Radiance Research AcademyInternational Journal of Current Research and Review2231-21960975-524125EnglishN-0001November30HealthcarePAINFUL DIABETIC PERIPHERAL NEUROPATHY- A CURRENT CONCEPTS REVIEW OF CLINICAL ASSESSMENT SCALES FOR USE IN RESEARCH AND PRACTICE
English0313P. Senthil KumarEnglish Prabha AdhikariEnglish Sydney C D’Souza. P.S JeganathanEnglishDiabetes is a global epidemic and one of the most leading complications of diabetes is peripheral neuropathy. Recent research and clinical practice focus is on symptomatic or painful diabetic peripheral neuropathy (PDPN). The objective of this review is to throw light on commonly used and wellestablished clinical assessment scales in PDPN patients. The various scales reported in the literature are describedchronologically in the review. This includes neuropathy disability score, neuropathy symptom profile, diabetic neuropathy symptom score, Michigan neuropathy screening instrument, neuropathic pain scale, neuropathy impairment score, Michigan diabetic neuropathy score, verbal neuropathy screening score, total neuropathy scale, diabetic neuropathy examination score, Leeds assessment of neuropathic symptoms and signs (LANSS) score, diabetic neuropathy symptom score, neuropathy-specific quality of life scale, neuropathic pain questionnaire (NPS), NPS- short form, brief pain inventory for diabetic peripheral neuropathy, neuropathic pain diagnostic questionnaire, short-LANSS score, and patient interpretation of neuropathy questionnaire. The review would facilitate researchers and clinicians to use these valid and reliable assessment scales in patients with painful diabetic peripheral neuropathy.
Englishmeasurement scales, diabetic neuropathy, neuropathic pain, clinical examination.Introduction
The term diabetes mellitus describes a metabolic disorder of multiple aetiology characterized by chronic hyperglycaemia with disturbances of carbohydrate, fat and protein metabolism resulting from defects in insulin secretion, insulin action, or both1 . The prevalence of diabetes for all age-groups worldwide was estimated to be 2.8% in 2000 and 4.4% in 2030. The total number of people with diabetes is projected to rise from 171 million in 2000 to 366 million in 2030. The prevalence of diabetes is higher in men than women, but there are more women with diabetes than men. The urban population in developing countries is projected to double between 2000 and 20302 . The microvascular complications of diabetes are termed collectively as "tripathy" which includes retinopathy, neuropathy and nephropathy and the macrovascular complications include peripheral vascular disease, cerebrovascular disease and cardiovascular disease3,4 . Diabetic peripheral neuropathy (DPN) is a common complication estimated to affect 30% to 50% of individuals with diabetes. Chronic sensorimotor distal symmetric polyneuropathy is the most common form of DPN. The prevalence of neuropathy in type 2 diabetes ranges from 27% to 63% and from 14% to 70% in diabetes mellitus in general.4 The higher prevalence of neuropathy in type 2 diabetes patients is related to greater age, male gender, longer diabetes duration, higher levels of glycosylated hemoglobin, lower HDL cholesterol, smoking; peripheral vascular disease and insulin use5 . Diabetic neuropathy has been defined as Peripheral somatic or autonomic nerve damage attributable solely to diabetes mellitus. It may be of two typessymmetrical and asymmetrical. The symmetrical type was the commonest and it affects the sensory and autonomic functions of mostly peripheral nerves whereas the asymmetrical type affects the cranial nerves in their sensory and motor functions.6 The first description of "diabetic neuropathy as a presence of pain and paresthesiae in lower limbs" was done by Rollo in 1798.7 The consensus of opinion at the San Antonio conference on diabetic neuropathy was that diabetic neuropathy was "a descriptive term meaning a demonstrable disorder, either clinically evident or subclinical that occurs in a setting of diabetes mellitus without other causes of neuropathy. The neuropathic disorder includes manifestations in both somatic and/or autonomic parts of the nervous system." Diabetic peripheral neuropathic pain (DPNP) affects approximately 11% of patients with diabetic peripheral neuropathy (DPN). The most common type of neuropathy in DM is DPN, with up to 50% of patients experiencing some degree of painful symptoms and 10% to 20% having symptoms severe enough to warrant treatment. A classic populationbased study found some degree of neuropathy in 66% of patients with DM. Among those with type 1 and type 2 DM, 54% and 45%, respectively, had DPN and 15% and 13%, respectively, were symptomatic.8 The purpose of this review paper is to describe the clinicians and researchers working on diabetes, diabetic peripheral neuropathy and neuropathic pain, to update on currently available assessment scales used for measurement purposes of screening, diagnosis and prognosis in this patient population. The scales are described chronologically below;
Materials and Methods
Independent search was carried out by testers using a well-defined search strategy as follows; We searched the databases- PubMed, CINAHL, EMBASE, SCOPUS, PROQUEST, OVID and Google scholar were searched using the key terms- neuropath*, scale, tool, questionnaire, inventory, score, instrument profile. A total of 112 studies were potentially identified by the authors. Studies published in English on development of a scale or measure was included and studies on comparison of scales (86 studies) or reliability (28) and validity (16) studies were excluded. Some of the excluded studies were on studying both reliability and validity (22 studies). A total of 19 studies were finally identified published from 1985 to 2006 and then considered for review. To avoid search bias, the testers performed independent searches and then disagreements were solved by consensus at various stages of the study. Results and main findings of the review: The 19 studies were on clinical assessment scales which are descriptively reported below;
Neuropathy Disability Score- NDS (1985)9 :
The total score of 10 based on four testsvibration perception threshold, temperature perception on dorsum of foot, pin-prick and Achilles reflex. Present/normal finding for first three tests is scored 0 and abnormal is given 1. The fourth test- Achilles reflex in addition has present with reinforcement scored 1 and abnormal/ absent is given score of 2. a score of greater than 3/10 indicates the presence of neuropathy which would be associated with profound disability.
Neuropathy Symptom ProfileNSP(1986)10:
NSP is a true-or-false questionnaire with several hundred questions about symptoms encountered in peripheral neuropathy, to be scored by optical reader and computer. Responses were grouped into scales called "Neuropathy," "Weakness," "Sensory," "Autonomic," and subsets of these.
Diabetic Neuropathy Symptom- DNS score (1988)11:
Patients were to be questioned regarding the presence or otherwise of symptoms, either positive or negative suggesting the presence of neuropathy. The questionnaire was the DNS score which was an adapted version of the earlier version- Neuropathy symptom score (NSS). The questions should be answered "yes" (positive- 1 point) if a symptom occurred more times a week during the last 2 weeks or "no" (negative- no point) if did not. The four questions were; Symptoms of unsteadiness in walking; burning/aching pain or tenderness of legs and feet; pricking sensations in legs and feet; and numbness in legs and feet. Score ranged from 0 to 4, where 0 indicated absence of polyneuropathy and 1-4 points indicated presence of polyneuropathy.
Michigan Neuropathy Screening Instrument- MNSI (1994)12:
MNSI has two parts- history and physical examination findings. The history part of MNSI questionnaire is self-administered by the patient. Responses are added to obtain the total score. Responses of "yes" to items 1-3, 5-6, 8-9, 11-12, 14-15 are each counted as one point. A "no" response on items 7 and 13 counts as 1 point. Item #4 is a measure of impaired circulation and item #10 is a measure of general asthenia and are not included in scoring. To decrease the potential for bias, all scoring information was eliminated from the patient version. The clinician?s portion based on physical examination consisted of the sum of scores varying from 0 to 1 for each abnormality revealed in foot appearance, Achilles reflexes presence and vibratory threshold (VPT) by tuning fork and monofilament testing.
Neuropathic pain scale- NPS (1997)13:
The NPS begins with an introduction that describes how people often experience pain sensations differently, and how pain unpleasantness differs from pain intensity. After the introduction, the NPS asks respondents to rate the severity of each of 10 pain domains by using 0 to 10 numeric rating scales, where 0 _ "no pain" or “not [sensation/item]" and 10 _ "the most [descriptor] pain sensation imaginable." The NPS items can be scored individually (to help identify a "profile" associated with a specific diagnosis or of the effects of a treatment on pain qualities) or can be combined into composite scores to determine the effects of treatments on pain quality overall. Because the quality of specific pain sensations can be distinguished from pain location (eg, deep, surface), the 6 NPS pain quality items (sharp, hot, dull, cold, sensitive, itchy) were combined into single composite measure of overall pain quality (NPS6) to help estimate changes after treatment on such a measure. In addition, a total NPS score (NPS10) created by averaging responses to all of the NPS items was computed to help explain the significant interaction and main effects that emerged from the analyses.
Neuropathy Impairment Score (NIS) and NIS (LL)-(1997)14:
The Neuropathy Impairment Score (NIS) was obtained by evaluating a standard group of muscles for weakness: 1, 25% weak; 2, 50% weak; 3, 75% weak; 3.25, movement against gravity; 3.5, movement with gravity eliminated; 3.75, muscle flicker without movement; and 4, paralyzed. A standard group of muscle stretch reflexes were graded as normal, 0; decreased, 1; or absent, 2. Touchpressure, vibration, joint position and motion, and pinprick were graded on index finger and great toe as normal, 0; decreased, 1; or absent, 2. For evaluating the NIS for the lower limbs (NIS(LL)), only neurologic abnormalities of the lower limb were to be tallied.
Michigan Diabetic Neuropathy ScoreMDNS,(1998)15:
MNSI scores together with quantitative neurological examination and electrophysiological evaluation constitute the MDNS score.
Verbal neuropathy screening score(1998)16:
The University of Texas Subjective Peripheral Neuropathy verbal questionnaire included 4 queries to identify the presence of burning, formication, numbness, and paresthesias: Do your feet ever feel numb? Do your feet ever tingle, as if electricity were traveling into your foot? Do your feet ever feel as if insects were crawling on them? Do your feet ever burn? A positive answer to any 1 of the 4 verbal questions constituted 1 point. A negative answer constituted 0 points.
Total Neuropathy Scale TNS and mTNSr (1999)17:
The scale has ten items each of which are scored on a five-point grading scale. The items include sensory symptoms, motor symptoms, autonomic symptoms, pin prick sensibility, vibration sensibility, deep tendon reflexes, muscle strength, vibration sensation with tuning fork % upper limit of normal, sural nerve sensory action potential % lower limit of normal, and common peroneal nerve compound muscle action potential % lower limit of normal. Total score ranges thus from 0 (normal) to 40 (abnormal). A score of ? 5 indicated the presence of significant neuropathy. The scale can also be used to detect changes with interventions as a prognostic measure. Modified 5-Item Total Neuropathy Scale- reduced (m-TNSr) version included five items from the original scale- sensory symptoms, pin sensibility, vibration sensibility, deep tendon reflexes and muscle strength scores thus making scores to range from 0 to 20. A higher score indicated severe neuropathy.
Diabetic Neuropathy Examination (DNE) score (2000)18:
This score was based on a thorough neurological examination, similar to its earlier version- the Neuropathy Disability Score (NDS). The DNE score consisted of eight items , two testing muscle strength, one tendon reflex, and five sensations. The maximum score is 16. A score of > 3 points is considered abnormal. Muscle strength- quadriceps femoris, tibialis anterior, ankle reflex, pinprick sensitivity, touch sensitivity, vibration perception, and joint position sensation. Only the right leg and foot are tested. The scores for each item include 0- normal and 1- mild/moderate deficit; muscle strength: MRC scale 3-4; reflex: decreased but present; sensation: decreased but present, and 2- severely disturbed/ absent; reflex- absent; sensation- absent. Maximum score was 16 points. A score of > 3 indicated presence of polyneuropathy.
Leeds Assessment of Neuropathic Signs and Symptoms- LANSS (2001)19:
Leeds Assessment of Neuropathic Symptoms and Signs Scale, which consists of five questions (pins and needles, red skin, sensitive skin, electric shock pain, burning pain,) and two clinical examination tests (allodynia, pin prick threshold) with cut off score of 12 or above out of a total score 24 indicating neuropathic pain with a sensitivity of 79% and specificity of 100% for identifying neuropathic pain.
Diabetic Neuropathy Symptom Score (2002)20:
The DNS score has the following items: (i) unsteadiness in walking, (ii) pain, burning or aching at legs or feet, (iii) prickling sensations in legs or feet, and (iv) numbness in legs or feet. Presence is scored 1, absence 0, maximum score 4 points. 0- absence of polyneuropathy and 1-4 indicated presence of polyneuropathy.
Neuropathy-specific quality of life NeuroQoL (2002)21:
The scale is a self-report measure which questions the presence and frequency of symptoms in the past 4 weeks. The first part has seven questions each of which are scored on a 5-point likert scale from "all the time" to "never." Each question is also accompanied with three options for bothersomeness (very much; some bother; none). The second part has on quality of perceived symptoms. The third part is for weakness, unsteadiness in standing and gait. The fourth part is on influence on work situations and finally on social influence and selfperceived quality of life .
Neuropathic pain questionnaire (2003)22 -
Neuropathic pain questionnaire consists of 32 items, for each of which patients are asked to rate their pain numerically from zero to hundred with anchors at either ends similar to visual analogue scale. The total discriminant function score at or above zero strongly indicates neuropathic pain.
Neuropathic pain questionnaire (short form):
(2003)23 - Neuropathic pain questionnaire (short form) was developed by the same authors with three items which were item subsets of the original neuropathic pain questionnaire which included tingling, numbness and increased pain due to touch, again with total discriminant score at zero or above for neuropathic pain.
Neuropathic pain symptom inventoryNPSI (2004)24:
NPSI assessed four distinct dimensions of neuropathic pain as a self administered questionnaire consisting of four distinct dimensions of neuropathic pain: spontaneous ongoing pain (6 items), spontaneous paroxysmal pain (4 items), evoked pain (4 items) and paresthesia/dysesthesia (4 items). Each item was to be scored from zero to ten numerical scale. Total score thus ranges from 0 to 180.
Brief Pain Inventory for Diabetic Peripheral Neuropathy- BPI-DPN (2005)25:
A version of the BPI modified specifically for use in assessing DPNP (BPI-DPN) was recently validated. Sensitivity using worst pain was 58% and specificity was 79%. The BPI-DPN uses 4 questions to assess pain severity (worst pain, least pain, average pain, and pain now) and 7 items to assess interference with daily life (general activity, mood, walking ability, normal work, relations with others, sleep, and enjoyment of life). Each question uses an 11-point scale (0 indicating no pain or effect to 10 indicating worst pain imaginable or completely interferes) and asks patients specifically about pain related to their diabetes during the past 24 hours. Item scores from 0 to 3 suggest mild pain or interference, whereas scores from 4 to 6 suggest moderate effect and those 7 or higher suggest severe pain or interference.
Neuropathic pain diagnostic questionnaire- DN4 (2005)26:
Neuropathic pain Diagnostic Questionnaire (DN4) consists of two questions (I and II) which were based on the interview of the patient and two questions (III and IV) were based on a standardized clinical examination. Question 1 has five items related to description of pain, question 2 has four items related to paresthesia or dysesthesia, question 3 has four items related to sensory deficits and; question 4 has four items related to evoked pain.
S- LANSS Score (2005)27:
This scale is a self-report measure which includes an initial numerical pain rating scale for "how bad is your pain" followed by pins and needles (0-5); colour changes (0-5); hypersensitivity to touch (0-3); electrical-shock sensation (0-2); burning sensation (0-1); response to gentle rubbing (0-5); and, response to gentle pressure (0-3). Total score ranges from 0 to 24 where a score ? 12 indicated presence of neuropathic pain.
Patient Interpretation of Neuropathy questionnaire- PIN-Q (2006)28:
The PIN questionnaire is a 44- item draft instrument which covered patients? 1) common-sense misperceptions about the nature of foot complications and their efforts to merge these beliefs with the practitioner?s diagnosis of DPN (illness identity), 2) levels of understanding of the causal links between DPN and foot ulceration and the self-care- and/or health care provider-related blame for the development of neuropathy/foot ulceration (causes), 3) perceptions of temporal unpredictability of foot ulceration (acute timeline), 4) foot selfcare efficacy beliefs and the perceptions that health care providers can prevent foot ulcers (controllability), 5) anticipation of foot ulceration and/or amputation (potential consequences), and 6) worry about these consequences.and anger directed at health care providers stemming from a perceived lack of a clear explanation about neuropathy and perceived lack of compassion (emotions). Responses to each statement were scored on a 5-point Likert scale (1 _ strongly disagree, 2 _ disagree, 3_uncertain, 4_agree, and 5_strongly agree).
Discussion
The review is a clinically and scientifically applicable of its kind for use both by clinicians and researchers involved with patients of painful diabetic peripheral neuropathy. Many of the scales are to be filled by patients10-13,16,20- 27 of which some of the scales study pain13,22,23,26 and its nature10-12,16,24,27 , whereas some others study the activity limitations25, and other study the impact on life-issues21,28; while some other scales are filled by clinicians9,14,15,17-19 . These scales are simple to understand, cost-effective, easy to administer and less-time consuming. In addition they are accurate and the scores are repeatable between testers and between test repetitions. Thus they form an invaluable part of clinical practice and research. Use of objective outcome measures not only improves documentation which the insurance payers demand but also improves interprofessional communication in a multidisciplinary rehabilitation. Some of the potential limitations of this review were the lack of meta-analysis of the tools and quality scoring of the diagnostic tools mentioned. Future research could be on developing a comprehensive clinical assessment tool to assess multifaceted impact of painful diabetic peripheral neuropathy on pain, activity limitation, clinical examination findings and psychosocial issues. We described the available clinical assessment scales for the most common yet most underestimated complication of the global epidemic which is further expected to rise due to our habits and lifestyle. The mentioned scales were previously studied for their diagnostic accuracy and responsiveness to change and hence they can be used by all health professionals involved in the treatment and/or research in patients with painful diabetic peripheral neuropathy.
Acknowledgments
The authors wish to acknowledge the developers of the scales and tools for granting permission to use the tools, and for developing and validating clinically and scientifically useful measures which can be used both for diagnosis and prognosis in patients with painful diabetic peripheral neuropathy.
Disclosures
This review was performed as part of review of literature for Doctoral thesis (PhD) of the first author.
Englishhttp://ijcrr.com/abstract.php?article_id=2242http://ijcrr.com/article_html.php?did=22421. World Health Organization. Definition, Diagnosis and Classification of Diabetes Mellitus and its Complications -Part 1: Diagnosis and Classification of Diabetes Mellitus. Report of a WHO Consultation. Geneva, 1999.
2. Wild S, Roglic G, Green J, Sicree R, King H. Global prevalence of diabetes- estimates for the year 2000 and projections for 2030. Diabetes Care 2004; 27:1047-1053.
3. Bell DSH. Current status of diabetes treatment. Southern Medical Journal 2002; 95: 24-29.
4. Deshpande AD, Harris-Hayes M, Schootman M. Epidemiology of diabetes and diabetes-related complications. Physical Therapy 2008; 88: 1254-1264.
5. Wheeler S, Singh N, Boyko EJ. The epidemiology of diabetic neuropathy. In. Veves A, Malik R. Eds. Diabetic Neuropathy: Clinical Management. Second edition, 2007, Springer.
6. Horowitz SH. Diabetic neuropathy. Clinical Orthopaedics and Related Research 1993; 296: 78-85.
7. Fernando D. Diabetic neuropathy: clinical features and natural history. International Journal of Diabetes in Developing Countries 1995; 15: 55-60.
8. Argoff CE, Cole BE, Fishbain DA, Irving GA. Diabetic peripheral neuropathic painclinical and quality of life issues. Mayo Clinic Proceedings 2006; 81(4, suppl): s3-s11.
9. Dyck PJ, Karnes JI, Daube J, O'Brien P, Service FJ. Clinical and neurological criteria for the diagnosis and staging of diabetic polyneuropathy. Brain 1985;108:861-80.
10. Dyck PJ, Karnes J, O"Brien PC, Swanson CJ. Neuropathy symptom profile in health, motor neuron disease, diabetic neuropathy and amyloidosis. Neurology 1986;53:1660-1664.
11. Dyck PJ. Detection, characterization and staging of polyneuropathy assessed in diabetics. Muscle Nerve 1988;11:21-32.
12. Feldman EL, Stevens MJ, Thomas PK, Brown MB, Canal N, Greene DA: Practical twostep quantitative clinical and electrophysiological assessment for the diagnosis and staging of diabetic neuropathy. Diabetes Care 1994;17:1281-1289.
13. Galer BS, Jensen MP. Development and preliminary validation of a pain measure specific to neuropathic pain: The Neuropathic Pain Scale. Neurology 1997; 48: 332-338.
14. Dyck PJ, Davies JL, Litchy WJ, O?Brien PC. Longitudinal assessment of diabetic polyneuropathy using a composite score in the Rochester Diabetic Neuropathy Study cohort. Neurology 1997;49:229- 239.
15. Lunetta M, Le Moib R, Grassob G, Sangiorgiob L. A simplified diagnostic test for ambulatory screening of peripheral diabetic neuropathy. Diabetes Research and Clinical Practice 1998;39:165-172.
16. Armstrong DG, Lavery LA, Vela SA; Quebedeaux TL, Fleischli JG. Choosing a Practical Screening Instrument to Identify Patients at Risk for Diabetic Foot Ulceration. Archives of Internal Medicine 1998; 158: 289-292.
17. Cornblath DR, Chaudhry V, Carter K, Lee D, Seysedadr M, Miernicki M, Joh T. Total neuropathy score: validation and reliability study. Neurology 1999;53:1660-1664.
18. Meijer JW, van Sonderen E, Blaauwwikel EE, Smit AJ, Groothoff JW, Eisma WH, Links TP. Diabetic Neuropathy Examination: a hierarchial scoring system to diagnose distal polyneuropathy in diabetes. Diabetes Care 2000; 23:750-753.
19. Bennett M. The LANSS pain scale: the Leeds assessment of neuropathic symptoms and signs. Pain 2001;92:147-157.
20. Meijer JW, Smit AJ, van Sonderen E, Groothoff JW, Eisma WH, Links TP. Symptom scoring systems to diagnose distal polyneuropathy in diabetes: the Diabetic Neuropathy Symptom Score. Diabetic Medicine 2002;19:962- 965.
21. Vileikyte L, Peyrot M, Bundy C, Rubin RR, Leventhal H, Mora P, Shaw JE, Baker P, Boulton AJM. The development and validation of a neuropathy and foot ulcerspecific quality of life instrument. Diabetes Care 2003;26:2549-2555.
22. Krause SJ, Backonja MM. Development of a neuropathic pain questionnaire. The Clinical Journal of Pain 2003;19:306-314.
23. Backonja MM, Krause SJ. Neuropathic pain questionnaireshort form. The Clinical Journal of Pain 2003;19:315-316. 24. Bouhassira D, Attal N, Fermanian J, Alchaar H, Gautron M, Masquelier E et al. Development and validation of the neuropathic pain symptom inventory. Pain 2004 ;108 :248- 257.
25. Zelman DC, Gore M, Dukes E, Tai KS, Brandenburg N. Validation of a modified version of the brief pain inventory for painful diabetic peripheral neuropathy. J Pain Symptom Manage. 2005; 29: 401-410.
26. Bouhassira D, Attal N, Alchaar H, Boureau F, Brochet B, Bruxelle J et al. Comparison of pain syndromes associated with nervous or somatic lesions and development of a new neuropathic pain diagnostic questionnaire (DN4). Pain 2005; 114:29-36.
27. Bennett MI, Smith BH, Torrance N, Potter J. The S-LANSS score for identifying pain of predominantly neuropathic origin: validation for use in clinical and postal research. The Journal of Pain 2005:149-158.
28. Vileikyte L, Gonzalez JS, Leventhal H, Peyrot MF, Rubin RR, Garrow A, Ulbrecht JS, Cavanagh PR, Boulton AJM. Patient interpretation of neuropathy questionnaire- an instrument for assessment of cognitive and emotional factors associated with foot self-care. Diabetes Care 2006;29:2617- 2624.
Radiance Research AcademyInternational Journal of Current Research and Review2231-21960975-524125EnglishN-0001November30HealthcareABSORPTION CORRECTION METHOD FOR ESTIMATION OF MEFENAMIC ACID AND TRANEXAMIC ACID IN COMBINED TABLET DOSAGE FORM
English1419Popat B. MohiteEnglish Shantaram G.KhanageEnglish Vaidhun H. BhaskarEnglishA new, simple, accurate and sensitive UVspectrophotometric absorption correction method has been developed for simultaneous determination of Mefanamic acid and Tranexamic acid in combined pharmaceutical dosage form. The method is based upon determination of Mefanamic acid at 352.0 nm and Tranexamic acid at 284.8 nm, in aqueous methanol (20 % v/v). Mefanamic acid and Tranexamic acid at their respective λmax 352.0 nm and 284.8 nm shows linearity in the concentration range of 4-40 μg/ml and 4-40 μg/ml respectively. The method was validated statistically.
EnglishMefanamic acid and Tranexamic acid, absorption correction method, standard additionIntroduction
Mefenamic acid is a synthetic antiinflammatory agent. Chemically it is a 2[(2,3,- dimethyl- phenyl)amino]benzoic acid. It is clinically useful in the treatment of inflammation. It is official in Indian pharmacopoeia1 It is listed in The Merck Index and Martindale2,3 . Chemically Tranexamic acid is Cis-4(amino methyl) cyclohexane carboxylic acid .TX is used in treatment of mennorhegia and fibrinolysis.It is listed in The Merck Index and Martindale4 . Literature survey reveals that only RP-HPLC5 and few spectrophotometric6,7 were reported methods are reported for the determination of Mefenamic acid and Tranexamic acid in combined with other drugs or alone. Hence the objective of the work is to develop new spectrophotometric methods for its estimation in bulk and formulations with good accuracy, simplicity, precision and economy.
Material And Method
A UV/Visible double beam spectrophotometer, model Jasco V-630 with 1cm UV matched quartz cells was used. One Pan Balance (shimadzu) was used for experimental purpose. Methanol used was of analytical grade. M/s Blue Cross Ltd, Nashik provided the samples of MF and TX respectively. Mefenamic acid was standardized by official method reported in Indian Pharmacopoeia and the purity of the sample was found to be 99.75%. The purity of MF was 99.70%. Accurately weighed quantities (100 mg) of MF and TX were dissolved separately in 20 ml methanol and volumes were made up to 100 ml with water (1000 pg/ml). These solutions were used as working standards. Aliquot portions of stock solutions of MF and TX were diluted appropriately with aqueous methanol (20% v/v) to obtain concentration 20 pg/ml of MF and 20pg/ml of TX. The working standard solutions were scanned from 200 to 400 nm to select the wavelengths for estimation. From the overlain spectrum shown in Fig.1, the wavelength selected for estimation of MF was 352.0 nm, where TX has no absorbance and for MF it was 352.0 nm, where absorbance of TX is corrected. Different binary mixture solutions of MF and TX were then run in entire range from 200 to 400 nm. The drug obey Beer"s law in the concentration range of 0 to 35 pg/ml. Quantitative estimation of these drugs was carried out by using following formulae"s. Cy= A 284.8 nm / A (1%, 1cm) 352.0 nm of TX. (1) Cx = CAx 284.8 nm / A (1%, 1cm) 352.0 nm of MF .(2) CAx 352.0 nm = A 352.0 nm - Ay 284.8 nm(3) Ay 284.8 nm =Cy X A (1%, 1cm) 352.0 nm of TX (4) Where, Cx and Cy are concentration (mg /100ml) of MF and TX, respectively, A 284.8nm and A 352.0 nm are absorbance of mixture at 284.8 nm and 352.0 nm, respectively, CAx 352.0 nm is corrected absorbance of MF and Ay 284.8 nm absorbance of TX at 352.0 nm.
Fig.1: Over lay spectra of the both the drugs at selected wavelength
Assay of Tablet
For the estimation of the drug in tablet formulation twenty tablets were weighed and their average weight was determined. The tablets were then finely powdered.Appropriate quantity equivalent to 5 mg MF and 10 mg TX was accurately weighed and as per standard addition method, 9, 10, 20 mg of pure MF was added to achieve 2:1 ratio of MF and TX. The powder was transferred to 100 ml volumetric flask and shaken vigorously with aqueous methanol for 15 min and filtered. Necessary dilutions are made with aqueous methanol to give final concentration 20pg/ml and 20 pg/ml of MF and TX respectively. The absorbance?s values were read at 252.0 nm and 284.8 nm and concentration was obtained by solving the absorption correction equations. Results of analysis of tablet formulation are shown in Table No.
1.The proposed method was validated on the basis of parameters namely accuracy, precision, specificity, ruggedness and linearity and range. The accuracy of the proposed method was ascertained by carrying out recovery studies using standard addition method. The recovery study was performed to determine if there was any positive or negative interference from excipients present in the formulation. Precision of an analytical method is expressed as SD or RSD of a series of measurements. It was ascertained by replicate estimation of drug by the proposed method. The specificity is the ability to assess unequivocally the analyte for the presence of interesting components that may be expected to be present, such as impurities, degradation product and matrix components. During the specificity study, accurately weighed quantities of tablet powder equivalent to 10 mg of TX were taken in different 100 ml volumetric flasks. To them 20 mg of pure drug Nebivolol was added and stored for 24 hours under different conditions, like room temperature (normal), at 50 after addition of 1.0 ml of 0.1 N of hydrochloric acid , at 50 after the addition of 1.0 ml of 0.1 N of sodium hydroxide, at 50 after the addition of 3 % of hydrogen peroxide and at 60 . After 24 hours,the contents of the flask were subjected to same procedures as previously described. Test for ruggedness was carried out by repeating the procedure under different conditions, i.e., on different days, at different time and by different analysts. Linearity and range study was done by preparing concentration in the range of 80 - 120 % of test concentration and absorbance values were recorded at 352.0 nm and at 284.8 nm. The plot of linearity and range is shown in Fig. 2
Fig 2(a): Calibration curve for MF at 352.0 nm
Fig 2 (b): Calibration curve for TX at 284.8 nm
Results and discussion:
An attempt has been made to develop a fast, sensitive, precise, reproducible and economical analytical method for simultaneous estimation of MF and TX in their combined dosage form. In this method drugs obey Beer?s law in the concentration range of 5 to 40 pg/ml. The absorption additivity study was carried out to see whether the drugs in mixture showed additivity or not. It was observed that both the drugs showed additivity of absorbance at selected wavelengths indicating that both the drugs do not interact with each other in the solvent system used. A (1%, 1cm) values were also calculated for both the drugs. For MF, A (1%, 1cm) was found to be 130.4 0.8944 at wavelength 352.0 nm and for TX, it was 119 +0.7071, 354.4 0.8944 at wavelength 284.8 nm and 352.0 nm respectively. The result of percentage estimation of drug is shown in Table No.1
Table 1: Result of statistical analysis of the tablet dosage form.
The method was validated as per the ICH and USP guidelines. The results of recovery study were found to be within the prescribed limit of 98 - 102 %, proving the accuracy and showing that the method is free from interference from excipients. The results are shown in Table No. 2.
Table No.2- Recovery studies data showing amount of drug recovered from sample
For precision, replicate estimation of both MF and TX in the same batch of tablets were done by proposed method, which yielded quite concurrent results, indicating reliability of the method. The values of SD or RSD are within the prescribed limit of 2 %, showing high precision of the method.. In the specificity study, the sample was exposed to different stress conditions like acid, alkali, Peroxide and heat. The study showed degradation of NBV under peroxide, but the exact nature of degradation of drug could not be found out. For ruggedness the proposed method was repeated under different conditions like different time, on different day and by different analyst. During the linearity study it was observed that absorbance values of MF and TX in the marketed formulation were linear in the range of 80 % to 120 % of the test concentration with R2 close to one for this method of analysis. From the study of validation parameters namely accuracy, precision ( SD and RSD), ruggedness (interday, intraday and different analyst), specificity, linearity and range, it was observed that the method is specific, accurate, precise,reproducible and rugged. Hence both the methods can beemployed for routine analysis of tablet dosage form.
Acknowledgements
We are highly thankful to Blue cross Lab. Ltd., Nashik for providing us the gift sample of the pure drug and to Principal M.E.S. College Pharmacy,Sonai for providing excellent research facilities.
Englishhttp://ijcrr.com/abstract.php?article_id=2243http://ijcrr.com/article_html.php?did=22431. Indian Pharmacopoeia - 2007,Vol- 1,2,3,Govt Of India Ministry Of Health and Family Welfare, Published By: The Indian Pharmacopoeia Comision,Ghaziabad,Page No- 156,358,1468
2. Budavari S. The Merck index: An Encyclopedia of Chemicals, Drugs and Biologicals.13th ed. Whitehouse Station (NJ): Merck Research Lab, Division of Merck 2001.1152.
3. Budavari S. The Merck Index: An Encyclopedia of Chemicals, Drugs and Biologicals.13th ed. Whitehouse Station (NJ): Merck Research Lab. Division of Merck 2001: 854.
4. Sweetman SC, Eds., In; Martindale, The Complete Drug Reference, London; Pharmaceutical Press; Division of the Royal Pharmaceutical Society of Great Britain, 2007.875 (Electronic version. Available on http://www.medicinecomplete.com)
5. Dhake A.S. Indian Journal of Pharmaceutical science,volume- 49,no-3P.33-36.
6. Sadek E L M,Baraka M. Indian Journal of Pharmaceutical science,volume-58,No-5,1987.356 7. Basvaiah K.Indian drugs .vol-41,No- 5, May -2004,303.
8. ICH Q2A; Guidelines on validation of analytical procedure; Definitions and terminology, Federal Register, 1996,60.
9. ICH Q2B; Guidelines on validation of analytical procedure; Methadololgy, Federal Register, 1996, 60. 10. 27464. http:/www.xbl.com
11. Daharwal S J, Garg G, Saudagar R B, Saraf S (2006) Methods of estimation of multicomponent formulations. Indian J Pharma Sci 19(8):102.
12. Stenlake J B, Backett A H (1997) Practical pharmaceutical Chemistry, 4th Edition, Part 2, C. B. S. Publishers, p281.
Radiance Research AcademyInternational Journal of Current Research and Review2231-21960975-524125EnglishN-0001November30HealthcareVENDOR DEVELOPMENT IN PHARMA INDUSTRY
English2029Manthan D JanodiaEnglish Kunal SaxenaEnglish D.SreedharEnglish Virendra S LigadeEnglish Ajay PiseEnglish Udupa N.EnglishVendor development is essential for buying of material in right quantity, of right quality, at right price from a right source, at right time and place. Thus, source selection begins after the user department forwards material requisition form to purchase department. The purchase department thus, calls
quotations, invites tenders, receives and processes them. The comparative statements, on the basis of offers made must exhibit in addition to price differentials, a brief history of tenders in respect of their quality standards dependability and performance reliability. After critical examination of all the aspects based on information supplied by them, a particular vendor is selected who can establish suitability criterion in most
effective manner. On asking, selected vendor generally supply „initial sample?. If approved, this would then be followed by „initial supply?. The evaluation of initial supply results should be supplemented by on-the-spot study team visits at the vendor?s plant consisting of production engineers, quality controllers, cost-accountants and finance expert. The team should make a detailed study of processes, organization and other allied matters necessary for vendor evaluation. This composite scheme would then form the basis for vendor selection rather than by results of a single sample as practiced in many organizations. On the basis of
this study, bulk supply orders should follow.
EnglishVendor Development:-
In a store and material organization, it is essential to have many sources of supplies so that supplies may be had as per requirements as well as at economic costs. From commercial point of view, it is always desirable to have more than one supplier for a particular item. Sometimes it helps to improve quality and import substitution. Thus, new sources have to be found from time to time for dropping out existing sources which prove inefficient. Vendor development is a continuous process and starts from collecting names and addresses from DGS and D, trade journals like eastern pharmacist, pharma times, newspaper advertisements, IDMA bulletin and also from trade directories like Directory of small scale industries, etc. The routine sales call by representative of supplier is another good source of information. Trade shows, technical exhibitions, pharmaceutical conferences and seminars give information regarding new materials and specifications.
Vendor Selection:-
Depending upon suppliers' reputation, quality, efficiency, industrial relations and technical excellence, materials should be selected. ompetence, efficiency and quality. After collecting the details, a list of prospective vendors may be drawn up for the evaluation. Following information may be needed:
Organizational Structure
Whether it is a proprietary/partnership/private limited or public limited company
Whether it is a government undertaking or a public sector corporation
Number of managerial personnel employed at various levels
Number of supervisory personnel employed at various levels Total strength of the workforce
Manufacturing Capability
A list of equipments installed at plant level Technical details and specifications of such equipments
Manufacturing capacity of particular items
Already committed capacity
Method of production planning
Methods of follow up and progress-chasing
Materials handling systems and equipments used
Expansion plans and future programs
Technical Skill and testing facility
Numbers of technical personnel
Experience of technical personnel
Delivery and quality required at competitive prices are most important. Before selecting any new material, the plant should be inspected for technical c
Design and development of facility
Frequency of calibration of gauges and equipments
Testing equipments used for purpose of quality control
Methods of sampling and testing data regarding past rejection rates
Financial Capacity
Initial capital investment and working capital requirements
Financial sources and loan facilities from banks, financial institutions, etc
Inventory turnover and profits, etc
Clearances of government duties and rates
Location and infrastructural facilities
Whether unit enjoys facilities with regard to location, power and transit, etc.
Past performance and after sales service
Whether the unit has good record of past performance and after sales service compared to other suppliers
Vendor Rating In a large store and material organization, where a large number of parts and components are supplied by different vendors, it becomes difficult to keep a track on their performance. Therefore, in order to compare performance of various vendors, it is essential ti rate them individually. The rating may be done as per following parameters:
-Quality Performance
-Delivery Performance
. Number of lots accepted * 100 = Weightage
Number of lots supplied
Delivery Performance: It can be done in two ways.
a) Adherence to time schedules
b) Adherence to quantity schedule
- Adherence to time schedule = Number of delivery made in time * weightage
Total number of scheduled delivery
- Adherence to quality schedule = Quantity supplied * weightage
Scheduled delivery
Price Performance: Price is another very important criteriaon for evaluating a vendor which can be worked out as
Minimum Price Offered * weightage
Vendor?s profile
Final evaluation, however will depend on judgment, which is substantiated by facts.
Vendor Quality Rating(VQR):- VQR is another aspect which characterizes the quality performances of vendors in a concise and meaningful form, VQR utilizes the information regarding the number of lots submitted and the percent of lots and total quality accepted. These are evaluated as an integral unit as below.
Resulting ratings may be numbered between 0 and 100 with high values representing good performance.
Eg. 1) Vendor A submits one perfect lot, where q = 1.00, s = 1.00, L = 1
These examples clearly indicate that B is the best vendor as we may have to expect based upon good performance over 10 lots. The performance of vendor A on single lot is not conclusive enough to give him a superior rating.
Supplier Quality Assurance Program
A supplier quality assurance program helps material management in obtaining assurance of quality of the items supplied by outside vendors, to the specifications needed at minimum cost. A good specification should be unambiguous and must be measured and expressed in a form which is capable of being translated into materials and further, limits of acceptance must also be stated clearly in respect of all factors. Following information will help the supplier to understand requirements from a quality standpoint.
1. Classification of quality characteristics
2. Acceptable quality level(AQL)
3. Inspection level
4. Method of checking For the supplier quality assurance to be effective, the system should be so designed that it does not merely act as a tool for supplier selection, rather it should be defect-prevention oriented.
Vendor Rating
Various systems of vendor rating are in vogue. More refined and more accurate the plan is, more difficult it becomes to administer. Hence a compromise is necessary for successful implementation. The plan prescribed here is a composite plan which considers all the essential factors so as to ensure the buyer, the required product quality standards at economic cost and in scheduled time. The three essential factors namely quality, service form the basis. The weightage given would vary according to purchasing manager.
The following definition indicates the scope of these factors in overall rating.
Quality
It is the measure of material, not in conformance with the given specifications. This takes into takes into account the number of defectives as well as seriousness of defects.
Service
Measures the promptness of vendor in keeping schedules of delivery, removing of rejected materials and nature of response to other activities.
Price
It is the measure of price differential for the same product supplied by different suppliers. Thus, in order to determine a vendor?s overall rating each factor is given weightage in terms of its importance to vendee and then these are multiplied by vendor?s final ratings. To compare between two or more suppliers the weightage factors must, however be constant, for all suppliers, supplying a particular material.
Eg. Suppose (a) Quality standard as 100per cent minus the percentage of defects (b) service is determined by 100 per cent minus 5 per cent for each failure (c) Price is evaluated by the lowest price quoted divided by the price paid. Thus, if price paid to vendor A was Rs. 100, the lowest offer being 85, the delivery was affected in 3 installments and rejection rate was 5 per cent, the overall rating for vendor A would be
Evaluating a new vendor
On completion of all potential supplier?s list, the buyers next step is to evaluate the individual supplier. By a process of elimination, a select list of supplier is prepared and negotiation starts. The list should be broad enough to bring in competition with respect to:
These may be followed by plant visits, enquiry with regard to financial competence, past services, etc. Even then, in some cases, the buyer may not be able to make a selection, but must develop a new source of supply. Such a necessity arises in many cases of growing industrial endeavours where existing supplier cannot satisfy buyer?s need.
Supplier's audit
The Q.C. department should have responsibilty together with other relevant departments for approving suppliers who can reliably supply starting and packaging materials that meet established specification.
Before suppliers are approved and included in the specifications they should be evaluated. The evaluation should take into account a supplier"s history and the nature of materials to be supplied. If an audit is required, it should determine the supplier"s ability to conform with GMP standards for active pharmaceutical ingredients.
Choosing Vendors
The purchasing department nearly always decides which company to buy from. Equipment buying is an exception, so are some trademark items. To choose vendors intelligently you ought to know which thinfgs are sold bby which company. This can be learnt from salesman who calls on you, from advertisements in technical and trade magazines, from trade directories and buyer?s giude. These should be a file of catalogs of vendor companies and their price and discount lists. Big companies keep a detailed file of vendor performance. For each vendor they keep a record showing the orders he got, price, service, delivery, quality information that will decide whether to choose him next time. While developing vendor, you should look at it overall. Price is important, though it is only a single thing to consider when picking vendors. Can and will the vendors deliver the order on the time? Will the material pass inspection after they get here? If they don"t, will the vendor fix things up right away without argument.
Schedule change
If you want to push through a rush order or cut your order, can he or will he take care of you? How about service of somethingn goes wrong? Will the vendors extend your credit for next 30 to 60 days? Price should never be forgotten but all these other aspects should also be noticed, while choosing vendors. A purchase group must constantly keep itself informed as to the best places to buy all items of materials required. In an ongoing situation, old established source will be, in all probability, the best source. However new sources should be investigated from time to time, and the performance of old sources evaluated periodically. If the npurchase requisition is for a new item, then from the list of potential sources, a selection should be made for enquiry by use of request for quotation.
Request for quotation
It is sent by purchasing group to all the selected possible sources of supply. It should be as complete as a purchase order except for the statement of price to be paid. It is upto vendor to submit price.
Selection of right source
Upon receipt of many quotations from the vendors, it then becomes the job of purchasing group to select the right source. Purchasing group is interested in thr reliability of prospective source of supply. Following questions may arise:
1. Will quality be maintained and shipments be made on schedule?
2. Does the vendor have adequate tools and equipments, trained personnel and finance to hand the contract?
3. What is the location of vendor?s plant in relation to purchaser?s plant?
4. What means of transportation are available between these two?
1. Selection of possible potential source of supply
-This process consists of selecting a fair number of vendors in accordance with established guidelines from whom quotations will be requested.
-For items, which are purchased frequently, the buyer usually has a few preffered suppliers from whom he purchases regularly
-For purchasing new items, refernce may be made to one or more of the following from which information can be obtained.
a) Catalogues
b) Trade Journals
c) Advertisements
d) Trade Exhibitions and fair
e) Trade Directories
When considering a potential source of supply, buyer should consider
i. Whether to purchase from local market or further field
ii. Whether to buy from single vendor or several vendors at time
iii. Whether to purchase directly from manufacturer or through wholesalers
2. Making request for quotations
Requets for quotation is made on prescribed quotation form to all selected sorces of supply
-The requets is not a purchase order, rather it is merelyan enquiry to know whether the vendor can supply the desired material by specified date and if so, at what rate?
-Quotation from contains terms and conditions under whichbuyer would like to purchase the materials.
3. Receipt analysisof quotation After receivinga number of quotations from different suppliers ther are studied and a comparative statement of rates and other terms and conditions mentioned in quotation is prepared.
4. Selection of right source of supply The comparative statement prepared serves a good guide in selecting the right source of supply. Other questions which might also be given thought are:
a. Will vendor maintain quality?
b. Will vendor supply material in time?
c. Does the vendor have adequate facility to handle contract?
d. How far the vendor plant is situated?
5. Issuing purchase orders
After selecting right supplier a purchase order is dispatched to him. The ourchase order constitutes a legal document and it serves as the vendor"s authority to ship the materials and bill the company.
-A purchase orderonce accepted by the vendor constitutes a contract for delivery of the article in accordance with the terms of purchase agreement.
-Purchase order is executed in six copies
i. 2 copies go to supplier. One he preserves and one signed and returned back.
ii. 1 copy goes to accounts section
iii. 1 copy goes to purchase service to follow up the order
iv. 1 copy sent to receving department
v. Last copy kept in files of purchasing department
6. Follow up and expediting the order
After placing the order purchase service section maintains contact with vendors in order to:
a) Obtain information as to the progress of the order
b) Ensure that delivery date will be met
c) Take corrective actions so that the materials can reach the plant as originally planned
7. Analysing receiving reports and processing discrepancies and rejections
- Receiving reports are the records of what has been actually received
- Receiving reports are compared with purchase order to find discrepancies i.e. variation in quantity, price, etc.
- Discrepancies found should be reported to supplier
- Before returning the material rejected during insepection, it is necessary for buyer to get vendor"s authorization for return and replacement.
8. Checking and approving vendor's invoices for payment
Invoices should be checked to ensure that
a) The correct material ( in quantity and quality)
b) Material has been supplied at agreed price and
c) Agreed discounts has been given
After confirming the above, payment is made to the vendor for the value of goods received.
Vendor approval
Objective: To provide a system to evaluate suppliers who supply material (raw and packing material) conforming to specified requirements. Procedure:
1) It is primary responsibility of purchasing department to establish and qualify a supplier
2) Wherever possible, purchasing should be from the manufacture rather through an agent. When an agent is used and if original manufacturers are not identified and if the material is not in original containers, additional controls must be instituted.
3) Written specifications shall be established in co-operation with production and Q>C> department.
4) Purchase orders shall include the specification or refer to a specification in the document provided to supplier
5) New vendor shall be required to meet the same specification as older vendors. They will also be required to supply appropriate samples and documentation to quality control prior to acceptance as an approved vendor.
6) For active ingredients supplier is to be audited initially and at periodic intervals. Thereafter, it is only to ensure that adequate process controls are in place for consisting of production and that the suppliers meet the GMP requirements. The need to audit and its frequency will be determined by suppliers past quality, history and nature of its suppliers. The suppliers certificate of analysis should be received for each batch of raw materials received. It is to be reviewed by Q.C. The performance of key suppliers should be monitored via rending to test data and reject/rework. Corrective action must be taken for unsatisfactory supplier performance.
7) It is the responsibility of purchase department keep the approved vendor list current.
8) Approved vendor list contains:-
a) Vendor?s name
b) Product supplied by vendor
c) Specification approved date: by QA, QC, production and purchasing department
d) Vendor approval date
e) Comments for additional information
Vendor Vendee Relations
Vendor or supplier is an important part of an organization. It is the basic objective of materials management to cultivate and maintain good relationship with supplier. Corporate plans are drawn up on the premise that materials and supplies will be forthcoming at right time, in right quality and proper quantity for which it is essential to have good vendor vendee relations. Purchasing plans are made successful only with suppliers? co-operation and goodwill. In case of emergencies and where actual material needs deviate substantially from anticipated initial requirements, a good vendor-vendee relation plays on important role. Even suppliers with a proven track record sometimes fail to keep delivery promises and not meet quality requirements always, due to some unavoidable reasons such as difficulties in manufacturing plants, labour trouble, transportation, etc. Purchasing department probably has more outside contacts with firms and individuals and buyer has the chance to enhance reputation and goodwill of his company especially by creating and maintaining good relationship with vendor.
Conclusion
It is important to have a good vendor development plan in a company. Vendor approval, vendor rating should be carried out periodically and if need arises, companies should change the vendors and approve vendors who can serve the company in a better way. It is equally important to have a good vendor vendee relations which helps companies to procure materials at right time in right quantity and at right price.
Englishhttp://ijcrr.com/abstract.php?article_id=2244http://ijcrr.com/article_html.php?did=22441. Amrine Harold T., Ritchey John A., Hulley Oliver S.,Manufacturing Organization and Management, 4th edition, pg: 250-253
2. Khanna O.P., Industrial Engineering and Management, Revised First edition, Pg: 23.9-23.11
3. Datta A.K., Materials ManagementProcedures, Text and Cases, 2nd Edition, pg: 88-104
4. Mohammad Ali and Gupta Jyoti, Drug Store and Business Management, pg: 82
5. Alexander, Cross and Hill, Industrial Marketing, pg: 93-101
6. Shah D.H., SOP guidelines Straight and Simple, pg:409
7. Moore, Manufacturing Management, pg: 725-726 V
Radiance Research AcademyInternational Journal of Current Research and Review2231-21960975-524125EnglishN-0001November30HealthcareDESIGN AND EALUATION OF BACLOFEN MUCO ADHESIVE BUCCAL TABLETS
English3041Gavaskar BasaniEnglishB.StephenrathinarajEnglishS.SudharshiniEnglish A.Kishore reddyEnglishGajanan v.ShindeEnglishThe purpose of this research work was to establish mucoadhesive buccal tablets of Baclofen in the forms of monolayered tablets. The tablets were prepared using Sodium methyl cellulose (NaMC ), sodium alginate and Methocel K15M as bioadhesive polymers to impart mucoadhesion. Buccal tablets were evaluated by different parameters such as weight uniformity, content uniformity, thickness, hardness, surface pH, Swelling index, ex vivo mucoadhesive strength, in vitro drug release, and in vitro drug permeation. The present study concludes that mucoadhesive buccal tablets of Baclofen can be a good way to bypass the extensive hepatic firstpass metabolism and to improve the bio availability of Baclofen.
EnglishMonolayered buccal Tablet, Buccal delivery, Mucoadhesion, BaclofenIntroduction
Amongst the various routes of drug delivery, oral route is perhaps the most preferred to the patient and the clinician alike. Accordingly, other absorptive mucosae are considered as potential sites for drug administration. Even though the rectal, vaginal, and ocular mucosae all offer certain advantages, the poor patient acceptability associated with these sites renders them reserved for local applications rather than systemic drug administration1 . Furthermore, oral transmucosal drug delivery bypasses first pass effect and avoids pre-systemic elimination in the GI tract. These factors make the oral mucosal cavity a very attractive and feasible site for systemic drug delivery. The precise mechanism of action of baclofen is not fully known. Baclofen is a muscle relaxant and anti spastic. Although baclofen is an analog of the putative inhibitory neurotransmitter gamma-aminobutyric acid (GABA), there is no conclusive evidence that actions on GABA systems are involved in the production of its clinical effects. Oral bioavailability is approximately 70%. Baclofen was selected as a model drug for the investigation because its oral dose is low (10mg)2 . Baclofen is a weak base and its pKa value is around 5, which satisfies the criterion for the selection of the drug. The log PC (partition coefficient) value for Baclofen is about 1.33. It indicates that Baclofen has sufficient lipophilicity to pass through the buccal membranes. The tmax of Baclofen is 1.0 hr by per oral route, which is long and variable3 . The dose of Baclofen is 20 mg twice a day, however, a lower effective dose is reported to be approximately 10 mg 4 . By observing the above points, it is inferred that Baclofen has a need to formulate into buccal tablets and the drug is suitable for it. A suitable buccal drug delivery system should be flexible and possess good bioadhesive properties, so that it can be retained in the oral cavity for the desired duration. In addition, it should release the drug in a predictable manner to elicit the required therapeutic response. In the present study, the objective was to prepare muoadhesive buccal tablets of Baclofen to prolong the residence time of the buccal tablets, which ensure satisfactory drug release to a mucosa and to avoid loss of drug resulting from wash out with saliva. The buccal tablets were evaluated by weight uniformity, thickness, hardness, surface pH, swelling index, ex vivo mucoadhesive strength, In vitro drug release and In vitro buccal permeation studies.
Materials and Method
Baclofen (99.96% purity), were gift samples from Cipla ltd .Pune. Carbopol 974p5 (Colorncon Asia Pvt ltd, Goa, India).
Methocel K15m6 (Colorncon Asia Pvt ltd, Goa, India).Sodium CMC7 (S.D.Fine chemicals Mumbai. India).PVP- K30. (S.D.Fine chemicals Mumbai. India).Sodium alginate. (S.D.Fine chemicals Mumbai. India)Lactose (Anhydrous) (Laxachem.organic Pvt ltdAmravati.India).Magnesium Stearate (Scientific India -Akola, India).Talc (Scientific India -Akola, India).All other reagents and chemicals used were of analytical reagent grade.
Preparation of Mucoadhesive Buccal tablets
Mucoadhesive buccal tablets containing Baclofen were prepared by direct compression method. The ingredients of the core layer (Table 1) were accurately and mixed by trituration in a glass mortar and pestle. The mix was then compressed using 8 mm die by a tablet press. In order to obtain constant tablet weight the mannitol was added as filler exceipent in the core layer. After compression of tablet the upper punch was removed carefully with out disturbing the set up and mixed ingredients of the
Table No. 1: - Composition of Baclofen mucoadhesive buccal tablets. backing layer (Table1) were added over the tablet and compressed again
DSC Thermograms of Films
DSC thermograms of the Baclofen and it containing Methocel K15 , Sodium CMC, Lactose, and Magnesium Stearate were recorded on a thermal analyzer (Shimadzu DT- 40, Kyoto, Japan). The samples were heated from 30 to 300 C at a heating rate of 10 C/min in an inert nitrogen atmosphere.
Ex vivo Mucoadhesive strength8-15
A modified balance method was used for determining the ex vivo mucoadhesive strength. Fresh sheep buccal mucosa was obtained from a local slaughterhouse and used within 2 hours of slaughter .The mucosal membrane was separated by removing underlying fat and loose tissues. The membrane was washed with distilled water and then with phosphate buffer pH 6.8 saliva solutions at 37o c.The Sheep buccal mucosa was cut into pieces and washed with phosphate buffer pH6.8. A piece of buccal mucosa was tied to the glass vial, which was filled with phosphate buffer. The glass vial was tightly fitted into a glass beaker (filled with phosphate buffer pH6.8 at 37o c+1 0 c) so that it just touched the mucosal surface. The buccal tablet was stuck to the lower side of a rubber stopper with cyanocarylate adhesive. The two sides of the balance were made equal before the study, by keeping a 5-g weight on the right-hand pan. A weight of 5 g was removed from the right hand pan. Which lowered the pan along with the tablet over the mucosa. The balance was kept in this position for 5 minutes contact time. The water (equivalent to weight) was added slowly with an infusion set (100 drops/min) to the right-hand pan until the tablet detached from the mucosal surface. This detachment force gave the mucoadhesive strength of then buccal tablet in grams (Table: 4).
Table No.4: - In-vitro Mucoadhesive strength study of prepared mucoadhesive buccal tablets of Baclofen.
Swelling Study15 The swelling study of tablets was determined by gravimetry.The swelling rate of the bioadhesive tablet was evaluated by using 1% agar gel plate (Table: 3). The average weight of the tablet was calculated (w1).The tablets were placed on gel surface in a Petri dish placed in an incubator at 37.10 c.Tablets was removed at different time intervals (1,2,3,4,5,6), wiped with filter paper and reweighed (w2).The swelling index was calculated by the formula. Swelling index = (w2. w1)/ w.
Surface pH study16,17
The surface pH of the buccal tablets was determined in order to investigate the possibility of any side effects in vivo. As an acidic or alkaline pH may cause irritation to the buccal mucosa, it was determined to using 1% agar gel plate (Table: 3). The average weight of the tablet was calculated (w1).The tablets were placed on gel surface in a Petri dish placed in an incubator at keep the surface pH as close to neutral as possible, The method adopted by Bottenberg et al used to determine the surface pH of the tablet. A combined glass electrode was used for this purpose (Table: 2). The tablet was allowed to swell by keeping it in contact with 1 ml of distilled water (pH 6.8 + 0.01) for 2 hours at room temperature. The pH was measured by bringing the electrode in contact with the surface of the tablet and allowing it to equilibrate for 1 minute.
Table no:2 Physico chemical properties of monolayer buccal tablet of Baclofen18-20.
In vitro dissolution studies21
In vitro release study of mucoadhesive buccal tablets of Baclofen was carried out using the USP II (paddle apparatus) method at 50 rpm. Medium used for release rate study was 500 ml of phosphate buffer (pH 6.8) solution containing 20% methanol for maintaining the sink conditions. During the course of study whole assembly was maintained at 370 c. 2 ml of sample was withdrawn at specific time interval and add same amount of phosphate buffer after with drawing 2ml of sample its dilute with phosphate buffer(pH 6.8) up to 10 ml . Then amount of Baclofen released was determined spectroscopically at 223nm22 (Figure :1)
Ex vivo Diffusion study23
Ex-vivo diffusion study of pure drug was carried out using fresh porcine oral mucosa tissue, which was procured from local slaughterhouse and placed in Krebs buffer pH 7.4. Isolation of the epithelium was done mechanically by using scissors and forceps. These studied were carried out using open end cylinder method .The mucous membrane was tied to one end of the two sided open ended cylinder, which acted as donor compartment. The buccal tablet containing 6.25mg of Baclofen was kept on the mucous membrane, in such a way that the lower surface of the tablet was in contact with the mucous membrane Then the donor compartment was fixed, so that mucous membrane was in contact with the receptor medium(Beaker), 100ml of phosphate buffer, (PH 6.8) in the receptor compartment. Samples of 2 ml were withdrawn at periodic intervals from the receptor compartment and replaced with the fresh phosphate buffer immediately and after suitable dilution the drug content was analyzed spectrophotometrically at 223nm against a blank.
In vivo drug diffusion study23
A healthy rabbit weight 2.5 to 3 kg was taken and checked for absence of any disease. The fore limbs and hind limbs were fixed, into the iron rod of mini operation table so rabbit was not dorsal position. The prepared tablet was placed in a buccal membrane (Cheek pouch) with the help of forceps. Dextrose solution was given continuously throughout the period of study. Periodically 5 ml of blood sample were taken using a syringe which contained 1ml of 3.8% sodium citrate solution to prevent blood clotting. This blood sample subjected for centrifuging at 2200 rpm for 20 minutes.2ml of supernatant liquid was taken from this and a suitable dilution (10ml by buffer solution) and sample is analyzed at 223 nm in UV-spectrophotometer. The drug content obtained was subtracted from initial drug content in buccal tablet. The value obtained is denotes amount of drug release from buccal mucosa of rabbits. (Table: 5)
Stability Protocol
Stability studies were carried out on the formulation tablets of batch were first wrapped in aluminum foil then placed in an amber colored bottle. It stored at 40o c for 45days.Tablet was evaluated for physical characteristics; mucoadhesive properties, and in vitro drug release and muco adhesive strength study after 45days. Results obtained were compared with data obtained for zero time at ambient temperature. (Table :7)
Results and Discussion
In the present work efforts have been made to develop mucoadhesive buccal tablets of Baclofen using direct compression techniques involving mucoadhesive polymers like carbopol, various cellulose ethers having different degree of solubility and swelling ability, such as Sodium carboxy methyl cellulose. Hydroxy Propyl Methylcellulose was selected in oral products, it primarily used table binder and extended release matrix. Polyvinylpyrrolidone (PVP-K 30) was included as tablet binder. The FTIR spectral analysis showed that there was no appearance or disappearance of any characteristic peak, which confirms the absence of chemical interaction between drug and polymers. The bulk density and tapped density for Sodium CMC, Sodium alginate, PVP K 30, Carbopol 974P, Methocel K15M, was found to be 0.357 + 0.011 gm/ml, 0.442 + 0.0131 gm/ml, 0.256 + 0.019 gm/ml 0.381 + 0.129 gm/ml and 0.312 + 0.005 gm/ml, 0.409 + 0.331 gm/ml, 0.263 + 0.003 gm/ml, 0.381+0.321 gm/ml 0.333 + 0.015, 0.416 + 0.0125 gm/ml respectively. The bulk density and tapped density for Baclofen was found to be 0.277 + 0.02 and 0.326 + 0.051 gm/ml respectively24 The blend of ingredients was analyzed for physical characteristics. The angle of repose of compressibility index values for all polymers was found between 19 to 32 % and Hausner ratio above 1.23 to 1.47. Compressibility index value of sodium alginate and carbopol 974P is 32.39 + 1.86, 30.42 + 0.064 indicate poor. It conclude that the potential strength of polymer particle or not satisfactory for compression which also supported by lower density value and hausner ratio above 1.25.It reveals that all the formulation blends were having good flow characteristics and flow rates. All the formulation passes the test for weight variation as per the IP standard + 7.5% deviation. Percentage of drug content for all formulations F1 to F12 were in the range of 98.91 + 0.23 to 103.91 + 0.03. Thickness, Hardness of F1 to F12 formulations were found to be 2.88 + 0.072 to 3.28 + 0.015, and 5.9 + 0.56 to 7.4 + 0.40 The bioadhesive and drug release profile are dependent upon swelling behavior of the tablets. Swelling index was calculated with respect to time. The swelling index was for all formulations F1 to F12 (After 6 hours) were in the range 53.14-0.035 to 62.54-0.071. Buccal tablets of all the formulations surface pH values in the range of 4.22 0.01 to 7.22 0.03 that indicates no risk of mucosal damage or irritation. The bio adhesives property tablets of Baclofen containing varying proportions of polymers was determined with an insight to develop the tablets with adequate bioadhesiveness.The highest adhesion force and highest strength of the mucoadhesive bond was observed with the formulation as followed by F7 to F8. Tablets of formulation F4 to F5 containing showed least adhesion force than tablet of all other formulation. The batch F10 and F11 shows 74.98%, 93.50% of drug release which contain,1:3,1:2 ratio of sodium CMC and methocel K15M.The batch F11 shows promising result by releasing 93.50% drug release by controlled manner at 8 hours. This is due to the methocel K15M along with sodium CMC absorbed water rapidly with maximum swelling at 4 hours and start to welling erosion and finally drug release of at constant manner by zero order kinetic and swelling gel diffusion mechanism by applying zero order regression and peppas value of regression is correlated with each other. The formulation F11 showed 93.50 + 1.10 percentage of drug released at 8 th hr with good swelling index and bioadhesion strength. The optimized batch F11 shows dissolution zero order regression value and regression value of peppas plot as 0.9924,0.9933 is best correlated with each other also this values for Ex-vivo diffusion follows 0.9972,0.9959 and for In-vivo diffusion its value was 0.9982,0.9963 also indicate that it follows zero order kinetic along with swelling gel diffusion mechanism. The optimized batch F11 further subjected for in-vivo diffusion study by using rabbit. The result indicate that 69.38% of drug diffuse through rabbit buccal mucosa over the 8 hour study period also correlated exvivo diffusion and in-vitro dissolution. The ex-vivo diffusion study of Baclofen using porcine mucosa shows the almost 78.81% drug was permeated through the mucosa in 8 hrs.Results of stability studies of formulation F11 indicate that it is stable at 400C, for 45 days. There was no significant difference observed for dissolution and bioadhesion data.
Conclusion
The mucoadhesive buccal tablets of Baclofen may be a good way to by pass the extensive hepatic first-pass metabolism and to improve the bioavailability of Baclofen through buccal mucosa.
Englishhttp://ijcrr.com/abstract.php?article_id=2245http://ijcrr.com/article_html.php?did=22451. Clarke E.C.G., Isolation and Identification of Drugs, the Pharmaceutical Press, London, 238, (1969).
2. Davidoff RA. Antispasticity drugs: Mechanisms of action. Ann Neurol 1985;17:107-16.
3. Meythaler JM, DeVivo MJ, Hadley M. Prospective Study on the use of bolus intrathecal baclofen for spastic hypertonia due to acquired brain injury. Arch Phys Med Rehabil 1996;77:461-6
4. Hulme A, MacLennan WJ, Ritchie RT, John VA, Shotton PA. Baclofen in the elderly stoke patient its sideeffects and pharmacokinetics. Eur J Clin Pharmacol 1985;29:467-9
5. Wade A. and Weller P. J., Handbook of Pharmaceutical Excipients, (2nded.) American Pharmaceutical Association, Washington D. C. and Royal Pharmaceutical Press, 71-73, (1994).
6. Gupta, A., Garg, S., and Khar, R. K., "Mucoadhesive buccal drug delivery system - A review", Indian Drugs, 29(13), 586-593, (1992).
7. Wade A. and Weller P. J., Handbook of Pharmaceutical Excipients, (2nded.) American Pharmaceutical Association, Washington D. C. and Royal Pharmaceu-tical Press, 78-80, (1994).
8 Bankar, G. S., Anderson, N.R., Lachman, L., Lieberman, H. A, and Kanig, J. L. (eds), The Theory and