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Abstract

The primary aim of the work is preparation, characterization, and evaluation of lacosamide used for formulation of transdermal patch for antiepileptic activity. Then optimization of lacosamide for comtrol relese action using central composite design[CCD] In this study, we present a state-of-the-art review of the neuro physiological view of epilepsy as a disease affecting neural networks.We describe the basic and advanced principles of epilepsy as a disease affecting neural networks, based on the use of different clinical and mathematical techniques from a neurophysiological perspective, and signal the limitations of these findings in the clinical context. The patient of Epilepsy disease, they does not able to take medicine on time because of seizures may occurs in clusters ,loss of consciousness repeatedly for this purpose long acting transdermal patches are prepared. Objectives: 1. In this study, we present a state-of-the-art review of the neuro physiological view of epilepsy as a disease affecting neural networks. 2. We describe the basic and advanced principles of epilepsy as a disease affecting neural networks, based on the use of different clinical and mathematical techniques from a neurophysiological perspective, and signal the limitations of these findings in the clinical context.

Keywords

Transdermal, Lacosamide, Epilepsy, controlled, Drug

Introduction

Transdermal patch generally refers to topical application delivers agents to healthy intact skin either for localized treatment of tissues underlying the skin or for systemic therapy. World Journal of Pharmaceutical Research SJIF Impact Factor 8.074 Volume 7, Issue 16, 1101-1115. Research Article ISSN 2277– 7105 *Corresponding Author D. Maheswara Reddy Santhiram College of Pharmacy, Nandyal. Article Received on 01 July 2018, Revised on 21 July 2018, Accepted on 11 August 2018, DOI: 10.20959/wjpr201816-13183 www.wjpr.net Vol 7, Issue 16, 2018. 1102 Reddy et al. World Journal of Pharmaceutical Research Transdermal Patch offers many advantages over the conventional dosage forms or controlled release oral systems. Transdermal patch provides constant blood levels, avoids first pass metabolism, increased patient compliance, and avoids dose dumping.[1,2]  Transdermal drug delivery systems are defined as self-contained, discrete dosage forms which, when applied to the intact skin, deliver the drug, through the skin, at a controlled rate to the systemic circulation.[3] Lacosamide (LC) is a novel antiepileptic drug (AED) and its mechanism of action distinguishes it from other AEDs. Unlike classical AEDs like phenytoin or carbamazepine which affect fast inactivation, LC enhances sodium channel slow inactivation. This results in stabilization of neuronal membranes and decrease in neuronal firing [1]. It has been suggested that the drug also binds to collapsin response mediator protein 2 (CRMP-2) which plays a role in neuronal differentiation. Collapsin response mediator protein 2 is associated with the development of epilepsy, but its role is not fully clear . Latest study indicates that CRMP-2 is also linked to the addiction-like behavior and LC can reduce the hippocampal CRMP-2 level in ethanol-addicted mice . However, another study indicated that the drug does not specifically bind to human CRMP-2 [4]. An important part of the mechanism of action of LC is its neuroprotective activity. The drug reduced the production of reactive oxygen species by increasing the expression of antioxidant enzymes and inhibiting lipid peroxidation [5]. It has been also shown that LC has a neuroprotective effect on the hippocampus which is a brain structure associated with memory processes [6]. Other studies also indicated the neuroprotective effect of LC on the hippocampus [7,8]. It is an important observation because memory disturbances can be not only a secondary effect of epilepsy or other central disorders but also a side effect of AEDs

Topical Drug Delivery System

Topical formulations contain an active ingredient, often a medication or drug or botanical, and a vehicle. The vehicle usually contains water, oil, alcohol or propylene glycol mixed with preservatives, emulsifiers, absorption promoters and fragrances. The table below describes different formulations.

 Controlled Drug Delivery Systems:                    Controlled drug delivery systems have been developed which are capable of controlling the rate of drug delivery, sustaining the duration of therapeutic activity and/or targeting the delivery of drug to a tissue.4 Controlled drug delivery or modified drug delivery systems are conveniently divided into four categories.

  1. Delayed release
  2. Sustained release
  3. Site-specific targeting
  4. Receptor targeting

More precisely, controlled delivery can be defined as:-

  1. Sustained drug action at a predetermined rate by maintaining a relatively constant, effective drug level in the body with concomitant minimization of undesirable side effects.
  2. Localized drug action by spatial placement of a controlled release system adjacent to or in the diseased tissue.
  3. Targeted drug action by using carriers or chemical derivatives to deliver drug to a particular target cell type.
  4. Provide physiologically/therapeutically based drug release system. In other words, the amount and the rate of drug release are determined by the physiological/ therapeutic needs of the body.

Epilepsy

Epilepsy is a chronic central nervous system disorder that occurs not only with the imbalance of glutamatergic neurons and inhibitory gamma-aminobutyric acid (g-GABA) neurons, but also with abnormal Central cholinergic neuronal regulation. Since long term usage of antiepileptic drugs cause high incidence of pharmacoresistance and untoward side effects, attention has been paid in recent years to screen bioactive compounds from natural medicinal plants for the treatment of several neurological disorders including Epilepsy. Keeping in view of relative importance of natural medicinal plants, the present study is mainly focused to characterize the anti-convulsant effect of Bacopa monnieri (BM), an Indian herb which is being extensively used in Ayurvedic treatments related to neurological complications. The present study is designed to assess the neurotoxicity of Pentylene tetrazole (PTZ), an epileptic compound with particular reference to Cholinergic system and ATPases in different brain regions of rat to explore the possible antiepileptic effect of different extracts of BM in comparison with Diazepam (DZ) (Reference control). The activity levels of Acetyl cholinesterase (AChE) and ATPases were decreased in different regions of brain during PTZ induced epilepsy which were increased in epileptic rats pretreated with different extracts of Bacopa monnieri except EAE and AE. In addition Acetylcholine (ACh), levels were increased during PTZ induced epilepsy when compared with normal control and levels were reversed on pretreatment with different extracts of BM. Recoveries of these parameters suggest that the bioactive factors present in the extracts offer neuroprotection by interrupting the pathological cascade that occurs during epileptogenesis.[10]

Lacosamide

The complicated dosing regimens required by many immediate release (IR) ASMs (such as twice- or three-times-daily dosing) commonly cause partial adherence to dosing routines, which can negatively affect seizure control (Getnet et al., 2016). Extended-release (XR) ASM formulations may offer clinical advantages over IR formulations by simplifying dosing routines to once per day, thereby increasing patient adherence and improving clinical outcomes (Hovinga et al., 2008; Wheless and Phelps, 2018). XR formulations are often better tolerated than IR formulations, as they can result in more gradual increases in drug plasma concentrations and potentially lower maximum concentrations (Cmax) (Wheless and Phelps, 2018). Lacosamide (LC) is a novel antiepileptic drug (AED) and its mechanism of action distinguishes it from other AEDs. Unlike classical AEDs like phenytoin or carbamazepine which affect fast inactivation, LC enhances sodium channel slow inactivation. This results in stabilization of neuronal membranes and decrease in neuronal firing . It has been suggested that the drug also binds to collapsin response mediator protein 2 (CRMP-2) which plays arole in neuronal differentiation. Collapsin response mediator protein  2 is associated with the development of epilepsy, but its role is not fully clear . Latest study indicates that CRMP-2 is also linked to the addiction-like behavior and LC can reduce the hippocampal CRMP-2 level in ethanol-addicted mice . However, another study indicated that the drug does not specifically bind to human CRMP-2 . An important part of the mechanism of action of LC is its neuroprotective activity. The drug reduced the production of reactive oxygen species by increasing the expression of antioxidant enzymes and inhibiting lipid peroxidation .

Advantages

  1. Make it more bioavailable.
  2. Cut down on how often you dose.
  3. The drug delivery method is painless and doesn't hurt.
  4. Stay away from liver first pass metabolism.
  5. Get patients to follow through more often, especially kids and older people.
  6. They offer long-lasting treatment with just one dose.
  7. Medication that can be taken by itself[11][12]
  8. Transdermal Nitroglycerin is one way to avoid the first pass impact. When taken by mouth, it is quickly broken down by the liner.
  9. The drugs that have a half-life at the start of the therapy can work for longer because they are stored and released slowly over time.
  10. The treatment with drugs can be stopped quickly by taking off the skin product.[13][14]

Disadvantages

  1. Small amount of the drug is put on the skin.
  2. Itching of the skin may happen.
  3. The amount of drug in the blood cannot get very high.
  4. Costs more.
  5. You should not take an electric drug.[15][16]
  6. We can only use strong drugs in transdermal patches because the skin naturally limits how much of the drug can get through.
  7. Some drugs, like scopolamine, have a skin patch that is put behind the ear, which is painful.
  8. Adhering for a long time is hard.[17][18]

Applications

  1. A nicotine patch that you put on your skin. This patch releases nicotine in controlled amounts to help you stop smoking.
  2. Sometimes, nitroglycerine patches are also given to people with Angina to help them feel better.
  3. Transdermal patches are another way to get clonidine, a drug used to treat high blood pressure, and ketoprofen, a non-steroidal anti-inflammatory drug.
  4. An antidepressant called selegiline, an MAOI, was the first drug to be delivered through the skin.
  5. Transdermal release agent for ADHD.
  6. Instead of pills that are put under the tongue, nitroglycerin patches are sometimes given to treat angina.
  7. Transdermal scopolamine is often used to help people who are sick from motion.
  8. A topical patch form of the blood pressure medicine clonidine is available.
  9. 9)In 2007, the drug Rivastigmine, which is used to treat Alzheimer's, came out as a patch under the brand name Exelon.
  10. 10) Caffeine patches, which are made to get caffeine into the body through the skin.[19]

Limitations of TDDS

  1. Skin that isn't very permeable.
  2. Only allowed for powerful drugs.
  3. Not good for molecules that are bigger than 500 Daltons
  4. 4)This method can't be used for drugs that melt easily because they don't mix well with water or fat.
  5. They're not good at all if they make your skin itch.
  6. Ionic drugs can't be sent through this method.[20]

Central composite Design               

Central composite design (CCD) is one of the tools used to study the effect of different variables on the dependent variables of any formulation. Based on the principle of design of experiments, CCD was employed to investigate the effect of two independent factors. Design of experiments encompasses the use of various types of experimental designs, generation of polynomial equations, and responses over the experimental domain to determine the optimum formulation. Multiple linear regression analysis of results leads to equations that adequately described the influence of the independent variables on the selected responses .

Literature Review

1.Keurentjes et al.,

2019,worked on the risk evaluation of dermal experience, extrapolative numerical models are used. In this exertion the accurateness to predict flux of the model is judged against experimental  human in vivo data of drugs practical in US-FDA approved TDS. A record of pharmacokinetic statistics of drugs practical in TDS was used and updated. Three mathematical models (QSAR) were used to analyze envisage fluxes, and compared to the human in vivo data. For more than half of the drugs applied in TDS, the forecast flux by the numerical models was at par comparable to the flux designed with the experimental in vivo data. The flux was more than- or underestimate

factor 10–100. All numerical models were appreciably correlated with the in vestigational in vivo data. The development of percutaneous penetration has numerous influencing factors, TDS minimize some of these reasons.

2.Ameen and Michniak-Kohn., 2019, offers an optional course of drug

administration mainly for Alzheimer’s disease patients from beginning to end which abolish gastrointestinal side effects and eventually improving compliance. They organized optimized matrix type patches of galantamine for the transdermal delivery and performed ex vivo and in vitro estimation. Four pressure sensitive adhesive with dissimilar functional groups, ten diffusion enhancers and four drug loadings were experimented to devise the optimized patch. The ex vivo penetration of the dissimilar formulated patches from end to end human cadaver skin by means of Franz diffusion examined

3.Ifeoma and Kevin., 2019,worked on hypokalemia which is one of the

majority and frequent type of electrolyte difference. Its defined as a serum potassium level of ?3.5 mEq/L. Potassium is important for proper nerve and muscle excitation. Presently, there are a number of potassium supplements, but they are affected by several shortcomings e.g. oral potassium tablets require a longer time to attain peak plasma concentration and parenteral administration can cause pain, swelling, trypanophobia with risk of hyperkalemia. Knowing these harms, it is decisive to extend a fitting substitute for potassium supplementation. Transdermal drug delivery is a hopeful alternative.

route has bulky plane vicinity which can be used for drug supervision and has the facility to impart sustained-release goods that can help sustain potassium levels. The intention of this assignment was to explore the effect of pressure of micro needle rollers on the infiltration of potassium chloride transversely through porcine skin. Permeation studies were accepted away in vitro using the Franz diffusion apparatus. The trans dermal change of potassium chloride was investigated using inductively attached plasma visual emission spectrometry. Micro channel categorization was accepted away by means of digital microscopy, bright field stereomicroscopy and confocal laser scanning microscopy. This indicates trans dermal change of potassium chloride achieved via passive diffusion whereas this suggest trans dermal change of potassium chloride achieved via micro needle-enhanced permeation.

4.Ameen and Michniak-Kohn., 2019, offers an optional course of drug

administration mainly for Alzheimer’s disease patients from beginning to end which abolish gastrointestinal side effects and eventually improving compliance. They organized optimized matrix type patches of galantamine for the transdermal delivery and performed ex vivo and in vitro estimation. Four pressure sensitive adhesive with dissimilar functional groups, ten diffusion enhancers and four drug loadings were experimented to devise the optimized patch. The ex vivo penetration of the dissimilar formulated patches from end to end human cadaver skin by means of Franz diffusion cells examined.

5.Geile et al., 2019,

worked on fentanyl is an effective copied opioid with amultiplicity of promising application. Transdermal fentanyl patches are repeatedly prearranged for patients with rigorous chronic or cancerrelated pain. The possiblity for mistreatment is well-known and dangers linked with illicit fentanyl ingestion are serious. Fentanyl toxicity due to accidental mistreatment is comparatively uncommon. This study listedcarefully all such examples and their importance in forensic assessmentand put in new parameters and study the obtainable femoral blood in the occasion of critical fentanyl patch misapplications. the molecules and therefore merely a small fraction of little molecules are allowed to assess the site of action. A original form of modification called the microneedles help to augment the penetration of the preparation throughout skin course and prevent a variety of harms connected with the conservative formulations. The main formulation occupy folds of the skin and get deposited, therefore generate micron size conduit that directthe drug straight to the epidermis or superior dermis section from wherethe drug can go into the circulation by passing the obstacle. There are avariety microneedles which can be fictitious like solid, dissolving,hydrogel, coated and hollow micro needles. Production technique chosen depends on the kind and fabric of the micro needle.  Ramadan et al., 2018, invented a elastic matrix type transdermal patch of lamivudine having monolithic polymeric film as an endeavor tosolve the problems like biological small half-life and fluctuations in plasma concentration with oral dose. They examined the film organoleptically,  physicochemical properties, their ex vivo permeation, in vivo pharmacokinetic parameters.

6.Zhou et al., 2018,distribute drugs all the way through the exterior of the skin for local or general administration. The drug absorption after inclusion all the way through the skin into the systemic circulation via vessel achieved at a definite rate by use of time-honored substantial and element enhancers to increase the transdermal permeation rate by increasing drug solubility, diffusion coefficient. Adverse consequence is not practicable control and increase in level of drug to toxic levels. Due to excess of penetration enhancers. Nano-formulations normally diverge insize and range from 10 nm to 100 nm. The smaller particle size result in improved permeability, stability, retention, and targeting, making nanoformulations appropriate for transdermal drug delivery. The different applications of nano-formulations (vesicles or nanoparticles and nanoemulsions) have been widely studied.

7.Kriplani et al., 2018,prepared and evaluated transdermal films of non steroidal anti-inflammatory drug. They prepared three transdermal patches using various concentrations of ethyl cellulose. They concluded that as the concentration of polymer enhance the thickness of patch, weight uniformity and folding endurance also enhance.

8.Emma et al., 2018, formulated patches of Ibuprofen drug using a poly ether- urethane-silicone crosslinked as the drug reservoir using solvent less process. They prepared patch also prepared hot-melt crosslinking technique at 75°c in 90% relative humidity lacking the accumulation of solvents. The formulations characterized such as dissolution and permeation studies with utilizing diffusion cells. The method for estimation was validated by HPLC methods to determine the drug content. The formulations also estimated by accelerated stability studies at 35°c with 60% relative humidity.

9.Szunerits and Boukherroub et al., 2018, reviewed the development in this field of transdermal drug delivey system. They also summarized examples of thermal technologies for local and systemic transdermal drug delivery. They reviewed execution of the novel approaches and its methods to conquer limitation for passive diffusion without altering skin integrity.

10.Verma et al., 2017, reviewed various evaluation methods for transdermal dosage for. They also discussed recent advancement in development of Transdemal drug delivery system. They discussed that TDDS is expensive substitute of conventional formulation.

11.Kattiet al., 2017 formulated and developed transdermal patch of Tizanidine Hydrochloride to overcome the limitation of bioavailability. They found that, Moringa oleifera gum has potential to modify drug release rate and having good film former and adhesive property. The transdermal patch revealed promising drug release within 12 hr

(84.36%), good stability and no irritancy.

12.Siji et al., 2016, investigated the result of backing films on transdermal delivery of cyclobenzaprine patch. Diverse backing films were selected to arrange the cyclobenzaprine transdermal patch. The cumulative amount of cyclobenzaprine at large from diverse patches was appraise in vitro. To examine the communication flanked by cyclobenzaprine and backing films, the separation trial and attenuated total reflectance Fouriertransform infrared (ATR-FTIR) spectroscopy were execute. The cumulative quantity of cyclobenzaprine released beginning the patch with Cotran™ 9700 as backing film. The quantity of cyclobenzaprine out beginning the patch with Cotran™ 9700 as backing film diminish radically after 7 d storage at room circumstance. The division experiments specify a strapping adsorption of cyclobenzaprine onto the

Cotran™ 9700, which could explicate the dwindle of cumulative quantity of cyclobenzaprine free beginning the patch with Cotran™ 9700 as backing film.

13.Indulekha et al., 2016, planned a temperature generate transdermal drug deliverance system (TDDS) with a thermo responsive polymer, poly(N-vinyl caprolactam) [PNVCL] support gel, someplace in patients canthemselves govern a pulsate of treatment on simple purpose of heat padlarger than the TDDS. The phase alteration heat of PNVCL was adjust to35 °C by embed it onto a pH sensitive biopolymer, Chitosan, to produce

14.Chitosan-g-PNVCL (CP) co-polymer which render the gel mutually thermo- and pH-responsive belongings. The submission of triggered delivery was explored by consignment acetamidophenol (a model hydrophilic drug) and etoricoxib (a model hydrophobic drug). In vitro

drug discharge experiments were achieved at three unusual temperature (25, 32 and 39 °C) at two different pH (5.5 and 7) to study its drug release with answer to heat and pH. In vitro skin permeation of both the drugs demonstrate enhanced drug liberate at what time the covering was subjected to superior temperature (39 °C). Furthermore, it was also institute that coat infiltration for hydrophobic drug was superior than

that of hydrophilic drug. The in vivo biocompatibility learning of the CP gel in rat coat proves that the gel is biocompatible. The results attain confirmed the potential employ of the thermo responsive CP gel as an ondemand restricted drug delivery arrangement. Narasimhulu et al., 2015, include various mechanisms, working process of transdermal film, application of penetration enhancers, different evaluations parameters etc.

15.Thejeswi et al., 2015, developed the transdermal patch using hydrophilic polymer of drug containing amphotericin B. Hydrophilic polymer applied to increase the bioavailability as approaches developed as penetrating poorly water soluble compounds.

16.Zhang et al., 2014,evaluated transdermal patch for identified organic matrices of drug excipient interaction process. Organic amines salt use for permeation enhancing for Diclofenac and was tested in vitro usingexcised rabbit skin as transdermal barrier in two-chamber diffusion  cell.They optimized concentration of percutaneous permeation enhancer and the loading dose of drugs. The result indicated that skin penetration of Diclofenac triethylamine salt was better than other organic amine salts. Singh et al., 2014, formulated placebo transdermal patches by using different polymers like ethyl cellulose, poly vinyl pyrrolidone and eudragit by solvent evaporation techniques. The formulations were characterized with a different number of parameters. The tensile strength, foldingendurance of prepared films was shown high plasticity in variouscombinations of polymers. The result easily concluded that the Di-nbutylphthalateat concentration 20% of polymers used as plasticizer for further developmental studies.

17.Banerjee et al., 2014,prepared “patches,” intended to transport a therapeutically efficient quantity of drug crosswise the skin. The superiority characteristic of the adhesive in TDDS is indispensible for manufacture intend and imperative to the protection, usefulness and superiority estimate of the concluding creation. Progress in the pasture of bonding agent knowledge has smoothed the technique for scheming TDDS that have extensive elasticity.

18.Agrawal et al., 2010, reviewed various transdermal formulations of psychotropic substance with methods and advantages. They state that effective therapeutic effect of drug need proper drug selection. New drug administration methods are investigated for better patient compliance and to increase drug effect in low dose. oral administration of psychotropic drugs is not suitable for psychiatric patients due to noncompliance.Preparation of transdermal patch of psychotropic drug is better option to improve patient compliance. Transdermal patches are better option for management of pain, pregnancy prevention and hormone replacement therapy. They have many advantages over conventional oral therapies. Transdermal patches provide continuous drug delivery resulting improve tolerability. Psychotropic drugs like Selegiline, fluoxetine, haloperidol, imipramine, methylphenidate and rivastigmine have been formulated as transdermal systems. New improvements with the use of permeation enhancers, transdermal gels, iontophoresis, electroporation and sonophoresis are better technologies for formulation of transdermal drug delivery of psychotropics substance.

19.Bhaskar et al., 2010,compared the oral Diclofenac tablets and transdermal Diclofenac patch for multiple premolar extractions inorthodontic treatment. They concluded that the transdermal Diclofenacpatch offer potent analgesia compared to conventional therapy for betterpatient compliance. This may be used as analgesia for schedule post extraction

20.Kumar et al., 2006,characterized UV spectroscopic method for quantification of Diclofenac Potassium and Tizanidine in tablet. They validated new analytical methods based on the simultaneous estimation of drugs in a binary mixture without previous separation. The binary

mixture was determined by mixed standards and three sampling wavelengths of 277 nm, 295 nm (isobestic point), and 320 nm in multiwavelength technique. The drugs were calculate approximately by using the absorptivity values of Diclofenac Potassium and Tizanidine at elected wavelengths of multiwavelength technique and simultaneous equation method separately. These three developed methods were required no separation, simple, accurate, rapid method used for quality control analysis of both drug.

DRUG PROFILE

Lacosamide

  1. Name oF Drug: Lacosamide
  2. Chemical Formula: C13H18N2O3
  3. IUPAC Name: N2-acetyl-N-benzyl-D-homoserinamide
  4. Molecular Weight: 250.294  g/mol
  5. Chemical Struc

Melting Point:143-144°C

CLINICAL PHARMACOLOGY

Mechanism of Action                      

The precise mechanism by which lacosamide exerts its antiepileptic effects in humans remains to be fully elucidated. In vitro electrophysiological studies have shown that lacosamide selectively enhances slow inactivation of voltage-gated sodium channels, resulting in stabilization of hyperexcitable neuronal membranes and inhibition of repetitive neuronal firing.

  1. Generic Name:               Vimpat (Vim-pat)
  2. Drug Class:                   Anticovulsants
  3. Therapeutic Class:         CYP3A4 inhibitors
  4. Similar Drugs:                levetiracetam

 Pharmacokinetics                         

The pharmacokinetics of lacosamide have been studied in healthy adult subjects (age range 18 to 87), adults with partial-onset seizures, adults with diabetic neuropathy, and subjects with renal and hepatic impairment. The pharmacokinetics of lacosamide are similar in healthy subjects, patients with partial-onset seizures, and patients with primary generalized tonic-clonic seizures. Lacosamide is completely absorbed after oral administration with negligible first-pass effect with a high absolute bioavailability of approximately 100%.

Pharmacodynamics                   

A pharmacokinetic-pharmacodynamic (efficacy) analysis was performed based on the pooled data from the 3 efficacy trials for partial-onset seizures. Lacosamide exposure is correlated with the reduction in seizure frequency. However, doses above 400 mg/day do not appear to confer additional benefit in group analyses. Cardiac Electrophysiology Electrocardiographic effects of lacosamide were determined in a double-blind, randomized clinical pharmacology trial of 247 healthy subjects. Chronic oral doses of 400 and 800 mg/day (equal to and two times the maximum daily recommended dose, respectively) were compared with placebo and a positive control (400 mg moxifloxacin). Lacosamide did not prolong QTc interval and did not have a dose-related or clinically important effect on QRS duration

Absorption and Bioavailability                 Lacosamide is completely absorbed after oral administration. The oral bioavailability oflacosamide tablets is approximately 100%. Food does not affect the rate and extent of absorption. After intravenous administration, Cmax is reached at the end of infusion. The 30- and 60- minute intravenous infusions are bioequivalent to the oral tablet. For the 15-minute intravenous infusion, bioequivalence was met for AUC.

EXCIPIENT PROFILE

PHARMACEUTICAL EXCIPIENTS

  1. HPMC
  2. PEG
  3. PROPYLENE GLYCOL
  4. METHANOL
  5. CHLOROFORM

1. HPMC

Hydroxy Propyl Methyl Cellulose [HPMC] [ Hypromellose Phthalate ]

 2. Synonyms:

Cellulose phthalate hydroxypropyl methyl ether; HPMCP; hydroxypropyl methylcellulose benzene-1,2-dicarboxylate; 2-hydroxypropyl methylcellulose phthalate; hypromellosi phthalas; Mantrocel HP-55; methylhydroxypropylcellulose phthalate..

3. Chemical Name and CAS Registry Number:-

Cellulose, hydrogen 1,2-benzenedicarboxylate, 2-hydroxypropyl methyl ether [9050-31-1]

4. Empirical Formula and Molecular Weight

Hypromellose phthalate is a cellulose in which some of the hydroxyl groups are replaced with methyl ethers, 2-hydroxypropyl ethers, or phthalyl esters. Several different types of hypromellose phthalate are commercially available with molecular weights in the range

20 000–200 000. Typical average values are 80 000–130 000.(1).

  1. Empirical formula And Structural Formula:-

C56H108030 

6. Functional Category:-

Coating agent.

Hypromellose phthalate occurs as white to slightly off-white, freeflowing flakes or as a granular powder. It is odorless or with a slightly acidic odor and has a barely detectable taste.

15. Regulatory Status:-

Included in the FDA Inactive Ingredients Database (oral capsules and tablets). Included in nonparenteral medicines licensed in the UK. Included in the Canadian List of Acceptable Non-medicinal Ingredients.

16. Related Substances:-

Cellulose acetate phthalate; hypromellose.

2.PEG

Polyethylene Glycol

1 Nonproprietary Names

BP: Macrogols

JP: Macrogol 400

Macrogol 1500

Macrogol 4000

PhEur: Macrogols

USP-NF: Polyethylene Glycol

2 Synonyms

Carbowax; Carbowax Sentry; Lipoxol; Lutrol E; macrogola; PEG; Pluriol E;

polyoxyethylene glycol.

3 Chemical Name and CAS Registry Number

a-Hydro-o-hydroxypoly(oxy-1,2-ethanediyl) [25322-68-3]

4 Empirical Formula and Molecular Weight

HOCH2(CH2OCH2)mCH2OH where m represents the average number of

oxyethylene groups. Alternatively, the general formula H(OCH2CH2)nOH may be

used to represent polyethylene glycol, where n is a number m in the previous formula

þ 1. See Table I for the average molecular weights of typical polyethylene glycols.

Note that the number that follows PEG indicates the average molecular weight of the

polymer.

5 Structural Formula

6 Functional Category

Ointment base; plasticizer; solvent; suppository base; tablet and capsule lubricant.

7 Applications in Pharmaceutical Formulation or Technology

Polyethylene glycols (PEGs) are widely used in a variety of pharmaceutical formulations, including parenteral, topical, ophthalmic, oral, and rectal preparations. Polyethylene glycol has been used experimentally in biodegradable polymeric matrices used in controlled-release systems. Polyethylene glycols are stable, hydrophilic substances that are essentially nonirritant to the skin; see Section 14. They do not readily penetrate the skin, although the polyethylene glycols are watersolubleand are easily removed from the skin by washing, making them useful as ointment bases. Solid grades are generally employed in topical ointments, with the consistency of the base being adjusted by the addition of liquid grades of polyethylene glycol. Mixtures of polyethylene glycols can be used as suppository bases, for

which they have many advantages over fats.

8 Description

The USP32–NF27 describes polyethylene glycol as being an addition polymer of ethylene oxide and water. Polyethylene glycol grades 200–600 are liquids; grades 1000 and above are solids at ambient temperatures. Liquid grades (PEG 200–600) occur as clear, colorless or slightly yellow-colored, viscous liquids. They have a slight but characteristic odor and a bitter, slightly burning taste. PEG 600 can occur as a solid at ambient temperatures.Solid grades (PEG>1000) are white or off-white in color, and range in consistency from pastes to waxy flakes. They have a faint, sweet odor. Grades of PEG 6000 and above are available as free flowing milled powders.

3.Propylene Glycol

1 Nonproprietary Names

BP: Propylene Glycol

JP: Propylene Glycol

PhEur: Propylene Glycol

USP: Propylene Glycol

2 Synonyms

1,2-Dihydroxypropane; E1520; 2-hydroxypropanol; methyl ethyl

5 Structural Formula

Functional Category

Antimicrobial preservative; disinfectant; humectant; plasticizer; solvent; stabilizing

agent; water-miscible cosolvent.

 Applications in Pharmaceutical Formulation or Technology

Propylene glycol has become widely used as a solvent, extractant, and preservative in

a variety of parenteral and nonparenteral pharmaceutical formulations. It is a better.

general solvent than

Description

Propylene glycol is a clear, colorless, viscous, practically odorless liquid, with a sweet,

slightly acrid taste resembling that of glycerin.

10 Typical Properties

Autoignition temperatu-3718C

Density -1.038 g/cm3 at 208C

Flammability -Upper limit, 12.6% v/v in air; lower limit, 2.6% v/v in air.

Flash point -998C (open cup)

Heat of combustion -1803.3 kJ/mol (431.0 kcal/mol)

Heat of vaporization -705.4 J/g (168.6 cal/g) at b.p.

Melting point -598C

4.METHANOL

Nonproprietary Names

BP: Racementhol

JP: dl-Menthol

PhEur: Menthol, Racemic

USP: Menthol

 Synonyms

Hexahydrothymol;2-isopropyl-5-methylcyclohexanol;4-isopropyl1methylcyclohexan-

3-ol; 3-p-menthanol; p-menthan-3-ol; dl

menthol; mentholum

5 Structural Formula

Functional Category

Flavoring agent; therapeutic agent.

Applications in Pharmaceutical Formulation or Technology Menthol is widely used in pharmaceuticals, confectionery, and toiletry products as a flavoring agent or odor enhancer. In addition to its characteristic peppermint flavor, lmenthol, which occurs naturally, also exerts a cooling or refreshing sensation that is exploited in many topical preparations. Unlike mannitol, which exerts a similar effect due to a negative heat of solution,

When administered orally in small doses menthol has a carminative action.8 Description Racemic menthol is a mixture of equal parts of the (1R,2S,5R)- and (1S,2R,5S)-isomers of menthol. It is a free-flowing or agglomerated crystalline powder, or colorless, prismatic, or acicular shiny crystals, or hexagonal or fused masses with a strong characteristic odor and taste. The crystalline form may change with time owing to sublimation within a closed vessel. The USP 32 specifies that menthol may be either naturally occurring l-menthol or synthetically prepared racemic or dl-menthol. However, the JP XV and PhEur 6.0, along with other pharmacopeias, include two separate monographs for racemic and l-menthol.

LD50 (rat, IM): 10.0 g/kg(9)

LD50 (rat, oral): 3.18 g/kg

 Handling Precautions

May be harmful by inhalation or ingestion in large quantities; may be irritant to the skin, eyes, and mucous membranes. Observe normal precautions appropriate to the circumstances and quantity of material handled. Eye protection, chemical resistant gloves, and respirators are recommended. Avoid prolonged or repeated exposure.

 Regulatory Status

Included in the FDA Inactive Ingredients Database (dental preparations, inhalations, oral aerosols, capsules, solutions, suspensions, syrups, and tablets; also topical preparations). Included in nonparenteral medicines licensed in the UK. Accepted for use in foods and confectionery as a flavoring agent of natural origin. Included in the

Canadian List of Acceptable Non-medicinal Ingredients.

5.CHLOROFORM

Chloroform, or trichloromethane (often abbreviated as TCM), is an organic compound with the formula CHCl3 and a common solvent. It is a very volatile, colorless, strong-smelling, dense liquid produced on a large scale as a precursor to refrigerants and PTFE. Chloroform is a trihalomethane that serves as a powerful anesthetic, euphoriant, anxiolytic, and sedative when inhaled or ingested. Chloroform was used as an anesthetic between the 19th century and the first half of the 20th century. It is miscible with many solvents but it is only very slightly soluble in water (only 8 g/L at 20°C).

In chemical nomenclature, a preferred IUPAC name (PIN) is a unique name, assigned to a chemical substance and preferred among all possible names generated by IUPAC nomenclature. The "preferred IUPAC nomenclature" provides a set of rules for choosing between multiple possibilities in situations where it is important to decide on a unique name. It is intended for use in legal and regulatory situations.Preferred IUPAC names are applicable only for organic compounds, to which the IUPAC has the definition as compounds which contain at least a single carbon atom but no alkali, alkaline earth or transition metals and can be named by the nomenclature of organic compounds (see below). Rules for the remaining organic and inorganic compounds are still under development. The concept of PINs is defined in the introductory chapter and chapter 5 of the "Nomenclature of Organic Chemistry: IUPAC Recommendations and Preferred Names 2013" (freely accessible), which replace two former publications: the "Nomenclature of Organic Chemistry", 1979 (the Blue Book) and "A Guide to IUPAC Nomenclature of Organic Compounds, Recommendations 1993". The full draft version of the PIN recommendations ("Preferred names in the nomenclature of organic compounds", Draft of 7 October 2004) is also available. ]

MATERIALS AND EQUIPMENTS

Material:-

Lacosamide was received as a gift sample from MEDLEY PHARMACEUTICALS LTD.MUMBAI. And HPMC ,PEG,Propylene Glycol ,Methanol and Chloroform all other chemicals were of analytical grade.

EQUIPMENTS

Experimental Work                      Preformulation study:

  1. Melting point

The melting point is determine by using manual physical methods using Thieles tube and liquid paraffin.

The melting point is typically around143-144°C.

Solubility

The       solubility        is         check   in various        solvents           like Distilled water,DMSO , Dimethyl Fromamide, Ethanol

  1. UV- Visible Callibration of lacosamide :-

A UV spectrophotometric procedure for analyzing lacosamide  in patch  involves preparing a lacosamide  stock solution, preparing calibration standards,selecting a wavelength, constructing a calibration curve, and preparing a sample. 100mg lacosamide  dissolve in 100ml phosphate buffer 6.8 (100ug/ml).Put out 10ml from above 100ug/ml solution and add 100ml again phospahte buffer 6.8(10ug/ml).From this 10ug/ml solution, put out 1,2,3,4,5ml and make up the volume in 10ml of volumetric flask with same phospahte buffer solution which make solution of 1ug/ml,2ug/ml,3ug/ml,4gu/mland 5ug/ml solutions The maximum absorption wavelength (?max) is typically around 207 nm. The sample is then prepared. The absorbance of the sample solution is measured at the ?max, and the concentration of lacosamide is determined using the calibration equation. Plot the callibration curve graph of concentratin VS absorbance.

FT-IR:-

The IR is done by using the BRUCKER IR spectrometer is a crucial method for characterizing and confirming the presence of functional groups in chemical compounds and formulations. Approximately 1–2mg of lacosamide powder, physical mixtures were placed in a mortar and then crushed until homogeneous then formed pellets with a pressure of 800 m Pa under vacuum and analyzed by Fourier-transform infrared (FTIR) spectrophotometer. Absorption spectra were recorded at wave number 500–4000 cm-1The IR spectrometer is then used to analyze the recorded spectrum to identify characteristic absorption bands lacosamide, compare it with reference spectra or literature data, and interpret the observed absorption bands in terms of structural features of lacosamide. The results of the IR spectroscopy analysis are reported, including the identified absorption bands and their assignments to specific molecular vibrations of lacosamide If necessary, differences or similarities between the experimental spectrum and reference data can be discussed.

  1. EXPERIENTAL DESIGN:

Materials for patch :

Materials commonly used for the preparation of transdermal patch  are summarized in Table Below

ormulation of transdermal patch:

The patches were developed by solvent casting evaporation technique. HPMC K4M  polymers were used. Different concentrations of polymers were added in 30 ml volume of solvent Methanol: Chloroform (3:2). The polymeric dispersion stirred with magnetic stirrer for about 10 min to form clear solution. Weighed amount of polyethylene Glycol 400 and propylene glycol was added to above solution. 5o mg of drug was mixed thoroughly by the use of magnetic stirrer for few minutes. The uniform solution was formed which was poured into petri plate and placed inverted funnel which will help to control the evaporation of solvent and will avoid the cracking of patches. This was kept aside for overnight. Dried patches were separated from the plate, cut and stored in desiccator.

The coefficient estimate represents the expected change in response per unit change in factor value when all remaining factors are held constant. The intercept in an orthogonal design is the overall average response of all the runs. The coefficients are adjustments around that average based on the factor settings. When the factors are orthogonal the VIFs are 1; VIFs greater than 1 indicate multi-colinearity, the higher the VIF the more severe the correlation of factors. As a rough rule, VIFs less than 10 are tolerable.

Final Equation in Terms of Coded Factors

floating time =

+18.05

+6.95 A

+0.1448 B

+3.81 AB

The equation in terms of coded factors can be used to make predictions about the response for given levels of each factor. By default, the high levels of the factors are coded as +1 and the low levels are coded as -1. The coded equation is useful for identifying the relative impact of the factors by comparision

Factor coding is Coded.

Sum of squares is Type III - Partial

The Model F-value of 3.68 implies there is a 5.61% chance that an F-value this large could occur due to noise. P-values less than 0.0500 indicate model terms are significant. In this case AB is a significant model term. Values greater than 0.1000 indicate the model terms are not significant. If there are many insignificant model terms (not counting those required to support hierarchy), model reduction may improve your model.

Fit Statistics

 

A negative Predicted R?2; implies that the overall mean may be a better predictor of your response than the current model. In some cases, a higher order model may also predict better. Adeq Precision measures the signal to noise ratio. A ratio greater than 4 is desirable.Your ratio of 6.608 indicates an adequate signal. This model can be used to navigate the design space.

Model Comparison Statistics

The coefficient estimate represents the expected change in response per unit change in factor value when all remaining factors are held constant. The intercept in an orthogonal design is the overall average response of all the runs. The coefficients are adjustments around that average based on the factor settings. When the factors are orthogonal the VIFs are 1; VIFs greater than 1 indicate multi-colinearity, the higher the VIF the more severe the correlation of factors. As a rough rule, VIFs less than 10 are tolerable.

Final Equation in Terms of Actual Factors

in vivo release =

+501.80392

-0.447313 HPMC

-2704.13037 PEG

+2.87117 HPMC * PEG

The equation in terms of coded factors can be used to make predictions about the response for given levels of each factor. By default, the high levels of the factors are coded as +1 and the low levels are coded as -1. The coded equation is useful for identifying the relative impact of the factors by comparing the factor coefficients.

Final Equation in Terms of Actual Factors

in vivo release =

+501.80392

-0.447313 HPMC

-2704.13037 PEG

+2.87117 HPMC * PEG

The equation in terms of actual factors can be used to make predictions about the response for given levels of each factor. Here, the levels should be specified in the original units for each factor. This equation should not be used to determine the relative impact of each factor because the coefficients are scaled to accommodate the units of each factor and the intercept is not at the center of the design space. 

Coefficients in Terms of Coded Factors

FT-IR:-
  1. Drug FTIR-

Approximately 1–2mg of Lacosamide powder, physical mixtures were placed in a mortar and then crushed until homogeneous then formed pellets with a pressure of 800 mPa under vacuum and analyzed by Fourier-transform infrared (FTIR) spectrophotometer. Absorption spectra were recorded at wave number 500–4000 cm-1 .

SUMMARY AND CONCLUSION

A new controlled release system of transdermal patch were formulated by an solvent evaporation  method using central composite design technique of design of experiments. The current study aimed to develop and optimize  control release  patch  in order to prolong the residence time of drug on gastric region, thereby, improving their solubility and bioavailability. The effect of  amounts as independent process variables on the properties or response of these newly developed beads containing lacosamide like drug encapsulating and drug release were optimized. The in-vitro drug release from this beads followed first orderand  evaluated. This properties of newly developed beads could possibly advantageous in term of advanced patient compliance with reduced dose interval

REFERANCE

  1. V. Dubey, D.Mishra, A.Asthana, NK Jain. Transdermal Delivery of a pineal Hormone: Melatonin via elastic Liposomes. Biomaterials. 27; 2006: 3491-3496.
  2. Panchagnula R. Transdermal delivery of drugs. Indian Journal Pharmacology. 29; 1997:140- 156.
  3. G. Cevc. Isothermal lipid phase- Transitions Chemistry and Physics of Lipids. 57; 1991: 293- 299.
  4. Boinpally R.R., Zhou S.L., Poondru S., Devraj G. and Jasti B.R. Lecithin vesicles for topical delivery of diclofenac. European journal of Pharmaceutics and Biopharmaceutics. 56(3); 2003:389-92.
  5. Cevc G, Blume G, Sehatzlein A, Gebauer D and Paul A. The skin a Pathway for Systemic Treatment with Patches and Lipid-Based Agent Carriers. Advance Drug Delivery Reviews. 18; 1996: 349- 378.
  6. 6.J.R .Walve, S.R Bakliwal, B.R Rane, S.P Pawar. Transferosomes: A surrogated carrier for transdermal drug delivery System. International journal of applied biology and pharmaceutical technology. 2(1); 2011: 2014-213
  7. Cevc, G.; Schatzlein, A.G.; Richardsen, H. Ultradeformable lipid vesicles can penetrate the skin and other semi-permeable barriers unfragmented. Evidence from double label CLSM experiments and direct size measurements. Biochim. et Biophys. Acta (BBA)-Biomembr. 2002, 1564, 21–30.
  8. Rajan, R.; Jose, S.; Mukund, V.P.B.; Vasudevan, D.T. Transferosomes—A vesicular transdermal delivery system for enhanced drug permeation. J. Adv. Pharm. Technol. Res. 2011, 2, 138–143.
  9. Cevc, G. Lipid vesicles and other colloids as drug carriers on the skin. Adv. Drug Deliv. Rev. 2004, 56, 675–711.
  10. Walve, J.R.; Bakliwal, S.R.; Rane, B.R.; Pawar, S.P. Transfersomes: A surrogated carrier for transdermal drug delivery system. Int. J. Appl. Biol. Pharm. Technol. 2011, 2, 204–213.
  11. Sivannarayana, P.; Rani, A.P.; Saikishore, V.; VenuBabu, C.; SriRekha, V. Transfersomes: Ultra deformable vesicular carrier systems in transdermal drug delivery system. Res. J. Pharm. Dos. Forms Technol. 2012, 4, 243–255. Journal of Pharmaceutical Negative Results ¦ Volume 13 ¦Special Issue 8 ¦ 2022 4321
  12. Sachan, R.; Parashar, T.; Soniya, S.V.; Singh, G.; Tyagi, S.; Patel, C.; Gupta, A. Drug carrier transfersomes: A novel tool for transdermal drug delivery system. Int. J. Res. Dev. Pharm. Life Sci. 2013, 2, 309–316
  13. Li, J.; Wang, X.; Zhang, T.; Wang, C.; Huang, Z.; Luo, X.; Deng, Y. A review on phospholipids and their main applications in drug delivery systems. Asian J. Pharm. Sci. 2015, 10, 81–98.
  14. Bhasin, B.; Londhe, V.Y. An overview of transfersomal drug delivery. Int. J. Pharm. Sci. Res. 2018, 9, 2175–2184.
  15. Gupta A., Aggarawal G., Singla S., Rora R., A, “Transfersomes: A Novel Vesicular Carrier for Enhanced Transdermal Delivery of Sertraline: Development, Characterization and performance Evaluation,” Sci Pharm, 2012; 80: 1061-1080.
  16. Wavle J.R BakliwalS.R, Rane B.R, Pawer S.P, “Transfersomes: A surrogated Carrier For Transdermal Drug Delivery System” International Journal of Applied Biology and Pharmaceutical Technology, Jan-Mar-2011; 2(1).
  17. Kavitha K, Bharath N, Mani T T., “Physical Permeation Enhancers for Transdermal Drug Delivery “Research of Journal of pharmaceutical, Biological and Chemical sciences, October- December 2011; 2(4): 66.
  18. Dave V., Kumar D., Lewis S., Paliwal S., “Ethosome for Enhanced Transdermal Drug Delivery of Aceclofenac” International Journal of Drug Delivery, 2010; 2: 81-9

Reference

  1. V. Dubey, D.Mishra, A.Asthana, NK Jain. Transdermal Delivery of a pineal Hormone: Melatonin via elastic Liposomes. Biomaterials. 27; 2006: 3491-3496.
  2. Panchagnula R. Transdermal delivery of drugs. Indian Journal Pharmacology. 29; 1997:140- 156.
  3. G. Cevc. Isothermal lipid phase- Transitions Chemistry and Physics of Lipids. 57; 1991: 293- 299.
  4. Boinpally R.R., Zhou S.L., Poondru S., Devraj G. and Jasti B.R. Lecithin vesicles for topical delivery of diclofenac. European journal of Pharmaceutics and Biopharmaceutics. 56(3); 2003:389-92.
  5. Cevc G, Blume G, Sehatzlein A, Gebauer D and Paul A. The skin a Pathway for Systemic Treatment with Patches and Lipid-Based Agent Carriers. Advance Drug Delivery Reviews. 18; 1996: 349- 378.
  6. 6.J.R .Walve, S.R Bakliwal, B.R Rane, S.P Pawar. Transferosomes: A surrogated carrier for transdermal drug delivery System. International journal of applied biology and pharmaceutical technology. 2(1); 2011: 2014-213
  7. Cevc, G.; Schatzlein, A.G.; Richardsen, H. Ultradeformable lipid vesicles can penetrate the skin and other semi-permeable barriers unfragmented. Evidence from double label CLSM experiments and direct size measurements. Biochim. et Biophys. Acta (BBA)-Biomembr. 2002, 1564, 21–30.
  8. Rajan, R.; Jose, S.; Mukund, V.P.B.; Vasudevan, D.T. Transferosomes—A vesicular transdermal delivery system for enhanced drug permeation. J. Adv. Pharm. Technol. Res. 2011, 2, 138–143.
  9. Cevc, G. Lipid vesicles and other colloids as drug carriers on the skin. Adv. Drug Deliv. Rev. 2004, 56, 675–711.
  10. Walve, J.R.; Bakliwal, S.R.; Rane, B.R.; Pawar, S.P. Transfersomes: A surrogated carrier for transdermal drug delivery system. Int. J. Appl. Biol. Pharm. Technol. 2011, 2, 204–213.
  11. Sivannarayana, P.; Rani, A.P.; Saikishore, V.; VenuBabu, C.; SriRekha, V. Transfersomes: Ultra deformable vesicular carrier systems in transdermal drug delivery system. Res. J. Pharm. Dos. Forms Technol. 2012, 4, 243–255. Journal of Pharmaceutical Negative Results ¦ Volume 13 ¦Special Issue 8 ¦ 2022 4321
  12. Sachan, R.; Parashar, T.; Soniya, S.V.; Singh, G.; Tyagi, S.; Patel, C.; Gupta, A. Drug carrier transfersomes: A novel tool for transdermal drug delivery system. Int. J. Res. Dev. Pharm. Life Sci. 2013, 2, 309–316
  13. Li, J.; Wang, X.; Zhang, T.; Wang, C.; Huang, Z.; Luo, X.; Deng, Y. A review on phospholipids and their main applications in drug delivery systems. Asian J. Pharm. Sci. 2015, 10, 81–98.
  14. Bhasin, B.; Londhe, V.Y. An overview of transfersomal drug delivery. Int. J. Pharm. Sci. Res. 2018, 9, 2175–2184.
  15. Gupta A., Aggarawal G., Singla S., Rora R., A, “Transfersomes: A Novel Vesicular Carrier for Enhanced Transdermal Delivery of Sertraline: Development, Characterization and performance Evaluation,” Sci Pharm, 2012; 80: 1061-1080.
  16. Wavle J.R BakliwalS.R, Rane B.R, Pawer S.P, “Transfersomes: A surrogated Carrier For Transdermal Drug Delivery System” International Journal of Applied Biology and Pharmaceutical Technology, Jan-Mar-2011; 2(1).
  17. Kavitha K, Bharath N, Mani T T., “Physical Permeation Enhancers for Transdermal Drug Delivery “Research of Journal of pharmaceutical, Biological and Chemical sciences, October- December 2011; 2(4): 66.
  18. Dave V., Kumar D., Lewis S., Paliwal S., “Ethosome for Enhanced Transdermal Drug Delivery of Aceclofenac” International Journal of Drug Delivery, 2010; 2: 81-9

Photo
Manisha Mahavir Sidanale
Corresponding author

Ashokrao Mane Institute of Pharmacy Ambap-416112

Photo
Pranjal Chougle
Co-author

Ashokrao Mane Institute of Pharmacy Ambap-416112

Photo
Nilesh Chougule
Co-author

Ashokrao Mane Institute of Pharmacy Ambap-416112

Manisha Mahavir Sidanale , Pranjal Chougle, Nilesh Chougule, Preparation And Evaluation Of Transdermal Patch Of Lacosamide For Epilepsy , Int. J. of Pharm. Sci., 2024, Vol 2, Issue 10, 1-26. https://doi.org/10.5281/zenodo.13870960

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