Preparation Of Nicotinamide Stick

Published Date: 02 Nov 2017

ABSTRACT

Acne is one of the most common skin diseases in the world. Although the patients usually don’t experience any pain, they will be annoyed by its physiological and dermatological problems especially cosmetically. This study was designed to show the efficacy of Nicotine amid as a stick in treating acne. Nicotine amide is vitamin B3 drug that can be used as an antimicrobial agent without the side effects of antibiotics. Also it has moisturizing and anti-inflammatory properties. To prepare stick formulation, various materials have been studied and some of them were chosen that had enough compatibility with nicotinamide and had no side effect on the skin. The water soluble formulation of stick was selected which was consisted of stearic acid, sodium hydroxide, propylene glycol and water. The pharmaceutical properties of the formulation such as consistency, transparency, spread ability on skin and pH were evaluated. The release of nicotine amid was studied by cell-France method and using cellulose sheet in buffer 6.8. The stability of formulation was studied at room temperature. For evaluated of anti-microbial effect of nicotinamide stick used staphylococcus aurous and wells plate method. The results show that the formulation was the desirable formulation which had pH 8.2, spread ability of ++, melting point 53.3˚C and freezing point 51.8˚C, respectively. The use of propylene glycol in this formulation as an enhancer helps the absorption of the drug. The microbial test shown that nicotinamide stick had anti-microbial effects; the zone of inhibition was about 15mm. This study showed that the stick form of nicotine amid is one of the most effective drug forms to cure the acne, because it is easy to use and just affects the area that is supposed to.

Keywords: Nicotinamide, Acne treatment, Medicated sticks.

Introduction:

Acne vulgaris is a common complex multifactorial skin disease1. It’s an inflammatory disease of pilosebaceous units which is characterized by the comedown’s formation. Acne occurs most frequent on face, neck, upper trunk, and upper arm2-4. Various factors for acne include hormonal activity, oily skin production, dirty skin, stress hyperactive sebaceous glands, and in females: menstruation, scrubbing of skin and contraceptive pills.

Staphylococcus epidermises and Propionibacterium acnes found in normal skin5-8; Propionibacterium acnes (P. acnes) – a Gram positive anaerobic microbial species– is caused pathogenic process of acne9-11. Acne occurs in girls more than boys, but the severity is more in boys. The prevalence is about 25-85 percent in the age 12-24years old1. We can cure the acne early to prevent scaring and reduce the treatment duration. Acne has different treatments such as Benzoyl peroxide, Topical retinoid, Antibiotics, Hormonal therapy and Nicotinic acid.

Benzoyl peroxide has bacteriostatic and comedolytic activity. It`s the first line therapy for inflammatory and non- inflammatory acne. It`s in the forms of lotions, creams, gels with 5%, 10% concentration. The gel forms are the most effective ones and also the most irritant ones12, 13.

Topical retinoid don’t have any antibacterial activities so that they used to be benzoyl peroxide or other antibiotics. They are in the forms of lotions, creams and gels. They cause open clogged pore. Photo-irritancy is one of the side effects of retinoid derivations that we can use sunscreen; other side effects are erythema, dryness especially dryness of lips and eyes, arthralgia, myalgia and lower back pain and depression14-16. It is necessary to check liver enzymes, cholesterol and triglyceride plasma concentration before and during treatment12, 17. Antibiotics include topical and systemic forms such as oral tetracycline and clindamycin, oral and topical erythromycin. Topical forms may cause Dryness and erythema in contact area and create contact allergic dermatitis infrequency. When acne is resistant to topical antibiotics or covers large areas of the body we can use oral forms because they overtake to skin sorely, cause liver and kidney disorder and GI dysfunction. These agents must be given at full dose for at least 3-4 months18-20. Hormonal therapy are often more effective than other ones in women; treatment should be taken for at least six to twelve months beside topical therapy but the first signs of response were seen after six to eight weeks. Topical therapy and hormonal therapy should continue together. Oral contraceptives that can be used include cyproterone and ethinylestradiol21-24. Nicotinic acid is one of the vitamin B groups (B3) with moisturizing, lightening, anti-irritation and anti-biotic effects without the side effects of antibiotics 25-30. The other names of nicotinic acid are vitamin pp, bionic and niacin 25. It can be used for mild to moderate acne31, 32. Some of side effects include dry skin, irritation, peeling, itching and redness 34- 39. Some studies showed that the nicotinamide gel is effective in decreasing the severity of acne40.

Many patients express difficulty in application of ointments, creams, gels etc. results in noncompliance and ineffective therapy. Recent advances in novel drug delivery systems (NDDS) help to increase efficacy and safety of drug components by using a new formulation and it will cause better patient compliance. One such approach is medicated sticks. An advantage of this drug delivery system includes patient compliance, convenience for efficient treatment include application without fingertip, immediate onset of action, reduced dosage regimen and economy41.

Materials and Methods:

Stearic acid (Merck, Germany), 1,2propan-diol (Merck, Germany), NaOH (Merck, Germany), Nicotinamide (Loba chemie Pvt. Ltd., Mumbai), purified water were used. Staphylococcus aurous (ATCC 1112), Nutrient-agar (Merck, Germany) and Nutrient-broth (Merck, Germany) were used for microbial test.

Preparation of nicotinamide stick

Medicated sticks of nicotinamide were prepared by heating and congealing according to the formulae given in Table1. Depending upon the speared ability, melting point, and other properties of non-medicated derma sticks, the formulae is chosen for the incorporation of the drug. Stearic acid was heated up to 75ºC in container on the water bath and melted (oily phase). Dissolved NaOH in purified water and made a NaOH solution so added to propylene glycol, heated the solution up to75ºC (aqueous phase). Added the aqueous phase slowly to the oily phase, stirring constantly about 10 minute and then Nicotinamide solution (Nicotinamide in water) –that was heated up to 45ºC- was added to them at this temperature with continuous stirring in order to get a uniform mixture in optimized formulation. The warm mixture was poured into the stick mould and cooled to get the desired shape of stick.

Preparation of inoculum and seed layer

Staphylococcus aurous was purchased from PTCC and sub cultured on Nutrient Agar at 37°C for 24 hours. The inoculum of staphylococcus was prepared by suspension of colony in Nutrient-broth and its concentration was measured in 580 nm by UV spectrophotometer for 108 CFU/ml. This microbial suspension was diluted to 105 CFU/ml. For preparation of seed layer 1 ml of 105staphylococcus aurous suspension was added to 9 ml nutrient-agar, so the microbial suspension concentration was reached to 104. The seed layer was poured on the base layer which prepared with nutrient agar to the plate.

Evaluation of sticks

Evaluation of sticks includes weight, thickness, length, pH, spreading, drug content, drug diffusion and microbial test.

For weight, thickness and length three sticks were selected randomly and weighed individually. For determination of weight variation the individual weights were compared with the average of three weights. As the shape of the stick is cylindrical the thickness and length was determined with the help of screw gauge and vernier caliper respectively. The average thickness was measured, by observing thickness at three different parts of the stick. For evaluation of drug content uniformity the stick equivalent to 20 mg of nicotinamide was extracted with methanol and liquid was filtered. The nicotinamide content was determined by measuring absorbance at 263 nm after suitable dilution with methanol. The drug content was calculated using the standard calibration curve. To find the mean percent, calculating the average of three determinations was done. For evaluation of in vitro drug diffusion using permeation cell which is made up of a glass cylinder with two walls, 10 cm height, 3.7 cm outer diameter and 3.1cm inner diameter. A cellulose membrane was fixed to the one end of the cylinder. Stick containing 0.4 mg of nicotinamide was taken on the cellophane membrane on the cylinder containing 30 ml of drug free pH 6.8 phosphate buffer. That cylinder was agitated using a magnetic stirrer and a temperature of 37ºC ± 1°C was maintained. Samples (1 ml) were withdrawn at specified intervals over a period of 160 min and analyzed for drug diffusion by measuring the absorbance at 263 nm. The volume of sample withdrawn at each interval was replaced with a fresh quantity of 6.8 phosphate buffer. Cumulative percent of nicotinamide released was calculated and plotted against time.

To evaluate anti-bacterial effect of Nicotinamide stick, well plate method was used .The wells were prepared by putting pastor pipet in solid agar (contains base and seed layers) with 9mm diameter.in each plate two wells were prepared which one of them was for Nicotinamide (with pH=7) and the other one was for mupirocin as blank. The suitable amount of sample and blank (about 20µg) put on the wells and the plate incubate for 24 hours in 37ºC. The zone of inhibition was measured in mm. this test was repeated 3 times.

Short-term stability studies on the selected formulation (A3) were carried out by storing the sticks at room temperature for a period of three weeks. At intervals of one week the sticks were examined for drug content uniformity and any physical change.

Results:

A total of six formulations were designed as the material was uniformly filled in mould with uniform length and diameter. Among the formulations, various concentrations of stearic acid (3.50- 6.80% w/w) was employed as stiffening agent as shown in Table 1. The drug content was found to be 93.3 to 96.56% as shown in Table 2. The in vitro drug diffusion was carried out for A3 formulation in pH 6.8 phosphate buffer over a period of 160 minutes as shown in Table 5. The percentage drug release is depicted in Fig.1. The data reveals that overall, formulation A3 showed 71.75% of drug release in 160 minutes.

The results in table1 and table 2 show that the more 1,2propan-diol and less stearic acid cause increase the amount of active ingredient will be releasing. Other results were carried out for A3 formulation are given in table 4.

The microbial test shown that nicotinamide stick had anti-microbial effects; the zone of inhibition was measured and compared with standard, it was about 15mm and for standard about 20 mm so the result was desirable.

Discussion:

Sticks have some good properties such as being portable, easy to use and change the dosage of administration for external use and applied directly to the affected site. Soft sticks are made of some ingredients as the base which have high and low melting point. Sometimes Material with a high melting point as the hardener is added. Medicated sticks of nicotinamide were prepared by heating and congealing method using stearic acid as stiffening agent and propylene glycol as cosolvent and humectant agent and cause drug permeation, while Nicotinamide provide potent anti-inflammatory and anti-bacterial activities without the risk of inducing bacterial resistance while it has lightening effect.

As it was mentioned in the tables and figures, absorbance of Nicotinamide in laboratory was studied and it increased by increasing the concentration of the nicotinamide in the 6.8 buffer. After that we used a piece of stick with a specific concentration of nicotinamide (that was known and it is mentioned in the diagrams) to indicate the absorbance of material in a period of time using cellulous paper. We read the absorbance of nicotinamide in specific times in the 6.8 buffer and calculated the concentration of nicotinamide and the result is shown in the diagram 1. We can understand from the diagrams and tables that about 71.75% of the nicotinamide that was used in that piece of stick was released in 160 min. So the drug release of this stick is favorable and we can test this product on the skin and be certain that the absorbance of that is desirable. Also other features of the stick were studied and we can say that this is one of the best products to use for treating the acne with a high degree of absorption and efficacy. It supposed to studied clinical efficacy of this product and compare with other products on the market. We can add salicylic acid to the formulation to increase effectiveness. Therefore the results are favorable add this form to drug list and Use it to topical medication for most product.

Also some studies have compared clindamycin phosphate 1% and nicotinamide 4%gel in treatment of acne and the result show that they are both similar in efficacy38.

In this study we just produced a model of nicotinamide stick with characteristics that are mentioned and evaluated the absorption of the nicotinamide stick in lab and microbial evaluation. So we suggest designing study and evaluating this product in group of patients who are suffering from acne.