Design and Development of Tramadol Hydrochloride Lozenges for Pediatrics

 

T. V. Rao*, K. Suma, K. Sahitya, A. Leelarani, A. Achireddy, P. Sreenubabu, N. Bhadramma

  Bapatla College of Pharmacy, Bapatla, Guntur (D.T)-522101 Andhrapradesh, India

 

ABSTRACT:

The illness are associated with fever, head ache and body aches so to cure the above/relief from the above, there was need to administer the drugs to the individuals, but in case of pediatric patients, it was difficult to administer the dosage forms like tablets, capsules, etc. There are many dosage forms available in the market but still there is a need for new dosage forms which acts effectively. In the present investigation an attempt has been made to prepare and evaluate the sugar based medicated tramadol hydrochloride hard lozenges for pediatrics to overcome the administration of dosage forms like tablets, capsules, etc. The lozenges were prepared by heating and congealing method on laboraty scale with corn syrup as base. All the formulations prepared were subjected to various physico-chemical parameters such as hardness, friability, content uniformity, weight variation, thickness, drug content and in vitro dissolution studies. Drug-excipients compatability studies were conducted by FT-IR spectroscopy and results revealed that no interactions were found between drug and excipients. The results of of in vitro drug release studies showed that formulations F3, F6 and F9 releases the drug 94.32, 95.42 and 95.66 percentage at the end of 30 mins. The hard lozenge can provide an attractive alternative formulation in the treatment of pain in pediatric patients.

 

 

 

INTRODUCTION:

The “Lozenges are flavoured medicated dosage forms intended to be sucked and hold in the mouth or pharynx¹,^2,3. These preparations are commonly used for the purpose of local or systemic effect”. Advantages of the Lozenges as dosage forms include increasing bioavailability, reduction in gastric irritation, bypass of first pass metabolism and increase in onset of action. New drug design to this area always benefit for the patient, physician and drug industry.

 

 

There are several dosage forms like in the market, there is a need for more dosage forms which acts effectively and locally as well as systemically. Oral thrush is a disorder caused by infection of the mouth due to fungus (yeast) candida albicans. In babies it may be a severe infection sometimes causing epidemics in schools by cross-infection. Tramadol hydrochloride tablet lozenges^4,5 are flavoured medicated dosage forms intended to be sucked and hold in mouth/pharynx. The present investigation is designed to improve patient compliance. These preparations are commonly used for the purpose of local or systemic effects through the buccal mucosa. Advantages of the Lozenges as dosage forms includes increases in bioavailability, reduction in dose size, and reduces gastric irritation, bypass first pass metabolism. When it is not effectively treated, oral thrush⁶ often leads to hospitalization, limitations on physical activity, insomnia nights and in some cases death.

 

MATERIALS AND METHODS:

MATERIALS:

Tramadol hydrochloride, a sample from hetero pharmaceuticals, HPMC300 cps from Fisher scientific products, Mumbai, Na CMC from fisher scientific products, Mumbai, methyl cellulose from S d fine chem. limited, Mumbai, citric acid from yarrow chem. Products, Mumbai, calcium carbonate from yarrow chem. Products. Mumbai, menthol from yarrow chem. Products. Mumbai, sucrose from local market bapatla, corn syrup from rajyalak shmienter prises, Hyderabad.

 

PREFORMULATION STUDIES:

Drug-excipient compatibility studies

The compatibility between tramadol hydrochloride and polymers ((HPMC, Na CMC, MC) used in the present study was carried out by FT-IR spectrophotometer. The spectrum was recorded in the wavelength region of 4000-400^cm-1. the spectra obtained for tramadol hydrochloride, HPMC, Na CMC, Methyl cellulose and the physical mixture of the drug and polymers were recorded

 

Preparation of Tramadol hydrochloride hard lozenges⁷:

Tramadol hydrochloride hard lozenges are prepared in laboratory scale by heating and congealing technique, the composition as given in Table no1. Required quantity of liquid glucose and sucrose are transferred into a copper bowl and then heated in a heating mantle at 150°C for 15 minutes. Then the temperature of the mixture was brought into 90°C, then polymers (HPMC, Na CMC, MC) Drug, flavor, calcium carbonate were added with stirring by using glass rod and the solution was transferred into a lubricated mould. It was allowed to cool for solidification, lozenges were collected and packed in a aluminum foil.

 

Table 1. THE COMPOSITION OF TRAMADOL HYDROCHLORIDE HARD LOZENGES:

S.no	Ingredients(mg)	Formulations
		F1	F2	F3	F4	F5	F6	F7	F8	F9
1	Tramadol hydrochloride	23	23	23	23	23	23	23	23	23
2	HPMC-3000cps	100	300	500	_	_	_	_	_	_
3	Sodium CMC	_	_	_	100	300	500	_	_	_
4	Methyl cellulose	_	_	_	_	_	_	100	300	500
5	Citric acid	50	50	50	50	50	50	50	50	50
6	Calcium carbonate	5	5	5	5	5	5	5	5	5
7	Menthol	50	50	50	50	50	50	50	50	50
8	Sucrose	2000	2000	2000	2000	2000	2000	2000	2000	2000
9	Corn syrup	1772	1572	1372	1772	1572	1372	1772	1572	1372

Each lozenge weighs 4 gm

 

EVALUATION OF TRAMADOL HYDROCHLORIDE LOZENGES⁸:

The formulated lozenges and were evaluated for the following parameters.

 

Thickness:

The thickness and diameter of the formulated lozenges were measured by using Vernier callipers.

 

Weight variation:

The formulated lozenges were tested for weight uniformity. 20 tablets were collectively and individually. From the collective weight, average weight was calculated. Each lozenge weight was then compared with average weight to as certain whether it is within permissible limits or not.

 

 

Hardness:

The lozenge crushing strength, which is the force required to break the lozenge by compression in the diametric direction was measured in triplicate using Pfizer tablet hardness tester.

 

Friability:

The Roche friability test apparatus was used to determine the friability of the lozenges. 5 pre weighed lozenges were placed in the apparatus, which was subjected to 100 revolutions. Then the lozenges were reweighed. The percentage friability calculated was using the formula.

 

Friability (%)=

 

Drug content⁹:

Lozenges were weighed and powdered. The quantity of powder equivalent to 100 mg of was dissolved in buffer diluted to 100ml with buffer then the solution was filtered and suitably diluted. The drug content was estimated spectrometrically.

 

In-vitro dissolution studies:

The rate of the drug absorption was determined by the rate of drug dissolution from the prepared formulations. Thus the rate of dissolution and bioavailability may be directly related to the efficiency of the formulation. In vitro dissolution studies were carried out in 900 ml phosphate buffer PH 6.8 using USP dissolution testing apparatus 2 (Model TDT 08L, Electro lab, Mumbai India) with a rotating stirrer speed at 100 rpm and temperature of dissolution medium maintained at 37± 0.5°C.5ml of aliquots were withdrawn at regular intervals, filtered and same amount of fresh dissolution medium was replaced at the same temperature. The filtered solutions were analyzed by using (Shimadzu, Japan) UV- spectrophotometer at 271 nm.

 

RESULTS AND DISCUSSION:

Patient compliance is one of the important aspect for administration of drugs and attractive, taste masking, ease of administration are also needed to the patient. In the present study Tramadol Hydrochloride sweetened lozenges were designed and evaluated for effective treatment of pain in children. Drug-excipients compatability studies i.e Tramadol Hydrochloride and polymers (HPMC, NaCMC, and MC) compatibility studies were conducted by using FT-IR spectral studies. The results of IR spectra of Tramadol Hydrochloride and polymers (HPMC, NaCMC, MC )individually and the physical mixture of Tramadol Hydrochloride and polymers (HPMC, NaCMC, MC) suggested that the characteristic peaks observed in Tramadol Hydrochloride pure samples were mostly identical with the peaks in the physical mixture of Tramadol Hydrochloride and polymers (HPMC, NaCMC, MC) adhering within their ranges without changes in the functionalities indicating their compatibility results given in table no 2 and fig 1,2,3,4,5,6,7 and 8. For formulation development, drug excipient interactions play an important role. So, formulations were subjected to compatability studies, so finally it was observed that there was no additional peaks in drug-polymer mixture and hence formulations were developed with the selected polymers in the second stage of present investigations.

 

Studies on Tramadol hydrochloride hard lozenges formulated with HPMC 3000CPS:

The prepared tramadol hydrochloride hard lozenges evaluated for physico-chemical parameters like hardness, friability, content uniformity, weight variation, thickness and drug content, results reported in the table no 3. The Thickness of tramadol hydrochloride hard lozenges for the formulations F1, F2, F3 were14.7±0.34, 14.4±0.28 and 14.6±0.13 mm, % weight variation was found to be 3.16±0.35, 3.56±0.22, 2.78±0.41, hardness of the formulation was to be 16.5±0.2816. 1±0.4116. 4±0.33kg/cm², % Friability was 0.95±0.35, 0.89±0.41, 0.92±32 and %drug content was found to be 97.3±0.23, 96.76±0.48, 95.74±0.32 the results revealed that all the formulations were observed in the pharmacopiea limits. In vitro drug release studies were conducted and the % of drug release for F1, F2, F3 was 91.70, 93.73, 94.14 observed at the end of 25, 25 and 30mins, percent drug release profiles of these formulations depicted in fig 8 and drug release data fitted into various kinetic equations, drug release mechanism exhibits first order kinetics depicted in fig 9 and results given in table no 4.

 

 

Figure 1. IR spectra of tramadol hydrochloride

 

 

Figure 2: IR spectra of HPMC

 

 

Figure 3: IR spectra of Na CMC

Table2. IR SPECTRAL VALUES FOR PHYSICAL MIXTURE OF DRUG AND EXCIPIENTS

Functional group	Observed wave number (cm-1)
	Tramadol hydrochloride	Physical mixture of Tramadol hydrochloride with polymers
		HPMC	Na CMC	MC
O-H stretching	3305.25	3305.83	3305.61	3305.77
C-O stretching of ethers	1045.70	1045.65	1045.28	1045.63
C-H stretching of alkyl group	2930.45	2930.29	2929.90	2930.25
C-H deformation of alkyl group	1480.42	1479.98	1480.36	1479.82
C=C of aromatic ring	1607.27 1579.16	1607.30 1579.05	1607.26 1578.92	1607.391579.09
Aromatic mono substituted C-H deformation	702.69	702.83	702.78	702.79

 

Table 3. EVALUATION PARAMETERS OF TRAMADOL HYDROCHLORIDE HARD LOZENGES USING CORN SYRUP AS BASE

Formulations	Thickness (mm)	Weight Variation (%)			Drug content (%)
			Hardness (kg/cm2)	Friability (%)
F1	14.7±0.34	3.16±0.35	16.5±0.28	0.95±0.35	97.3±0.23
F2	14.4±0.28	3.56±0.22	16.1±0.41	0.89±0.41	96.76±0.48
F3	14.6±0.13	2.78±0.41	16.4±0.33	0.92±0.23	95.74±0.32
F4	14.5±0.35	2.55±0.23	16.8±0.32	0.97±0.42	98.34±0.26
F5	14.7±0.41	3.45±0.22	16.3±0.22	0.91±0.31	97.92±0.37
F6	14.5±0.22	3.56±0.15	16.9±0.11	0.93±0.15	98.6±0.11
F7	14.6±0.26	2.99±0.32	16.7±0.21	0.93±0.42	96.87±0.36
F8	14.7±0.13	3.14±0.27	16.4±0.52	0.97±0.26	98.8±0.14
F9	14.8±0.35	3.32±0.14	16.3±0.31	0.94±0.41	95.4±0.23

 

Table 4: IN-VITRO DRUG RELEASE KINETICS OF OF TRAMADOL HCl HARD LOZENGEs

Formulation	Correlation coefficient values		Release rate constant (K)(min1)	T50 (min)	T90 (min)
	Zero order	First order
F1	0.9231	0.9785	0.085	8.15	27.09
F2	0.9012	0.9921	0.099	7	23.2
F3	0.8976	0.9879	0.088	7.87	26.17
F4	0.8965	0.9658	0.098	7.07	23.5
F5	0.9076	0.9788	0.107	6.47	21.5
F6	0.9103	0.9678	0.0996	6.95	23.1
F7	0.8956	0.9895	0.091	7.61	25.3
F8	0.9032	0.9523	0.101	6.86	22.8
F9	0.9034	0.9443	0.104	6.66	22.14

 

Studies on Tramadol hydrochloride hard lozenges formulated with NaCMC:

The prepared tramadol hydrochloride hard lozenges evaluated for physico-chemical parameters like hardness, friability, content uniformity, weight variation, thickness and drug content, results reported in the table no 3. The Thickness of the formulations F4, F5, F6 was found to be14.5±0.35, 14.7±0.41, 14.5±0.22, % weight variation was found to be 2.55±0.23, 3.45±0.22, 3.56±0.15, hardness of the formulations were 16.8±0.32, 16.3±0.22, 16.9±0.11kg/cm²,% Friability was 0.97±0.42, 0.91±0.31, 0.93±0.15% and % Drug content was observed 98.34±0.26, 97.92±0.37, 98.6±0.11 %. The % drug release for F4, F5, F6 are 91.7, 93.6, 93.7observed at the end of 25, 25 and 30minS.The % Drug release profiles of these formulations depicted in fig 10 and drug release data fitted into various kinetic equations, drug release mechanism exhibits first order kinetics depicted in fig 11, results reported in table no 4.

 

 

 

 

Studies on Tramadol hydrochloride hard lozenges formulated with MC:

The Thickness for formulations F7, F8, F9 is 14.6±0.2614.7±0.13, 14.8±0.35. The % weight variation was found to be 2.99±0.32, 3.14±0.27, 3.32±0.14, hardness of the formulations were16.7±0.21, 16.4±0.52, 16.3±0.31kg/cm², % friability was 0.93±0.42, 0.97±0.26, 0.94±0.41% and % drug content was found to be 96.87±0.36, 98.8±0.14, 95.4±0.23 %. The % drug release for F7, F8, F9 was 93.2, 94.6, 95.8 observed at the end of 25, 25 and 30minS.The % drug release profiles of these formulations depicted in fig 12 drug release data fitted into various kinetic equations, drug release mechanism exhibits first order kinetics depicted in fig 13, results reported in table no 4.

 

 

Figure 4: IR spectra of methyl cellulose

 

 

Figure 5: IR spectra of physical mixture of trmadol hydrochloride + HPMC

 

 

Figure 6: IR spectra of physical mixture of trmadol hydrochloride+Na CMC

 

 

Figure 7: IR spectra of physical mixture of trmadol hydrochloride + methyl cellulose

 

Figure 8: invitro dissolution % drug release profiles of tramadol hydrochloride hard lozenges formulated with HPMC using corn syrup as base

 

 

Figure 9: first order plots of tramadol hydrochloride hard lozenges formulated with HPMC by using corn syrup as base

 

 

Figure 10: invitro dissolution %drug release profiles of tramadol hydrochloride hard lozenges formulated with NaCMC using corn syrup as base

 

 

Figure 11: first order plots of tramadol hydrochloride hard lozenges formulated with NaCMC using corn syrup as base

 

Figure 12: invitro dissolution %drug release profiles of tramadol hydrochloride hard lozenges formulated with MC using corn syrup as base

 

 

Figure 13: first order plots of tramadol hydrochloride hard lozenges formulated with MC using corn syrup as base

 

In order to enhance the flow of saliva an acid lent is employed in the dry mouth lozenges. These are generally present in amount ranging from about 0.1 to 0.5% by weight of lozenges.

 

Corn syrup allows the production of pleasent tasting product for the delivery of tasting of tramadol hydrochloride. The unique proportion of this vehicle are preserved in the final form while contain active ingredients which modifies the stimulatory taste receptors in the oral cavity to the extents of suppressing bitterness and other forms of unpleasant taste imported by actives.

 

The maximum amount of drug was released from the formulations formulated with sodium CMC and HPMC 3000 cps at the end of 30 mins (F6, F7) due to the chemical structure and gelling of swellable property of the polymers ie viscosity of gelling formation by the polymers, while penetration of the saliva/media and also corn syrup as vehicle was responsible for the release of drug. This novel product which is recognized to be unique to its delivery system and made it on lab scale and industrial scale for the treatment of pain in the children and compatabile to the patients, by the consumer for fast result when compared to the tablets/liquid preparations.

CONCLUSION:

From the present study it was suggested that corn syrup based tramadol hydrochloride will be ideal dosage forms for the treatment of pain to the pediatrics. By incorporation of synthetic polymers yields good results and release the drugs for a prolonged period of 30 mins. Lozenges by their nature are intented to slowly dissolve in the mouth over a relatively long period of time. Eg; usually about 2-15 mins or more as needed. The taste bud and olfactory senses are able to detect even the slightest bitterness of unpleasant mouth feel and taste during such a long residence time in the mouth represents a substantial challenges it is desirable to provide a palatable dosage form of tramadol hydrochloride hard lozenges.

 

REFERENCES:

1.       Gilbert S. Banker, Neil R. Anderson. Tablets Leon Lachman Herbert A. Liberiman. Theory and Practice of Industrial pharmacy edition3rd 1987; 331

2.       Harsh Mohan. “The oral cavity and salivary Glands”. Text book of Pathology .4th edn, Jaypee Brothers, Medical Publishers (P) Ltd, New Delhi,2000; 494-96.

3.       Ross and Wilson. “Anatomy and Physiology in health and illness–Diseases of the mouth”.9th edn, Churchill Livingstone, 2001; 319.

4.       Larry L Augsburger, Stephen W Hoag. “Formulation of Specialty Tablets for Slow Oral Dissolution”. Loyd V. Pharmaceutical dosage forms: tablets: Rational design and formulation. 3^rd Edition, AllenUniversity of Oklahoma college of pharmacy, Oklahoma City, Oklahoma, U.S.A. (2), 2009; 361-81.

5.       N.K. Jain. “Mucoadhesive Drug Delivery”. Controlled and Novel Drug Delivery. Edition-5, CBS Publishers and Distributors, New Delhi, 2005; 353-76.

6.       Marcel Dekker. “Medicated Lozenges”. Marcel Dekker Inc. 2^nd Edn. New York and Basel, 1991;339-467.

7.       Purushotham RK, Shivappa NN, Zakaullah S, Arshiya SA, Ashok KC, Anand C. “Mediacted lozenges of ketoconazole for pediatric oral thrush patients”. Int J Inst Pharm LifeSc 1 (3), 2011;25-33.

8.       Dharamjit P, Saumya D. “Formulation development and optimisation of paracetamol medicated lozenges for pediatric use”. Int J Pharm Sci Res 3 (1), 2012;138-40.

9.       Rajesh K, Mahalaxmi R, Deepak K. “Investigating the suitability of isomalt and liquid glucose as sugar substitute in the formulation of salbutamol sulfate hard candy lozenges”. J Chem and Pharm Res 3 (4), 2011; 69-75.

 

 

 

 

 

 

 

 

 

 

 

Received on 24.03.2018        Modified on 25.04.2018

Accepted on 30.04.2018       ©A&V Publications All right reserved