	8.91 ±0.56
3	25.75 ±1.46	25.23 ±0.97	19.94 ±0.97	23.78 ±1.46	16.59 ±0.95	15.55 ±0.97
4	41.46 ±0.46	38.16 ±0.97	31.99 ±0.94	36.13 ±1.40	32.97 ±0.95	25.17 ±0.94
5	52.29 ±0.23	49.49 ±0.95	41.33 ±0.97	47.00 ±1.22	43.33 ±0.47	34.27 ±1.21
6	62.75 ±0.23	58.46 ±0.73	45.90 ±0.47	54.10 ±0.98	53.63 ±0.96	45.44 ±0.97
7	71.86 ±1.49	68.16 ±0.73	50.37 ±0.72	66.11 ±1.46	63.15 ±1.21	54.15 ±0.93
8	83.79 ±1.46	75.46 ±0.72	64.81 ±0.92	74.56 ±0.74	73.77 ±0.73	66.80 ±0.97
9	91.48 ±1.13	83.16 ±0.71	72.81 ±1.21	80.95 ±0.97	79.11 ±0.47	71.83 ±0.73
10	92.76 ±0.23	87.76 ±0.49	75.97 ±1.22	85.79 ±0.97	81.59 ±0.96	74.61 ±0.73
11	95.78 ±0.46	90.13 ±0.97	81.60 ±1.94	86.71 ±0.73	83.17 ±0.73	75.86 ±0.97
12	97.46 ±0.89	93.49 ±1.21	84.02 ±1.47	91.78 ±0.71	84.89 ±0.74	92.10 ±1.21

Fig 5: In-vitro dissolution studies.

CONCLUSION:

The sustained release matrix tablet of cytisine was prepared by direct compression. Formulation F1-F6 is considered to be the best with the desired drug release. The polymers which have been used in the best formulation F3 containing polymer (HPMC K₄M) release can be so well controlled that it almost coincides the theoretical release pattern for the drug by proper adjustment of polymer ratio Hence the mono layer tablet designed possesses all the qualities of a sustained release formulation.

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Received on 20.05.2018 Modified on 28.06.2018

Res. J. Pharma. Dosage Forms and Tech.2018; 10(3):133-138.

DOI: 10.5958/0975-4377.2018.00021.6

FORMULATION CODE	DRUG (mg)	POLYMER		MCC (mg)	MAGNESIUM STEARATE (mg)
FORMULATION CODE	Cytisine	HPMC K₄M (mg)	HPMC K100M (mg)	MCC (mg)	MAGNESIUM STEARATE (mg)
F1	6	8	-	103.6	2.4
F2	6	16	-	95.6	2.4
F3	6	24	-	87.6	2.4
F4	6	-	8	103.6	2.4
F5	6	-	16	95.6	2.4
F6	6	-	24	87.6	2.4