This document provides an overview of transdermal drug delivery systems (TDDS). It discusses the skin structure and factors that influence drug permeation across the skin. The key components of TDDS include the drug, penetration enhancers, backing layer, release liner and adhesive. Evaluation of TDDS involves in vitro and in vivo methods to assess adhesion, drug release and permeation. The rate of permeation across skin depends on parameters like the drug concentration gradient and permeability coefficient of the skin. Successful TDDS design requires understanding the skin barriers and methods to overcome them.
Mucoadhesive drug delivery system interact with the mucus layer covering the mucosal epithelial surface, & mucin molecules & increase the residence time of the dosage form at the site of the absorption.
Mucoadhesive drug delivery system is a part of controlled delivery system.
Since the early 1980,the concept of Mucoadhesion has gained considerable interest in pharmaceutical technology.
combine mucoadhesive with enzyme inhibitory & penetration enhancer properties & improve the patient complaince.
MDDS have been devloped for buccal ,nasal,rectal &vaginal routes for both systemic & local effects.
Hydrophilic high mol. wt. such as peptides that cannot be administered & poor absorption ,then MDDS is best choice.
Mucoadhesiveinner layers called mucosa inner epithelial cell lining is covered with viscoelasticfluid
Composed of water and mucin.
Thickness varies from 40 μm to 300 μm
General composition of mucus
Water…………………………………..95%
Glycoproteinsand lipids……………..0.5-5%
Mineral salts……………………………1%
Free proteins…………………………..0.5-1%
The mechanism responsible in the formation of mucoadhesive bond
Step 1 : Wetting and swelling of the polymer(contact stage)
Step 2 : Interpenetration between the polymer chains and the mucosal membrane
Step 3 : Formation of bonds between the entangled chains (both known as consolidation stage)
Electronic theory
Wetting theory
Adsorption theory
Diffusion theory
Fracture theory
Advantages over other controlled oral controlled release systems by virtue of prolongation of residence of drug in GIT.
Targeting & localization of the dosage form at a specific site
-Painless administration.
-Low enzymatic activity & avoid of first pass metabolism
If MDDS are adhere too tightlgy because it is undesirable to exert too much force to remove the formulation after use,otherwise the mucosa could be injured.
-Some patient suffers unpleasent feeling.
-Unfortunately ,the lack of standardized techniques often leads to unclear results.
-costly drug delivery system
Transdermal Drug Delivery System (TDDS) is the one of the novel technology to deliver the molecules through the skin for long period of time.
Transdermal Drug Delivery System (TDDS) are defined as self contained, discrete dosage forms which are also known as “patches” 2, 3 when patches are applied to the intact skin, deliver the drug through the skin at a controlled rate to the systemic circulation
Mucoadhesive drug delivery system interact with the mucus layer covering the mucosal epithelial surface, & mucin molecules & increase the residence time of the dosage form at the site of the absorption.
Mucoadhesive drug delivery system is a part of controlled delivery system.
Since the early 1980,the concept of Mucoadhesion has gained considerable interest in pharmaceutical technology.
combine mucoadhesive with enzyme inhibitory & penetration enhancer properties & improve the patient complaince.
MDDS have been devloped for buccal ,nasal,rectal &vaginal routes for both systemic & local effects.
Hydrophilic high mol. wt. such as peptides that cannot be administered & poor absorption ,then MDDS is best choice.
Mucoadhesiveinner layers called mucosa inner epithelial cell lining is covered with viscoelasticfluid
Composed of water and mucin.
Thickness varies from 40 μm to 300 μm
General composition of mucus
Water…………………………………..95%
Glycoproteinsand lipids……………..0.5-5%
Mineral salts……………………………1%
Free proteins…………………………..0.5-1%
The mechanism responsible in the formation of mucoadhesive bond
Step 1 : Wetting and swelling of the polymer(contact stage)
Step 2 : Interpenetration between the polymer chains and the mucosal membrane
Step 3 : Formation of bonds between the entangled chains (both known as consolidation stage)
Electronic theory
Wetting theory
Adsorption theory
Diffusion theory
Fracture theory
Advantages over other controlled oral controlled release systems by virtue of prolongation of residence of drug in GIT.
Targeting & localization of the dosage form at a specific site
-Painless administration.
-Low enzymatic activity & avoid of first pass metabolism
If MDDS are adhere too tightlgy because it is undesirable to exert too much force to remove the formulation after use,otherwise the mucosa could be injured.
-Some patient suffers unpleasent feeling.
-Unfortunately ,the lack of standardized techniques often leads to unclear results.
-costly drug delivery system
Transdermal Drug Delivery System (TDDS) is the one of the novel technology to deliver the molecules through the skin for long period of time.
Transdermal Drug Delivery System (TDDS) are defined as self contained, discrete dosage forms which are also known as “patches” 2, 3 when patches are applied to the intact skin, deliver the drug through the skin at a controlled rate to the systemic circulation
Gastro retentive drug delivery system (GRDDS)Shweta Nehate
Oral route is the most acceptable route for drug administration. Apart from conventional dosage forms several other forms were developed in order to enhance the drug delivery for prolonged time period and for delivering drug to a particular target site. Gastro-retentive drug delivery system (GRDDS) has gainned immense popularity in the field of oral drug delivery recently. it is a widely employed approach to retain the dosage form in the stomach for an extended period of time and release the drug slowly that can address many challenges associated with conventional oral delivery, including poor bioavailability. different innovative approaches are being applied to fabricate GRDDS. Gastroretentive drug delivery is an approach to prolong gastric residence time, there by targeting site-specific drugs release in the upper gastrointestinal tract (GIT) for local or systemic effects. It is obtained by retaining dosage form into stomach and by releasing the in controlled manner.
Various approaches to Targeted Drug Delivery Systems (TDDS) in its formuation and evaluation in a pharmaceutical industry and research is outlined in this presentation.
Controlled Release Oral Drug Delivery System
Controlled drug delivery is one which delivers the drug at a predetermined rate, for locally or systemically, for a specified period of time.
This presentation includes introduction, physiology of GIT, factors affecting GRDDS, Advantages and disadvantages, approaches to GRDDS and their mechanism, some of the marketed products using GRDDS mechanism.
Gastro retentive drug delivery system (GRDDS)Shweta Nehate
Oral route is the most acceptable route for drug administration. Apart from conventional dosage forms several other forms were developed in order to enhance the drug delivery for prolonged time period and for delivering drug to a particular target site. Gastro-retentive drug delivery system (GRDDS) has gainned immense popularity in the field of oral drug delivery recently. it is a widely employed approach to retain the dosage form in the stomach for an extended period of time and release the drug slowly that can address many challenges associated with conventional oral delivery, including poor bioavailability. different innovative approaches are being applied to fabricate GRDDS. Gastroretentive drug delivery is an approach to prolong gastric residence time, there by targeting site-specific drugs release in the upper gastrointestinal tract (GIT) for local or systemic effects. It is obtained by retaining dosage form into stomach and by releasing the in controlled manner.
Various approaches to Targeted Drug Delivery Systems (TDDS) in its formuation and evaluation in a pharmaceutical industry and research is outlined in this presentation.
Controlled Release Oral Drug Delivery System
Controlled drug delivery is one which delivers the drug at a predetermined rate, for locally or systemically, for a specified period of time.
This presentation includes introduction, physiology of GIT, factors affecting GRDDS, Advantages and disadvantages, approaches to GRDDS and their mechanism, some of the marketed products using GRDDS mechanism.
Overview of Transdermal Drug Delivery Systemijtsrd
Transdermal drug delivery systems are topically administered medicaments. Transdermal drug transport structures TDDS are the dosage shape of adhesive patch this is positioned on the skin to deliver specific dose of medication through the skin and in to the blood stream. The main objective of transdermal drug delivery system is to deliver drug into systemic circulation through skin at predetermined rate with minimal inter and intrapatients variation. This article gives a brief overview over principles behind transdermal drug delivery, as well as the advantages and disadvantages of transdermal therapeutic system and the recent innovations in the field of transdermal drug delivery and also describe the methods of preparation of different types of transdermal patches, evaluation parameters and some available marketed products. Sayali Dhepe | Manisha Sukre | Vikram Veer "Overview of Transdermal Drug Delivery System" Published in International Journal of Trend in Scientific Research and Development (ijtsrd), ISSN: 2456-6470, Volume-6 | Issue-4 , June 2022, URL: https://www.ijtsrd.com/papers/ijtsrd50107.pdf Paper URL: https://www.ijtsrd.com/pharmacy/pharmaceutics/50107/overview-of-transdermal-drug-delivery-system/sayali-dhepe
HERBAL TRANSDERMAL PATCHES By SAILI. P. RAJPUT SailiRajput
Wound is the term which means the damage or tearing of cells and its anatomy and cell function. Wound are classified as surgical, traumatic, diabetic, venous, arterial wound and etc. The wound healing is a process which involves coagulation, Ephilization, granulation, and remodelling of tissue.
The proposed study was done and performed to evaluate the wound healing capacity of the herbs like ocimum sanctum (tulsi) and aloe vera when formulated in form of transdermal patches.
In this study Natural wound healing was enhanced by the various phytochemicals present in tulsi and aloe vera. The present study includes the drug delivery through transdermal patches for treating, curing, preventing various skin allergy, infection or wound healing.
The main aim of this study was to formulate the herbal transdermal patches in which tulsi plant extract is loaded in aloe vera patches which help to treat the skin infection like rashes, redness, and in wound healing.
Herbal formulation is still the mainstay about 75-80 % of world’s population in various country for health care because it has fewer side effects. And they also have better compatibility as compare to synthetic drugs.
Herbal formulation consists of the extract of herbs, plants and its part like root system and shoot system which are rich in various phytochemicals which helps to treat various injuries, disease or infection. In various study it has been seen and observed that the plants like tulsi and aloe have the wound healing activities.
Various Research Study and Surveys States that there are Topical and Transdermal Medicated Formulation for Dealing with Treatment of Skin Infections but this Study States the Transdermal Drug Delivery System has wide range of Advantages over Topical Formulation.
In Present Study the Advantage of Transdermal Formulation over Topical Formulation is briefly Discussed. And from various aspects its observed that the transdermal formulation has wide range of advantages over topical formulation. This TDDS has wide scope in future so it involves various New Approaches like Iontophoresis, Photomechanical waves etc.
The Transdermal Drug Delivery System Aims in Drug Targeting and Controlled Release of Drug.
Transdermal Drug Delivery system of Novel Drug Delivery System which also involves various drug delivery systems like Sustain Release system , Delayed release System, Targeted release system, Modified release system, Extended release system and many more.
The Transdermal drug delivery system is used to produce clinical effects like local anesthesia and anti-inflammatory activities.
TDDS has a very wide scope now-a-days because it has many advantages over old and traditional drug delivery systems.
There are wide scope for new innovations in TDDS as is its developing in medical field
TDDS tends to enhance the Bioavailability of and drug and also Bypass the First Pass Metabolism.
TDDS helps to maintain the drug concentration in given therapeutic
Transdermal drug delivery has made an important contribution to medical practice, but has yet to fully achieve its potential as an alternative to oral delivery and hypodermic injections. First-generation transdermal delivery systems have continued their steady increase in clinical use for delivery of small, lipophilic, low-dose drugs. Second-generation delivery systems using chemical enhancers, non-cavitational ultrasound and iontophoresis have also resulted in clinical products; the ability of iontophoresis to control delivery rates in real time provides added functionality. Third-generation delivery systems target their effects to skin’s barrier layer of stratum corneum using microneedles, thermal ablation, microdermabrasion, electroporation and cavitational ultrasound. Microneedles and thermal ablation are currently progressing through clinical trials for delivery of macromolecules and vaccines, such as insulin, parathyroid hormone and influenza vaccine. Using these novel second- and third-generation enhancement strategies, transdermal delivery is poised to significantly increase impact on medicine.
Transdermal drug delivery systems (TDDS), also known as "patches," are dosage forms designed to deliver a therapeutically effective amount of drug across a patient's skin. The adhesive of the transdermal drug delivery system is critical to the safety, efficacy and quality of the product. In the Drug Quality Reporting System (DQRS), the United States Food and Drug Administration (FDA) has received numerous reports of "adhesion lacking" for transdermal drug delivery systems. This article provides an overview of types of transdermals, their anatomy, the role of adhesion, the possible adhesion failure modes and how adhesion can be measured. Excerpts from FDA reports on the lack of adhesion of transdermal system products are presented. Pros and cons of in vitro techniques, such as peel adhesion, tack and shear strength, in vivo techniques used to evaluate adhesive properties are discussed. To see a decrease in "adhesion lacking" reports, adhesion needs to become an important design parameter and suitable methods need to be available to assess quality and in vivo performance. This article provides a framework for further discussion and scientific work to improve transdermal adhesive performance.
Transdermal delivery systems are topically administered medicaments in
the form of patches that deliver drugs for systemic effects at a
predetermined and controlled rate.
• Transdermal Drug Delivery System (TDDS) are defined as self-contained,
discrete dosage forms which are also known as “patches”, when patches
are applied to the intact skin, deliver the drug through the skin at a
controlled rate to the systemic circulation.
• TDDS are dosage forms designed to deliver a therapeutically effective
amount of drug across a patient’s skin.
• Currently transdermal delivery is one of the most promising methods for
drug application. It reduces the load that the oral route commonly places
on the digestive tract and liver.
• Transdermal delivery not only provides controlled, constant
administration of drugs, but also allows continuous input of drugs with
short biological half-lives and eliminates pulsed entry into systemic
circulation, which often causes undesirable side effects.
• A transdermal drug delivery device, which may be of an active or a
passive design, is a device which provides an alternative route for
administering medication. These devices allow for pharmaceuticals to be
delivered across the skin barrier.
• A drug is applied in a relatively high dosage to the inside of a patch,
which is worn on the skin for an extended period of time. Through a
diffusion process, the drug enters the bloodstream directly through the
skin.
Transdermal drug delivery system- structure of skinAkankshaPatel55
Transdermal drug delivery systems (TDDS) have transcended the realm of simple nicotine patches and entered an exciting era of innovation. Gone are the days of bulky, uncomfortable adhesives; in their place stand sophisticated systems capable of delivering a myriad of therapeutic agents through the seemingly impregnable barrier of the skin. To truly understand the magic behind this technology, we delve deeper, exploring its intricate mechanisms and promising future. The journey begins with a microscopic waltz at the skin's outermost layer, the stratum corneum. Drug molecules, meticulously formulated into miniscule particles, are incorporated into a semi-permeable patch. This patch acts as a launchpad, adhering snugly to the skin and initiating the drug's odyssey. Guided by the principles of Fick's Law of Diffusion, the drug embarks on a clandestine mission. Driven by a concentration gradient, it permeates the intercellular lipids of the stratum corneum, navigating a labyrinthine path formed by keratinocytes. This passive journey, governed by factors like drug lipophilicity and skin thickness, determines the rate and extent of absorption. However, diffusion plays just the first act in this multi-part drama. Once traversing the stratum corneum, the drug encounters the viable epidermis, a dynamic landscape teeming with enzymes and metabolic pathways. Here, some compounds may undergo degradation, limiting their systemic bioavailability. To overcome this hurdle, scientists devise ingenious strategies:
Penetration Enhancers: Chemical agents like propylene glycol or oleic acid temporarily disrupt the skin's lipid packing, easing the drug's passage.
Iontophoresis: Electric current gently guides charged molecules through the skin, bypassing enzymatic barriers and boosting delivery.
Microneedle Technology: Tiny, painless needles create transient microchannels, facilitating the delivery of larger molecules like proteins and peptides. The Symphony of Controlled Release:
A key advantage of TDDS lies in their ability to sustain drug release over extended periods. This controlled release symphony is orchestrated by sophisticated reservoir systems:
Matrix Systems: The drug is homogeneously dispersed within a polymer matrix, gradually diffusing out over time.
Reservoir Systems: A distinct drug reservoir separates from the adhesive layer, allowing for precise and prolonged delivery.
Programmable Systems: Advanced patches incorporate microfluidic channels and microchips, enabling customized release profiles and even pulsatile delivery for specific therapeutic needs.
Benefits Beyond Convenience:
The charm of TDDS extends far beyond the mere convenience of avoiding needles. They offer distinct advantages over traditional oral and parenteral routes:
Enhanced Bioavailability: By bypassing first-pass metabolism in the liver, certain drugs achieve higher systemic concentrations through transdermal delivery.
Improved Patient Compliance: Continuous, hassle-free adminis
Pulmonary Thromboembolism - etilogy, types, medical- Surgical and nursing man...VarunMahajani
Disruption of blood supply to lung alveoli due to blockage of one or more pulmonary blood vessels is called as Pulmonary thromboembolism. In this presentation we will discuss its causes, types and its management in depth.
Report Back from SGO 2024: What’s the Latest in Cervical Cancer?bkling
Are you curious about what’s new in cervical cancer research or unsure what the findings mean? Join Dr. Emily Ko, a gynecologic oncologist at Penn Medicine, to learn about the latest updates from the Society of Gynecologic Oncology (SGO) 2024 Annual Meeting on Women’s Cancer. Dr. Ko will discuss what the research presented at the conference means for you and answer your questions about the new developments.
ARTIFICIAL INTELLIGENCE IN HEALTHCARE.pdfAnujkumaranit
Artificial intelligence (AI) refers to the simulation of human intelligence processes by machines, especially computer systems. It encompasses tasks such as learning, reasoning, problem-solving, perception, and language understanding. AI technologies are revolutionizing various fields, from healthcare to finance, by enabling machines to perform tasks that typically require human intelligence.
Lung Cancer: Artificial Intelligence, Synergetics, Complex System Analysis, S...Oleg Kshivets
RESULTS: Overall life span (LS) was 2252.1±1742.5 days and cumulative 5-year survival (5YS) reached 73.2%, 10 years – 64.8%, 20 years – 42.5%. 513 LCP lived more than 5 years (LS=3124.6±1525.6 days), 148 LCP – more than 10 years (LS=5054.4±1504.1 days).199 LCP died because of LC (LS=562.7±374.5 days). 5YS of LCP after bi/lobectomies was significantly superior in comparison with LCP after pneumonectomies (78.1% vs.63.7%, P=0.00001 by log-rank test). AT significantly improved 5YS (66.3% vs. 34.8%) (P=0.00000 by log-rank test) only for LCP with N1-2. Cox modeling displayed that 5YS of LCP significantly depended on: phase transition (PT) early-invasive LC in terms of synergetics, PT N0—N12, cell ratio factors (ratio between cancer cells- CC and blood cells subpopulations), G1-3, histology, glucose, AT, blood cell circuit, prothrombin index, heparin tolerance, recalcification time (P=0.000-0.038). Neural networks, genetic algorithm selection and bootstrap simulation revealed relationships between 5YS and PT early-invasive LC (rank=1), PT N0—N12 (rank=2), thrombocytes/CC (3), erythrocytes/CC (4), eosinophils/CC (5), healthy cells/CC (6), lymphocytes/CC (7), segmented neutrophils/CC (8), stick neutrophils/CC (9), monocytes/CC (10); leucocytes/CC (11). Correct prediction of 5YS was 100% by neural networks computing (area under ROC curve=1.0; error=0.0).
CONCLUSIONS: 5YS of LCP after radical procedures significantly depended on: 1) PT early-invasive cancer; 2) PT N0--N12; 3) cell ratio factors; 4) blood cell circuit; 5) biochemical factors; 6) hemostasis system; 7) AT; 8) LC characteristics; 9) LC cell dynamics; 10) surgery type: lobectomy/pneumonectomy; 11) anthropometric data. Optimal diagnosis and treatment strategies for LC are: 1) screening and early detection of LC; 2) availability of experienced thoracic surgeons because of complexity of radical procedures; 3) aggressive en block surgery and adequate lymph node dissection for completeness; 4) precise prediction; 5) adjuvant chemoimmunoradiotherapy for LCP with unfavorable prognosis.
Acute scrotum is a general term referring to an emergency condition affecting the contents or the wall of the scrotum.
There are a number of conditions that present acutely, predominantly with pain and/or swelling
A careful and detailed history and examination, and in some cases, investigations allow differentiation between these diagnoses. A prompt diagnosis is essential as the patient may require urgent surgical intervention
Testicular torsion refers to twisting of the spermatic cord, causing ischaemia of the testicle.
Testicular torsion results from inadequate fixation of the testis to the tunica vaginalis producing ischemia from reduced arterial inflow and venous outflow obstruction.
The prevalence of testicular torsion in adult patients hospitalized with acute scrotal pain is approximately 25 to 50 percent
Couples presenting to the infertility clinic- Do they really have infertility...Sujoy Dasgupta
Dr Sujoy Dasgupta presented the study on "Couples presenting to the infertility clinic- Do they really have infertility? – The unexplored stories of non-consummation" in the 13th Congress of the Asia Pacific Initiative on Reproduction (ASPIRE 2024) at Manila on 24 May, 2024.
New Drug Discovery and Development .....NEHA GUPTA
The "New Drug Discovery and Development" process involves the identification, design, testing, and manufacturing of novel pharmaceutical compounds with the aim of introducing new and improved treatments for various medical conditions. This comprehensive endeavor encompasses various stages, including target identification, preclinical studies, clinical trials, regulatory approval, and post-market surveillance. It involves multidisciplinary collaboration among scientists, researchers, clinicians, regulatory experts, and pharmaceutical companies to bring innovative therapies to market and address unmet medical needs.
Ozempic: Preoperative Management of Patients on GLP-1 Receptor Agonists Saeid Safari
Preoperative Management of Patients on GLP-1 Receptor Agonists like Ozempic and Semiglutide
ASA GUIDELINE
NYSORA Guideline
2 Case Reports of Gastric Ultrasound
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We specializes in exporting high quality Research chemical, medical intermediate, Pharmaceutical chemicals and so on. Products are exported to USA, Canada, France, Korea, Japan,Russia, Southeast Asia and other countries.
New Directions in Targeted Therapeutic Approaches for Older Adults With Mantl...i3 Health
i3 Health is pleased to make the speaker slides from this activity available for use as a non-accredited self-study or teaching resource.
This slide deck presented by Dr. Kami Maddocks, Professor-Clinical in the Division of Hematology and
Associate Division Director for Ambulatory Operations
The Ohio State University Comprehensive Cancer Center, will provide insight into new directions in targeted therapeutic approaches for older adults with mantle cell lymphoma.
STATEMENT OF NEED
Mantle cell lymphoma (MCL) is a rare, aggressive B-cell non-Hodgkin lymphoma (NHL) accounting for 5% to 7% of all lymphomas. Its prognosis ranges from indolent disease that does not require treatment for years to very aggressive disease, which is associated with poor survival (Silkenstedt et al, 2021). Typically, MCL is diagnosed at advanced stage and in older patients who cannot tolerate intensive therapy (NCCN, 2022). Although recent advances have slightly increased remission rates, recurrence and relapse remain very common, leading to a median overall survival between 3 and 6 years (LLS, 2021). Though there are several effective options, progress is still needed towards establishing an accepted frontline approach for MCL (Castellino et al, 2022). Treatment selection and management of MCL are complicated by the heterogeneity of prognosis, advanced age and comorbidities of patients, and lack of an established standard approach for treatment, making it vital that clinicians be familiar with the latest research and advances in this area. In this activity chaired by Michael Wang, MD, Professor in the Department of Lymphoma & Myeloma at MD Anderson Cancer Center, expert faculty will discuss prognostic factors informing treatment, the promising results of recent trials in new therapeutic approaches, and the implications of treatment resistance in therapeutic selection for MCL.
Target Audience
Hematology/oncology fellows, attending faculty, and other health care professionals involved in the treatment of patients with mantle cell lymphoma (MCL).
Learning Objectives
1.) Identify clinical and biological prognostic factors that can guide treatment decision making for older adults with MCL
2.) Evaluate emerging data on targeted therapeutic approaches for treatment-naive and relapsed/refractory MCL and their applicability to older adults
3.) Assess mechanisms of resistance to targeted therapies for MCL and their implications for treatment selection
Ethanol (CH3CH2OH), or beverage alcohol, is a two-carbon alcohol
that is rapidly distributed in the body and brain. Ethanol alters many
neurochemical systems and has rewarding and addictive properties. It
is the oldest recreational drug and likely contributes to more morbidity,
mortality, and public health costs than all illicit drugs combined. The
5th edition of the Diagnostic and Statistical Manual of Mental Disorders
(DSM-5) integrates alcohol abuse and alcohol dependence into a single
disorder called alcohol use disorder (AUD), with mild, moderate,
and severe subclassifications (American Psychiatric Association, 2013).
In the DSM-5, all types of substance abuse and dependence have been
combined into a single substance use disorder (SUD) on a continuum
from mild to severe. A diagnosis of AUD requires that at least two of
the 11 DSM-5 behaviors be present within a 12-month period (mild
AUD: 2–3 criteria; moderate AUD: 4–5 criteria; severe AUD: 6–11 criteria).
The four main behavioral effects of AUD are impaired control over
drinking, negative social consequences, risky use, and altered physiological
effects (tolerance, withdrawal). This chapter presents an overview
of the prevalence and harmful consequences of AUD in the U.S.,
the systemic nature of the disease, neurocircuitry and stages of AUD,
comorbidities, fetal alcohol spectrum disorders, genetic risk factors, and
pharmacotherapies for AUD.
Recomendações da OMS sobre cuidados maternos e neonatais para uma experiência pós-natal positiva.
Em consonância com os ODS – Objetivos do Desenvolvimento Sustentável e a Estratégia Global para a Saúde das Mulheres, Crianças e Adolescentes, e aplicando uma abordagem baseada nos direitos humanos, os esforços de cuidados pós-natais devem expandir-se para além da cobertura e da simples sobrevivência, de modo a incluir cuidados de qualidade.
Estas diretrizes visam melhorar a qualidade dos cuidados pós-natais essenciais e de rotina prestados às mulheres e aos recém-nascidos, com o objetivo final de melhorar a saúde e o bem-estar materno e neonatal.
Uma “experiência pós-natal positiva” é um resultado importante para todas as mulheres que dão à luz e para os seus recém-nascidos, estabelecendo as bases para a melhoria da saúde e do bem-estar a curto e longo prazo. Uma experiência pós-natal positiva é definida como aquela em que as mulheres, pessoas que gestam, os recém-nascidos, os casais, os pais, os cuidadores e as famílias recebem informação consistente, garantia e apoio de profissionais de saúde motivados; e onde um sistema de saúde flexível e com recursos reconheça as necessidades das mulheres e dos bebês e respeite o seu contexto cultural.
Estas diretrizes consolidadas apresentam algumas recomendações novas e já bem fundamentadas sobre cuidados pós-natais de rotina para mulheres e neonatos que recebem cuidados no pós-parto em unidades de saúde ou na comunidade, independentemente dos recursos disponíveis.
É fornecido um conjunto abrangente de recomendações para cuidados durante o período puerperal, com ênfase nos cuidados essenciais que todas as mulheres e recém-nascidos devem receber, e com a devida atenção à qualidade dos cuidados; isto é, a entrega e a experiência do cuidado recebido. Estas diretrizes atualizam e ampliam as recomendações da OMS de 2014 sobre cuidados pós-natais da mãe e do recém-nascido e complementam as atuais diretrizes da OMS sobre a gestão de complicações pós-natais.
O estabelecimento da amamentação e o manejo das principais intercorrências é contemplada.
Recomendamos muito.
Vamos discutir essas recomendações no nosso curso de pós-graduação em Aleitamento no Instituto Ciclos.
Esta publicação só está disponível em inglês até o momento.
Prof. Marcus Renato de Carvalho
www.agostodourado.com
Novas diretrizes da OMS para os cuidados perinatais de mais qualidade
Transdermal Drug Delivery Systems - A writeup
1. TRANSDERMAL DRUG DELIVERY SYSTEMS
2014
A review write up covering major portion in TDDS includes, introduction, factors, formulations & evaluation aspects..
AL AMEEN COLLEGE OF PHARMACY
Bangalore
2. TABLE OF CONTENTS
Contents
Introduction ______________________________________________________________ 1
Objective __________________________________ 1
Advantages _______________________________________________________________ 1
Disadvantages ____________________________________________________________ 2
Characteristics of Ideal TDDS ___________________________________________ 2
Examples of TDDS _______________________________________________________ 2
Skin (Function, Structure, Mechanism, Permeation – Mechanism, Overcome, Factors) ____________ 3
General Components of TDDS__________________________________________ 11
Formulation Approaches in TDDS _____________________________________ 15
Evaluation of TDDS _____________________________________________________ 20
Evaluation of Adhesive _________________________________________________ 22
Invitro Evaluation _______________________________________________________ 24
Invivo Evaluation _______________________________________________________ 28
Invitro-Invivo Correlation ______________________________________________ 28
References _______________________________________________________________ 28
3. AACP SURAJ C.
Page 1 2013-14 Advanced Drug Delivery System.
INTRODUCTION
Transdermal drug delivery systems utilize skin as a site for continuous drug administration into the systemic circulation.
In simple words TDDS is defined as “a system, where the medicament leaves the formulation and travels into the skin to provide its pharmacological action when applied topically”.
Ex: patches, creams, gels, ointments.
The main aim is to achieve localized or systemic medication through topical application to intact skin.
OBJECTIVES
1. CONTROLEED DRUG DELIVERY: Delivery of the drug at a controlled rate to the intact skin for systemic absorption.
2. ALTERNATE ROUTE SPECIFICITY: System should possess proper physicochemical characteristics to permit ready release of the drug and facilitate its partition from delivery system in to stratum corneum.
3. STABILITY OF THE PATCH: The patch should adhere well to the skin and its physical size and appearance and its placement on the body should not be deterrent to use.
4. NO ADVERSE EFFECTS: The system adhesive, vehicle and active agents should be non- sensitizing and non-irritating to the skin.
5. SKIN STABILITY: System should not permit proliferation of the skin bacteria beneath occlusion.
ADVANTAGES OF TDDS
i. Evades GI Conditions: Avoid GIT drug absorption difficulties caused by GIT pH, enzymatic activity and drug interaction with food, drink or other orally administered drugs.
ii. Alternative to Oral Administration: Substitutes for oral administration of medication when that route is unsuitable as in instance of vomiting or diarrhoea.
iii. No 1st Pass Metabolism: Avoids first pass metabolism of the drug i.e., the initial pass of a drug substance through systemic and portal circulation following GI absorption.
iv. Convenience in administration: Avoid the risk and inconveniences of parenteral and oral therapy and variable absorption metabolism associated with oral therapy.
v. Controllled release: Provides controlled plasma levels of very potent drugs.
vi. Good for Narrow therapeutic index drugs: Allows administration of drugs having narrow therapeutic index.
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vii. Termination advantage: Provide capacity to terminate drug effects rapidly by removal of drug application from surface of the skin.
viii. Emergency administration: Provide ease of administration of medication in emergencies like unconscious, non-responsive, etc.
DISADVANTAGES OF TDDS
I. Irritating drugs: Unsuitable for drugs which are irritating or sensitizing to skin.
II. Adherence problem: Adhesive may not adhere well to all skin types.
III. Not for high blood levels: Drugs that require high blood levels cannot be administered.
IV. Inconvenience in wear: Uncomfortable to wear.
V. Economic value: May not be economical.
CHARACTERISTICS FOR IDEAL TDDS
a) Drug properties independent: the system should deliver the drug regardless to the size and structure at the specified rate of delivery.
b) Selected delivery profile: delivery of the drug as per specified quantity – time profile.
c) Ease of Multiple drugs administration: ideal drug delivery system (IDDS) should be able to deliver more than one therapeutic agent at a time.
d) Flexibility: the IDDS should have the capability for changing or adjusting the rate and amount of delivery.
e) Target specific: this should focus towards drug transport to target site.
f) Ample Capacity: the system is capable of making repeated deliveries between replacements.
g) Conevenience: the TDDS raises or causes no new problems or concerns.
h) Reliability: the TDDS consists of few parts and has reliability in keeping with other delivery systems.
i) Market place value: the TDDS offers high value by featuring maximum functionality at minimum system complexity and cost.
EXAMPLES OF TDDS
TRANSDERM-NITRO: nitroglycerin once a day medication for angina – NOVARTIS.
TRANSDERM-SCOP: scopolamine for 72 hrs in the treatment of motion sickness – NOVARTIS.
TRANS-VER-SAL: salicylic acid for topical keratolytic action – DOAK.
Several other for Antihypertensives, antiangina, antihistamine, anti-inflammatory, analgesic and steroids.
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SKIN
SKIN FUNCTIONS:
1. Protective barrier for internal organs.
2. Ability to sense changes in temperature, pressure or pain.
3. Regulation of body temperature.
4. Excretion of fluids and electrolytes.
5. Stores fat.
6. Provides site for drug absorption.
STRUCTURE OF SKIN
The skin is a multilayered organ, complex in both structure and function.
THE LAYERS OF THE SKIN:
1) EPIDERMIS:
A. Composed of the stratum corneum and stratum germinatum.
B. The outermost stratum corneum layer (10-15μ) is quite dry and consists primarily of blocks of cytoplasmic protein matrices (keratins) embedded in the extracellular lipid.
C. The keratins containing cells known as corneocytes, has an interlocking arrangement.
D. The stratum cells are continuously replenished by the slow upward migration of cells produced by the basal cell layers of stratum germinativum.
2) DERMIS:
A. Composed of a network of collagen and elastin fibers embedded in a muco- polysaccharide matrix, which contains blood vessels, lymphatic and nerve endings, thereby providing physiological support the epidermis.
B. It is well supplied by blood to convey nutrients, remove waste products, regulate body temperature and pressure.
3) HYPODERMIS:
A. Subcutaneous fat layer is a sheet of fat – containing areolar tissue, known as superficial fascia, attaching the dermis to underlying structures.
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MECHANISM OF ABSORPTION:
Primary mechanism of absorption is passive diffusion.
There are two potential routes of drug absorption.
1. Hair follicular/sweat glands (transfollicular):
Water soluble substances are diffused through skin appendages faster than that of other layers of the skin.
Sweat glands and hair follicles act as shunt i.e., easy pathway for diffusion through the rate limiting stratum corneum.
2. Stratum corneum (transepidermal):
Within the stratum corneum molecule penetrate either transcellularly or intercellularly.
Intercellular region are filled with lipid rich amorphous materials. Two possible ways of diffusion are,
a. Transcellular – diffusion occur through the cells.
b. Intercellular – diffusion occur through the intercellular space present between the cells.
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FUNDAMENTALS OF SKIN PERMEATION:
Kinetics for successful development of TDDS involves following steps:
1. Sorption by stratum corneum.
2. Penetration of drug through viable epidermis.
3. Uptake of drug by capillary network in dermal papillary layer.
HOW TO OVERCOME BARRIER- TDDS?
Two important layers in skin: the dermis & the epidermis.
- To circumvent this, it is required to engineer the drugs to be both water-soluble & lipid soluble (best mixture is about 50 % of the drug being each)
- Outermost layer- epidermis 100 to 150 micrometers thick, has no blood flow & includes the stratum corneum.
- S corneum =most imp to transdermal delivery →composition allows to keep water within the body & foreign substances out.
- Stratum corneum = thin, tough, relatively impermeable membrane →usually the rate limiting step in TDDS.
- Dermis: (Beneath epidermis), dermis contains system of capillaries that transport blood throughout the body. If the drug is able to penetrate the stratum corneum, it can enter the blood stream. Passive diffusion =occurs too slowly for practical use.
- “Lipid-soluble substances” readily pass through →intercellular lipid bi-layers of cell membranes.
- “Water-soluble drugs” →pass through skin because of hydrated intracellular proteins”.
- Sweat ducts & hair follicles: Also paths of entry, but = considered rather insignificant.
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Rate permeation across skin is given by:
dQ/ dt = Ps(Cd – Cr)
Where,
dQ/dt – Rate of permeation.
Cd – Concentration of skin penetrants in donor compartment.
Cr – Concentration of skin penetrants in receptor compartment.
Ps – Permeability coefficient of skin tissue to penetrants.
Ps = Ks Dss / hs
Where,
Ks – Partition coefficient for interfacial partitioning of the penetrant molecule from solution medium.
Dss – Apparent diffusivity for steady state diffusion of penetrant molecule through a thickness of skin tissue.
hs – Total thickness of the skin tissues.
NOTE: If Ks/d, Dss & hs are constants then Ps is also constant.
Cd>> Cr ----- constant rate of drug permeation .
dQ/ dt = Ps Cd
To maintain the Cd at a constant value, the drug to be released at a rate (Rr) which is always greater than the rate of skin uptake (Ra). i.e., Rr>>Ra.
The drug concentration on the skin surface (Cd) is maintained at a level greater than the equilibrium solubility of the drug in the stratum corneum (Ces) i.e.,
Cd>>(Ces ) and the maximum rate of skin permeation is reached:
dQ/dt = Ps Ces
FACTORS AFFECTING SKIN PERMEATION:
The principle mechanism across mammalian skin is by passive diffusion through transdermal route at steady state. The following factor effects the permeability.
1. Biological factor
a) Skin age
b) Skin condition
c) Regional site
d) Skin metabolism
e) Circulatory effect
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f) Species difference
2. Physiological and pathological condition of the skin like
a. Reservoir effect of horny layer
b. Lipid film
c. Skin hydration
d. Skin temperature
e. Effect of vehicles
3. Physico-chemical property of drug molecules.
a. solubility and Partition coefficient
b. pH condition
c. polarity
d. crystallinity and melting point
e. penetrant concentration
f. molecular weight
4. Physiochemical properties of drug delivery system.
a. Release characteristic
b. Composition of drug delivery system
c. Permeation enhancer
1. Biological Barrier
Skin age:
Skin of foetus, young ones and elders are permeable than adult tissue.
Children’s are more susceptible for skin toxic effect of drugs and other additives in system.
Skin condition:
Skin is tough barrier to penetration but only when it is intact.
Many agents can damage tissue thereby promotes permeation.
Defective st. corneum results in increase permeability
Rational skin site:
Diffusion is faster in scrotal, trunk, arm region when compare to palm or foot.
Skin metabolism:
Catabolic enzyme activity in viable epidermis is substantial.
Infect the viable epidermis is metabolically active than dermis.
If the topically applied drug is subjected to biotransformation during skin permeation and systemic bioavailability can be affected markedly.
Circulatory effects:
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Changes in peripheral circulation of blood flow through dermis could affect percutaneous absorption.
Thus an increased blood flow could reduce time for a penetrant remains in dermis and so raise the concentration gradient across the skin.
Species difference:
Different species of mammalian skin display wide difference in anatomy between common laboratory animals.
2. Physiological and pathological effect
Reservoir effect of horny layer:
It is a deeper layer sometimes it acts as depot.
And modify transdermal permeation characteristics of drugs.
Reservoir effect is due to irreversible binding of part of applied drug on skin.
This binding can be reduced by treatment of skin surface with anionic surfactants.
Lipid film:
Lipid film on skin surface act as protective layer to prevent removal of moisture from skin and helps in maintaining barrier function of st.corneum.
Defatting of this film found to decrease transdermal absorption.
Skin hydration:
Enhances permeability.
Hydration can be achieved by covering or occluding skin with plastic sheeting, increases hydration appear to open up dense, closely packed cells of skin and increases its porosity.
Skin temperature:
It is directly proportional to the temperature.
This is mainly due to – Thermal energy required for diffusivity.
- Solubility of drug in skin tissue.
- Increased vasodilatation of skin vessels.
- Occlusion of skin surface increases the temperature by 2-3 centigrade result in increased molecular motion and skin permeation.
Effect of vehicle:
A vehicle can influence the percutaneous absorption by its potential effect on physical states of skin.
Ex: Grease, paraffin bases are most occlusive while w/o bases are less. Humectants in bases may dehydrate skin therefore decrease percutaneous absorption.
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3. Physico-chemical property of the drug molecules:
Solubility and partition coefficient:
Solubility of drug greatly influence on ability to penetrate in to skin.
Partition coefficient which is the index of relative solubilisation of drug in vehicle and st.corneum has profound influence on transfer of drug from vehicle in to skin.
Drug solubility on the other hand determines concentration of drug present on absorption site.
Thus can effect rate and extent of drug absorption.
The vehicle partition coefficient roughly proportional to relative solubility in st.corneum and vehicle.
Skin permeation can be increase by increasing lipophilic character of drug, therefore drug having both lipid and water solubility are well absorbed through skin.
pH condition:
Application of solution whose pH value are very high or very low can be destructive to skin hence moderate pH favourable for drugs to penetrate through skin.
The flux of ionisable drugs can be affected by changes in pH that alters the ratio of charged and uncharged species and their skin permeability.
Penetration concentration:
Generally higher the concentration of dissolved drug in vehicle faster the absorption.
At conc. higher than the solubility excess solid drug function as reservoir and helps to maintain a constant drug for prolonged period of time.
Crystallinity and melting point:
The concentration of drug in any medium is related to heat of fusion and melting point.
According to theory, the solubility of the drug is related to two important thermodynamic parameter, heat of fusion and melting point.
Hard crystalline material with enthalpies of fusion are less soluble than soft, low melting compounds.
Hydrophobic molecules generally have low degree of crystallinity and owing to the very small net negative free energy of hydrophobic molecules in water, therefore hydrophobic drugs are low solubility in water.
Polarity:
The polarity of a drug molecule affect its skin permeability by imparting the partition co efficient.
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4. Physico-chemical properties of drug delivery system:
Release characteristic:
Solubility of drug in the vehicle determines release rate.
The mechanism of drug release depends on,
-whether drug molecules are dissolve or suspended in delivery system.
- Interfacial partition coefficient of drug from delivery system to skin tissue.
- pH of the vehicle.
Composition of drug delivery system:
It not only affects the rate of drug release but also permeability of st,corneum by means of hydration mixing with skin lipids or other sorption promoting effects.
Eg: Methyl salicylates is more lipophilic than its parent acid. When applied to skin from fatty vehicle, the methyl salicylates yielded higher percutaneous absorption.
Enhancement of skin permeation:
Permeation of most of the drugs can be improved by addition of permeation enhancer in to the delivery system.
Because majority of drugs will not penetrate through skin at rate sufficiently high for therapeutic efficiency.
COMPONENTS OF TDDS
The components of TDDS are:
1. Polymeric membrane
2. Drug reservoir
3. Permeation enhancers
4. Other excipients- Adhesive and backing membrane.
POLYMERIC MEMBRANE:
• Polymer controls the release of the drug from the device.
DRUG RESERVOIR
ADHESIVE LAYER
DRUG-IMPERMEABLE METALLIC PLASTIC LAMINATE
RATE CONTROLING POLYMERIC MEMBRANE
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• Molecular weight, physical characteristics and chemical functionality of the polymer must allow the diffusion of the drug substances at a desirable rate.
• Should be chemically non-reactive or it should be an inert drug carrier.
• The polymer must not decompose on storage or during is shelf life.
• Polymer and it’s decompose product should not be toxic.
• Easy to manufacture and fabricate into desired product.
• Mechanical properties of polymer should not deteriorate excessively.
• The cost of the polymer should not be excessively high or inexpensive.
Examples of polymers:
1. Natural Polymers:
E.g. cellulose derivatives, zein, gelatin, shellac, waxes, gums, natural rubber and chitosan etc.
2. Synthetic Elastomers:
E.g.: polybutadiene, hydrin rubber, polyisobutylene, silicon rubber, nitrile, acrylonitrile, neoprene, butylrubber etc.
3. Synthetic Polymers:
E.g. polyvinyl alcohol, polyvinyl- chloride, polyethylene, Polypropylene, polyacrylate, polyamide, polyurea, polyvinylpyrrolidone, polymethyl-methacrylate
DRUG RESERVOIR:
Drug reservoir can be prepared by dispersion of drug in liquid or solid state synthetic polymer base.
Drug reservoir may be in,
- Reservoir system
- Matrix system
- Microreservoir system
The important drug properties that affect its diffusion from devices as well as across the skin include molecular weight, chemical functionality and physical properties.
1. PHYSICO-CHEMICAL PROPERTIES OF DRUG:
o Should have molecular weight less than 500 Daltons.
o Should have affinity for both lipophilic and hydrophilic phase.
o Should have low melting point.
2. BIOLOGICAL PROPERTIES OF DRUG:
o Should be potent with daily dose of few mg/day.
o Should have short half-life.
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o Drugs must not induce irritant or allergic response
o Drugs which degrade in the GIT or are in activated by hepatic first pass effect are suitable candidates.
o Drugs which have to be administered for long period of time or which causes adverse effects to non-target tissues can also be formulated.
PERMEATION ENHANCERS
The compounds which promotes skin permeability by altering the skin as a barrier of flux of a desired penetrant.
The flux J of the drug across the skin can be written as:
J = D. dc/dx
Where,
D – Diffusion coefficient.
C – Concentration of diffusing molecule.
dx – Spatial co-ordinate.
The concentration gradient is thermodynamically in origin and diffusion co-efficient is related to size and shape of permeant and energy required to make a hole for diffusion.
IDEAL PROPERTIES OF PENETRATION ENHANCERS:
Pharmacologically inert.
Nontoxic, non-allergic and non-irritating.
Immediate and predictable action.
Upon removal, skin should immediately and fully recover its normal barrier properties.
Compatible with all drugs and excipients
Odourless, elastic, colourless and inexpensive.
MECHANISM – PERMEATION ENHANCERS:
They act by three mechanisms:
A. Reduces the resistance of stratum corneum by altering its physicochemical properties.
B. Alteration of hydration of stratum corneum.
C. Affecting the structure of lipids and protein in intercellular channel through solvent action or denaturation and sometimes carrier mechanism is observed.
TYPES – PERMEATION ENHANCERS:
1. CHEMICAL PENETRATION ENHANCERS: The various types of chemical penetration enhancers are-
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Enhancers include a wide range of chemical entities that increase skin permeability, such as sulphoxides, alcohols, polyols, alkanes, fatty acids, esters, amines and amides, terpenes, surfactants, cyclodextrin, water etc., some of them are:
a) Solvents or water: acts by hydrating the stratum corneum, chemically inactive and non- damaging.
E.g. Urea, pyrrolidones.
b) Lipid modifiers: they interact with organised intercellular lipid of horny layer and increase permeability of skin.
E.g. Ethanol.
c) Protein modifiers: surfactants interact with keratin to open dense keratin structure and make it permeable.
E.g. Dimethyl sulfoxide.
d) Partitioning promoters: increase partitioning of the drug into horny layer.
E.g. Propylene glycol.
e) Ion pairs: lipophilic ion pair is made by adding suitable opposite charge to drug. This complex readily penetrates skin.
E.g. Anionic and cationic surfactants.
f) Prodrug: some drugs do not pass horny layer easily due to physicochemical properties of drug and skin, so prodrug with optimal partition coefficient has been employed.
Eg. Steroids and anti-inflammatory agents.
g) Liposome: colloidal drug particles are made with phospholipids and cholesterol to increase permeability.
2. PHYSICAL PENETRATION ENHANCERS: * (given in detail about 3 types in end)
a) Electroporation: this includes short duration voltage to increase permeability, creating hydrophilic pores in the skin and increase the penetration of the drug. The pulse of 100V is applied per millisecond.
E.g., calcitonin
b) Sonophorosis: ultrasound pulses are passed through the probe into the skin fluidizing the lipid bilayer by the formation of bubbles caused by cavitation. The force of cavitation causes the formation of holes in the coenocytes, enlarging of intercellular spaces and perturbation of stratum corneum lipids.
c) Laser ablation: utilizes high power pulses from a laser source and vaporizes the stratum corneum, creating discrete permeable windows through which the drug molecules passes easily.
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d) Needle array: Needles of approximately with or without center hollow channels are placed onto the skin surface to penetrate the stratum corneum and epidermis without reaching the nerve endings present in the upper dermis.
Eg: These needles are made up of silicon or hollow metals.
e) Ionotophoresis: the basic principle of iontophoresis is a small current is applied to the skin. This provides the driving force to enable penetration of the charged molecule into the skin. A drug reservoir is placed on the skin under the active electrode with same charge as the penetrant.
f) Stratum corneum removal: This involves the removal of stratum corneum by adhesive tape to increase the drug penetration.
g) High velocity particles: this includes powder jet system which fires solid particles through horny layer to lower skin layer, using supersonic shockwaves of helium gas at high pressure. It is pain free, target delivery, fast release and safe on skin.
OTHER EXCIPIENTS:
1. ADHESIVES
Should not irritate or sensitize skin or cause imbalance in normal skin flora during its contact time with skin.
Should adhere to skin aggressively during dosing interval without its position being disturbed by activities like bathing, exercise etc.
Should not leave an un-washable residue on skin.
Should have an excellent contact with skin at macroscopic and microscopic level.
Pressure sensitive adhesives are used.
Eg. Polyisobutylenes, acrylic acids and silicones.
2. BACKING MEMBRANE:
Are flexible and provide good bond to drug reservoir.
Prevent the drug leaving the dosage form from the top and accept printing.
Eg. Metallic plastic laminate, plastic backing with absorbent pad and occlusive are plate (aluminium foil).
FORMULATION APPROACHES IN TDDS
1. Membrane Moderated TDDS
2. Adhesive Diffusion Controlled TDDS
3. Matrix Dispersion TDDS
4. Microreservoir Type TDDS
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MEMBRANE MODERATED TDDS:
The drug reservoir is totally encapsulated in a shallow compartment molded from a drug- impermeable metallic plastic laminate and a rate controlling polymeric membrane.
The drug reservoir, the drug is either dispersed in a solid polymer matrix (e.g polyisobutylene) or suspended in an unleachable, viscous liquid medium.
E.g., silicone fluid to form a paste like suspension or dissolved in a releaseable solvent (eg. Alkylalcohol).
The rate limiting membrane can be either micro-porous or non-porous in nature (ethylene- vinyl acetate).
On the external surface of the polymeric membrane, a thin layer of drug compatible, hypoallergenic adhesive polymer like silicone or polyacrylate adhesive is applied.
The rate of drug release from this type of transdermal drug delivery system can be adjusted by varying the polymer composition, permeability coefficient and thickness of the rate limiting membrane and adhesive.
The intrinsic rate of drug release from this type of drug delivery system is defined by:
OR
dQ/dt = CR
1/Pm + 1/Pa
where,
CR -the drug concentration in the reservoir compartment.
Pa and Pm -permeability co-efficients of the adhesive layer and rate-controlling membrane.
Pm and Pa are defined as :
DRUG RESERVOIR
ADHESIVE LAYER
DRUG-IMPERMEABLE METALLIC PLASTIC LAMINATE
RATE CONTROLING POLYMERIC MEMBRANE
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Pm = Km/r .Dm/δm
Pa = Ka/m. Da /δa
Where,
Km/r and Ka/m – partition coefficients for the interfacial partitioning of the drug from the reservoir to the membrane and from the membrane to the adhesive.
Dm and Da – diffusion co-efficient in the rate controlling membrane and adhesive layer.
δa and δm – are the thickness of the rate controlling membrane and adhesive layer.
Example of formulation: The membrane permeation-controlled transdermal drug delivery has been applied to the development of transdermal system for controlled percutaneous absorption of estradiol and prostaglandin derivative.
ADHESIVE DIFFUSION CONTROLLED TDDS:
Simpler version of membrane moderated drug delivery system.
The drug reservoir in a compartment is fabricated from a drug-impermeable metallic plastic backing.
The drug reservoir is formulated by dispersing the drug in an adhesive polymer and then spreading the medicated adhesive, by solvent casting, onto a flat sheet of drug impermeable metallic plastic backing to form a thin drug reservoir layer.
Over the drug reservoir layer, layers of non-medicated, rate-controlling adhesive polymer of constant thickness are applied to produce an adhesive diffusion-conrolled drug delivery system.
The rate of drug release is defined by:
dQ/dt = Ka/r .Da.CR /δa
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Where,
Ka/r – partition coefficient for interfacial partitioning of drug from the reservoir to adhesive layer.
Examples: This system is best illustrated by development of
nitroglycerin-releasing transdermal system (Deponit system/Pharma-Schwartz) and
isosorbide dinitrate-releasing transdermal system (Frandol tape/ Toaeiyo) for once a day medication of angina pectoris.
MATRIX DISPERSION – TYPE SYSTEMS
The drug reservoir is formed by homogeneously dispersing the drug solids in a hydrophilic or lipohilic polymer matrix and the medicated polymer is molded into medicated disc with a defined surface area and controlled thickness.
Drug-reservoir containing polymer disc is then glued onto an occlusive base plate in a compartment fabricated from impermeable plastic backing.
The adhesive polymer is spread along the circumference to form a strip of adhesive rim around the medicated disc.
The rate of drug release from the matrix dispersion type TDDS is defined as:
dQ/dt = (ACpDp/2t)1/2
Where,
A – initial drug loading dose dispersed in the polymer matrix.
Cp and Dp – are solubility and diffusivity of the drug in the polymer.
At steady state, a Q versus t drug release profile is obtained as defined:
Q/t = [(2A – Cp)CpDp]1/2
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Examples: This TDDS is exemplified by development of nitro-glycerin-releasing transdermal system (Nitro-Dur system/Key), approved by FDA for once a day medication of angina pectoris.
MICRO-RESERVOIR SYSTEMS:
It is a combination of the reservoir and matrix dispersion-type drug delivery systems.
The drug reservoir is formed by suspending the drug solids in an aqueous solution of water- soluble polymer and dispersing the drug suspension in a lipophilic polymer by mechanical force to form unleachable microscopic spheres of drug reservoirs.
This thermodynamically unstable suspension is stabilized by cross-linking the polymer chains to produce a polymeric disc.
Example: Nitro glycerin – releasing transdermal system ( Nitrodisc system/ Searle) for once a day treatment of angina pectoris.
The rate of drug release from the microreservoir drug delivery system is defined by:
Where,
Kl, Km and KP - are partition coefficients for the interfacial partitioning of drug in the liquid compartment and the polymeric matrix.
Dl, DP and DS- drug diffusivities in the liquid compartment, polymer coating membrane and elution solution.
Sl and SP – solubilities of the drug in the liquid compartment and polymer matrix.
δl, δP and δd – thicknesses of the liquid layer, polymer coating membrane and hydrodynamic diffusion layer.
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β – is the ratio of the drug concentration at the inner edge of the interfacial barrier over the drug solubility in the polymer layer.
EVALUATION OF TDDS
Transdermal drug delivery system requires systemic evaluation at various stages of its development. These evaluation are described below:
Physico-chemical Evaluation
In vitro release study
In vivo Evaluation
Invitro-In vivo Correlation
PHYSICO-CHEMICAL EVALUATION
1. Thickness of the patch:
The thickness of the prepared patch is measured by using a digital micrometer at different point of patch.
This determines the average thickness and standard deviation for the same to ensure the thickness of the prepared patch
2. Weight uniformity :
The prepared patches are dried at 60°C for 4 h before testing.
A specified area of patch is to be cut in different parts of the patch and weighed in digital balance.
The average weight and standard deviation values are to be calculated from the individual weights.
3. Folding endurance :
A specific area of strip is cut and repeatedly folded at the same place till it broke.
The number of times the film could be folded without breaking gave the value of folding endurance.
4. Percentage moisture content :
The prepared patches are weighed individually and to be kept in a desiccator containing fused calcium chloride at room temperature.
After 24 h, the films are to be reweighed and the percentage moisture content determined by below formula………
Percentage moisture content (%) = [Initial weight – Final weight / Final weight] ×100
5. Percentage moisture uptake:
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The prepared patches are to be weighed individually and to be kept in a desiccator containing saturated solution of potassium chloride in order to maintain 84% Rhesus factor (RH).
After 24 h, the films are to be reweighed and the percentage moisture uptake determined by the formula
Percentage moisture content (%) = [Initial weight - Final weight / Final weight]×100
6. Water vapor permeability (WVP) evaluation:
Water vapor permeability can be determined by a natural air circulation oven.
The WVP can be determined by the following formula………….
WVP = W/A
Where,
WVP = expressed in g/m2 per 24 h,
W = the amount of vapor permeated through the patch expressed in g/24 h,
A = surface area of the exposure samples expressed in…….
m2.weight / initial wt × 100
7. Drug content:
A specified area of patch is to be dissolved in a suitable solvent in specific volume.
Then, the solution is to be filtered through a filter medium and the drug content analyzed with the suitable method (UV or HPLC technique).
Then, the average of three different samples is taken.
8. Content uniformity test:
Ten (10) patches were selected and content determined for individual patches.
If 9 out of 10 patches have content between 85 to 115% of the specified value and one has content not less than 75 to125% of the specified value, then transdermal patches pass the test of content uniformity.
But if 3 patches have content in the range of 75 to 125%, then additional 20 patches are tested for drug content. If these 20 patches have range from 85 to 115%, then the transdermal patches pass the test.
9. Percentage elongation break test :
The percentage elongation break was determined by noting the length just before the break point and determined from the formula………..
Elongation percentages = L1 - L2 × 100
L2
Where ,
L1 = final length of each strip;
L2 = initial length of each strip.
10. Flatness test:
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Three longitudinal strips were cut from each film at different portion like one from the center, other one from the left side, and another one from the right side.
The length of each strip was measured, and the variation in length because of non-uniformity in flatness was measured by determining percentage constriction, with 0% constriction equivalent to 100% flatness.
Constriction (%) = I1- I2 × 100 I1
Where,
I1 = initial length of each strip.
I2 = final length of each strip.
11. Polariscope examination:
This test is to be performed to examine the drug crystal from patch by polariscope.
A specific surface area of piece is to be kept on object slide and observe for drug crystal.
To distinguish whether the drug crystal are present in amorphous or crystalline form.
12. Stability studies:
Stability studies were conducted according to the International Conference on Harmonization (ICH) guidelines by storing the TDDS samples at 40 ± 0.5°C and 75 ± 5% RH for 6 months.
The samples were withdrawn at 0, 30, 60, 90 and 180 days and analyzed suitably for the drug content.
EVALUATION OF ADHESIVE
Pressure sensitive adhesive are evaluated for the following properties:
1. Peel adhesion properties
2. Tack properties
o Thumb tack test
o Roll ball tack test
o Quick stick (peel-tack) test
o Probes tack test
3. Shear strength test
1. Peel adhesion properties
Peel adhesion is the force required to remove an adhesive coating from a test substrate.
It is important in transdermal devices because the adhesive should provide adequate contact of device with the skin and should not damage the skin on removal.
Peel adhesion properties are affected by the molecular weight of the adhesive polymer, the type and amount of additives and polymer composition.
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It is tested by measuring the force required to pull a single coated tape applied to a substrate at an angle of 180°. No residue on the substrate indicates ‘adhesive failure’ which is desirable for transdermal devices.
2. Tack properties
Tack is the ability of a polymer to adhere to a substrate with little contact pressure. It is important in transdermal devices which are applied with finger pressure.
The tack tests include,……….
a. Thumb tack test:
This is a subjective test in which evaluation is done by pressing the thumb briefly into the adhesive.
Experience is required for this test.
b. Roll ball tack test:
This test involves measurement of the distance that a stainless steel ball travels along an upward-facing adhesive.
The less tacky the adhesive, the farther the ball will travel.
c. Quick stick (peel-tack) test:
The peel force required to break the bond between an adhesive and substrate is measured by pulling the tape away from the substrate at 90° at a speed of 12 inch/min.
d. Probes tack test:
The force required to pull a probe away from an adhesive at a fixed rate is recorded as tack(expressed in grams).
3. Shear strength test:
It is the measurement of the cohesive strength of an adhesive polymer.
Adequate cohesive strength of a device will mean that the device will not slip on application and will leave no residue on removal.
It is affected by molecular weight as well as the type and amount of tackifier added.
Shear strength or creep resistance is determined by measuring the time it takes to pull an adhesive coated tape off a stainless steel plate when a specified weight is hung from the from the tape which pulls the tape in a direction parallel to the plate.
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IN VITRO EVALUATION OF TDDS
The paddle over disc method (USP apparatus V) can be employed for assessment of the release of the drug from the prepared patches.
Dry films of known thickness were cut into definite shape, weighed, and fixed over a glass plate(disc) with an adhesive.
The glass plate was then placed in a 500 ml of the dissolution medium or phosphate buffer (pH 7.4), and the apparatus was equilibrated to 32 ± 0.5°C.
The paddle was then set at a distance of 2.5 cm from the glass plate and operated at a speed of 50 rpm.
Samples (5 ml aliquots) can be withdrawn at appropriate time intervals up to 24 h and analyzed by UV spectrophotometer or HPLC.
The experiment was performed in triplicate and the mean value calculated
IN VITRO SKIN PERMEATION STUDIES
An in vitro permeation study can be carried out by using diffusion cell on thick abdominal skin of male Wurstar rats weighing 200 to 250 g.
Hair from the abdominal region is removed carefully by using an electric clipper.
The dermal side of the skin was thoroughly cleaned with distilled water to remove any adhering tissues or blood vessels, equilibrated for an hour in dissolution medium or phosphate buffer pH 7.4 before starting the experiment.
It was placed on a magnetic stirrer with a small magnetic needle for uniform distribution of the diffusant.
The temperature of the cell was maintained at 32 ± 0.5°C using a thermostatically controlled heater.
The isolated rat skin piece was mounted between the compartments of the diffusion cell, with the epidermis facing upward into the donor compartment.
Sample volume of definite volume was removed from the receptor compartment at regular intervals, and an equal volume of fresh medium was replaced.
Samples were filtered through filtering medium and analyzed spectrophotometrically or using HPLC.
Flux was determined directly as the slope of the curve between the steady-state values of the amount of drug permeated (mg cm2) versus time in hours.
Permeability coefficients were deduced by dividing the flux by the initial drug load (mg cm2).
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KINETIC EVALUATION OF TRANSDERMAL THERAPEUTIC SYSTEMS
The release and skin permeation kinetics of drug from these technologically different transdermal therapeutic systems can be evaluated, using a two-compartment diffusion cell assembly, under identical conditions.
It is carried out by mounting, individually, the full-thickness abdominal skin, which has been freshly excised from either human cadaver or hairless mouse, on an eight-cell Franz diffusion assembly.
The drug delivery systems are then applied with their drug-releasing surface in intimate contact with the stratum corneum surface of the skin.
The skin profile of the drug is followed by sampling the receptor solution at predetermined intervals for a duration of up to 30h and assaying drug concentrations in the samples by a sensitive analytical method, such as HPLC method.
In-vitro Drug Release Kinetics:
Using Franz diffusion cell assembly, the controlled release kinetics of drugs from these technologically-different transdermal therapeutic system can be evaluated and compared.
E.g. :
The results indicated that nitroglycerin is released at a constant rate profile Transderm-Nitro system (a membrane-moderated transdermal therapeutic system) and Deponit system(an adhesive diffusion-controlled transdermal drug delivery system).
The release rate of nitroglycerin from the Transderm-Nitro system is almost 3 times greater than that from the Deponit system.
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This suggests that the rate controlling membrane of Deponit system plays a greater rate-controlling role over the release of nitroglycerin than does the rate-controlling membrane in the Transderm-Nitro system.
E.g. :
Similarly, the release rate of nitroglycerin from Nitro-Dur system(a matrix dispersion- type transdermal therapeutic system) is about twice greater than that from Nitrodisc system(a microreservior-type transdermal therapeutic system).
- Nitrodisc–2.443±0.136mg/cm2/day,
- Nitro-Dur–4.124±0.047mg/cm2/day,
- Transderm-Nitro–0.843±0.035mg/cm2/day,
- Deponit – 0.324±0.011mg/cm2/day.
In Vitro Skin Permeation Kinetics-Animal Model:
The skin permeation studies showed that all four transdermal therapeutic systems provide a constant rate of skin permeation.
Ex:
A highest rate of skin permeation was observed with Nitrodisc system, which is no different from the rate of skin permeation for pure Nitroglycerin.
For Nitro-Dur system the same rate of skin permeation was observed initially and 12hr later the rate slowed down.
On the other hand the rate of skin permeation of nitroglycerin delivered by Transderm–Nitro was found to be to be 30% lower than the rate achieved by pure nitroglycerin.
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The lowest rate of skin permeation was observed with Deponit system , which is only 37% of the skin permeation rate for pure nitroglycerin.
- Nitrodisc – 0.426 ± 0.024mg/cm2/day,
- Nitro-Dur – 0.408 ± 0.024mg/cm2/day,
- Tansderm-Nitro – 0.338 ± 0.17mg/cm2/day,
- Deponit – 0.175 ± 0.016mg/cm2/day.
In Vitro Skin Permeation Kinetics –Human Cadaver:
The permeation of nitroglycerin across the human cadaver skin was investigated for Transderm-Nitro system and Nitro-Dur system.
The results indicated that the skin permeation of nitroglycerin through human cadaver abdominal epidermis also follows the same kinetic profile as observed with hairless mouse abdominal skin, suggesting that the hairless mouse skin could be an acceptable animal model for human in the skin permeation kinetic studies of nitroglycerin.
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In Vivo Transdermal Bioavailability In Humans:
The transdermal bioavailability of nitroglycerin resulted from the 24-32hr topical applications of various transdermal therapeutic system in human volunteers.
Results suggest that a prolonged, steady state plasma level of nitroglycerin is achieved within 1-2hr and maintained for a duration of at least 24hr as a result of continuous transdermal infusion of drug at a controlled rate from the transdermal therapeutic system.
In-vitro – In-vivo Correlation:
To further examine the feasibility of using hairless mouse skin as animal model for studying transdermal controlled permeation kinetics of drug across the human skin, the in vivo rate of skin permeation should be determined for comparison.
It can be calculated from the steady state plasma level data using the following equation,
(Q /t)i.v = (CP)SS.Ke.Vd
Where,
Ke = first-order rate constant for elimination of drug and Vd is the apparent volume of distribution of drug.
This in vivo - in vitro agreement provides additional evidence that hairless mouse skin could be an acceptable animal model for studying skin permeation kinetics of systemically effective drugs, like nitroglycerin, in humans.
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DELIVERY SYSTEMS HAIRLESS MOUSE HUMAN CADEVER IN VIVOd Nitroglycerin alone 0.476a 0.312b - Nitrodisc 0.426 - 0.473 Nitro-Dur 0.408 0.487c 0.412 Transderm-Nitro 0.338 0.461c 0.428 Deponit 0.175 - -
NOTE:
a determined from skin permeation studies of pure nitroglycerin across full-thickness hairless mouse abdominal skin at 37°C.
b determined from an aqueous solution of nitroglycerin at 30°C.
C determined from skin permeation studies at 37°C using the epidermis isolated from human cadaver abdominal skin.
REFERENCES
1. Y.W Chein, Novel Drug Delivery Systems, 2nd edition Marcel Dekker, New York .
2. Robinson, J.R., Lee V.H.L, Controlled Drug Delivery Systems, Marcel Dekker, New York. p. 523 – 547.
3. Comprehensive Journal of Pharmaceutical Sciences Vol. 1(1), pp. 1 - 10, Feb. 2013