This document discusses approaches for injectable controlled release formulations. It begins by defining controlled release as the delivery of a drug at a predetermined rate to maintain optimal levels over a prolonged duration. It then discusses various approaches including dissolution controlled, adsorption type depots, encapsulation systems, and esterification type depots. Specific examples are provided for each approach. The document also discusses formulations like microparticles, nanoparticles, and liposomes that can provide controlled release when administered via injection.
Introduction
Structure
Niosomes Vs. Liposome
Advantages & Disadvantages
Properties of Niosomes
Method of Manufacturing
Evaluation of Niosomes
Applications
Marketed products
Introduction
Structure
Niosomes Vs. Liposome
Advantages & Disadvantages
Properties of Niosomes
Method of Manufacturing
Evaluation of Niosomes
Applications
Marketed products
Pharmacosomes are the colloidal dispersions of drugs covalently bound to lipids, and may exist as ultrafine vesicular, micellar, or hexagonal aggregates, depending on the chemical structure of drug-lipid complex.
NIOSOMES , GENERAL CHARACTERISTICS OF NIOSOME , TYPES OF NIOSOMES , OTHERS TYPES OF NIOSOMES , NIOSOMES VS LIPOSOMES , COMPONENTS OF NIOSOMES , Non-ionic surfactant , Cholesterol , Charge inducing molecule , METHOD OF PREPARATION , preparation of small unilamellar vesicles , Sonication , Micro fluidization , preparation of large unilamellar vesicles , Reverse Phase Evaporation , Ether Injection , preparation of Multilamellar vesicles , Hand shaking method , Trans membrane pH gradient drug uptake process (remote loading) , Miscellaneous method :Multiple membrane extrusion method , The “Bubble” Method , Formation of Niosomes From Proniosomes , SEPARATION OF UNENTRAPPED DRUGS , Gel Filtration , Dialysis , Centrifugation , FACTORS AFFECTING THE PHYSICOCHEMICAL PROPERTIES OF NIOSOMES , Membrane Additives , Temperature of Hydration , PROPERTIES OF DRUGS , AMOUNT AND TYPE OF SURFACTANT
Structure of Surfactants , Resistance to Osmotic Stress , Characterization of niosomes ,Therapeutic applications of Niosomes , For Controlled Release of Drugs , To Improve the Stability and Physical Properties of the Drugs , For Targeting and Retention of Drug in Blood Circulation , Proniosomes , Aspasomes , Vesicles in Water and Oil System (v/w/o) ,Bola - niosomes , Discomes , Deformable niosomes or elastic niosomes , According to the nature of lamellarity ,Small Unilamellar vesicles (SUV) 25 – 500 nm in size.,Large Unilamellar vesicles (LUV) 0.1 – 1μm in size , Multilamellar vesicles (MLV) 1-5 μm in size , According to the size:Small Niosomes (100 nm – 200 nm) , Large Niosomes (800 nm – 900 nm),Big Niosomes (2 μm – 4 μm)
Pharmacosomes are the colloidal dispersions of drugs covalently bound to lipids, and may exist as ultrafine vesicular, micellar, or hexagonal aggregates, depending on the chemical structure of drug-lipid complex.
NIOSOMES , GENERAL CHARACTERISTICS OF NIOSOME , TYPES OF NIOSOMES , OTHERS TYPES OF NIOSOMES , NIOSOMES VS LIPOSOMES , COMPONENTS OF NIOSOMES , Non-ionic surfactant , Cholesterol , Charge inducing molecule , METHOD OF PREPARATION , preparation of small unilamellar vesicles , Sonication , Micro fluidization , preparation of large unilamellar vesicles , Reverse Phase Evaporation , Ether Injection , preparation of Multilamellar vesicles , Hand shaking method , Trans membrane pH gradient drug uptake process (remote loading) , Miscellaneous method :Multiple membrane extrusion method , The “Bubble” Method , Formation of Niosomes From Proniosomes , SEPARATION OF UNENTRAPPED DRUGS , Gel Filtration , Dialysis , Centrifugation , FACTORS AFFECTING THE PHYSICOCHEMICAL PROPERTIES OF NIOSOMES , Membrane Additives , Temperature of Hydration , PROPERTIES OF DRUGS , AMOUNT AND TYPE OF SURFACTANT
Structure of Surfactants , Resistance to Osmotic Stress , Characterization of niosomes ,Therapeutic applications of Niosomes , For Controlled Release of Drugs , To Improve the Stability and Physical Properties of the Drugs , For Targeting and Retention of Drug in Blood Circulation , Proniosomes , Aspasomes , Vesicles in Water and Oil System (v/w/o) ,Bola - niosomes , Discomes , Deformable niosomes or elastic niosomes , According to the nature of lamellarity ,Small Unilamellar vesicles (SUV) 25 – 500 nm in size.,Large Unilamellar vesicles (LUV) 0.1 – 1μm in size , Multilamellar vesicles (MLV) 1-5 μm in size , According to the size:Small Niosomes (100 nm – 200 nm) , Large Niosomes (800 nm – 900 nm),Big Niosomes (2 μm – 4 μm)
Prix Galien International 2024 Forum ProgramLevi Shapiro
June 20, 2024, Prix Galien International and Jerusalem Ethics Forum in ROME. Detailed agenda including panels:
- ADVANCES IN CARDIOLOGY: A NEW PARADIGM IS COMING
- WOMEN’S HEALTH: FERTILITY PRESERVATION
- WHAT’S NEW IN THE TREATMENT OF INFECTIOUS,
ONCOLOGICAL AND INFLAMMATORY SKIN DISEASES?
- ARTIFICIAL INTELLIGENCE AND ETHICS
- GENE THERAPY
- BEYOND BORDERS: GLOBAL INITIATIVES FOR DEMOCRATIZING LIFE SCIENCE TECHNOLOGIES AND PROMOTING ACCESS TO HEALTHCARE
- ETHICAL CHALLENGES IN LIFE SCIENCES
- Prix Galien International Awards Ceremony
micro teaching on communication m.sc nursing.pdfAnurag Sharma
Microteaching is a unique model of practice teaching. It is a viable instrument for the. desired change in the teaching behavior or the behavior potential which, in specified types of real. classroom situations, tends to facilitate the achievement of specified types of objectives.
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
MANAGEMENT OF ATRIOVENTRICULAR CONDUCTION BLOCK.pdfJim Jacob Roy
Cardiac conduction defects can occur due to various causes.
Atrioventricular conduction blocks ( AV blocks ) are classified into 3 types.
This document describes the acute management of AV block.
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Flu Vaccine Alert in Bangalore Karnatakaaddon Scans
As flu season approaches, health officials in Bangalore, Karnataka, are urging residents to get their flu vaccinations. The seasonal flu, while common, can lead to severe health complications, particularly for vulnerable populations such as young children, the elderly, and those with underlying health conditions.
Dr. Vidisha Kumari, a leading epidemiologist in Bangalore, emphasizes the importance of getting vaccinated. "The flu vaccine is our best defense against the influenza virus. It not only protects individuals but also helps prevent the spread of the virus in our communities," he says.
This year, the flu season is expected to coincide with a potential increase in other respiratory illnesses. The Karnataka Health Department has launched an awareness campaign highlighting the significance of flu vaccinations. They have set up multiple vaccination centers across Bangalore, making it convenient for residents to receive their shots.
To encourage widespread vaccination, the government is also collaborating with local schools, workplaces, and community centers to facilitate vaccination drives. Special attention is being given to ensuring that the vaccine is accessible to all, including marginalized communities who may have limited access to healthcare.
Residents are reminded that the flu vaccine is safe and effective. Common side effects are mild and may include soreness at the injection site, mild fever, or muscle aches. These side effects are generally short-lived and far less severe than the flu itself.
Healthcare providers are also stressing the importance of continuing COVID-19 precautions. Wearing masks, practicing good hand hygiene, and maintaining social distancing are still crucial, especially in crowded places.
Protect yourself and your loved ones by getting vaccinated. Together, we can help keep Bangalore healthy and safe this flu season. For more information on vaccination centers and schedules, residents can visit the Karnataka Health Department’s official website or follow their social media pages.
Stay informed, stay safe, and get your flu shot today!
Tom Selleck Health: A Comprehensive Look at the Iconic Actor’s Wellness Journeygreendigital
Tom Selleck, an enduring figure in Hollywood. has captivated audiences for decades with his rugged charm, iconic moustache. and memorable roles in television and film. From his breakout role as Thomas Magnum in Magnum P.I. to his current portrayal of Frank Reagan in Blue Bloods. Selleck's career has spanned over 50 years. But beyond his professional achievements. fans have often been curious about Tom Selleck Health. especially as he has aged in the public eye.
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Introduction
Many have been interested in Tom Selleck health. not only because of his enduring presence on screen but also because of the challenges. and lifestyle choices he has faced and made over the years. This article delves into the various aspects of Tom Selleck health. exploring his fitness regimen, diet, mental health. and the challenges he has encountered as he ages. We'll look at how he maintains his well-being. the health issues he has faced, and his approach to ageing .
Early Life and Career
Childhood and Athletic Beginnings
Tom Selleck was born on January 29, 1945, in Detroit, Michigan, and grew up in Sherman Oaks, California. From an early age, he was involved in sports, particularly basketball. which played a significant role in his physical development. His athletic pursuits continued into college. where he attended the University of Southern California (USC) on a basketball scholarship. This early involvement in sports laid a strong foundation for his physical health and disciplined lifestyle.
Transition to Acting
Selleck's transition from an athlete to an actor came with its physical demands. His first significant role in "Magnum P.I." required him to perform various stunts and maintain a fit appearance. This role, which he played from 1980 to 1988. necessitated a rigorous fitness routine to meet the show's demands. setting the stage for his long-term commitment to health and wellness.
Fitness Regimen
Workout Routine
Tom Selleck health and fitness regimen has evolved. adapting to his changing roles and age. During his "Magnum, P.I." days. Selleck's workouts were intense and focused on building and maintaining muscle mass. His routine included weightlifting, cardiovascular exercises. and specific training for the stunts he performed on the show.
Selleck adjusted his fitness routine as he aged to suit his body's needs. Today, his workouts focus on maintaining flexibility, strength, and cardiovascular health. He incorporates low-impact exercises such as swimming, walking, and light weightlifting. This balanced approach helps him stay fit without putting undue strain on his joints and muscles.
Importance of Flexibility and Mobility
In recent years, Selleck has emphasized the importance of flexibility and mobility in his fitness regimen. Understanding the natural decline in muscle mass and joint flexibility with age. he includes stretching and yoga in his routine. These practices help prevent injuries, improve posture, and maintain mobilit
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.
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Injectable drug delivery systems
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Approaches for Injectable Controlled Release
Formulation
1. Introduction
2. Advantage &Disadvantage
3. Process
4. Approaches
By
Mukesh kumar Sah 1st m.pharm
Re-edited by
Suraj Choudhary
INTRODUCTION
It is defined as
“The delivery of drug at predetermined rate, and maintaining optimal and effective
drug level for prolonged duration.”
Parenteral dosage form, are designed for the drugs having poor aqueous solubility which
undergoes first by pass metabolism poor aqueous solubility.
The ingredient used for parenteral controlled release formulation should be sterile, pyrogen
free, non-irritating, bio-compatible and biodegradable into nontoxic compounds.
ADVANTAGES
1. Improved patient convenience and compliance.
2. Prolonged steady state drug plasma concenter tion.
3. Maxium utilization of drug.
4. Less frequency of dosing.
5. Reduction in health care cost through improved therapy.
DISADVANTAGES
1. Decreased systemic availability
2. Poor in vitro-in vivo correlation
3. Possibility of dose dumping.
4. Retrieval of drug is difficult in case of toxicity, poisoning or hypersensitivity
reactions.
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5. Reduced potential for dosage adjustments.
6. Higher cost of formulations.
PROCESS
1. Dissolution controlled
2. Adsorption type depot preparation
3. Encapsulation type preparation
4. Esterification type depot prepation
1. DISSOLUTION CONTROLLED
The rate of dissolution is controlled by slow dissolution of drug particle in the formulation or tissue
fluid surrounding the formulation.
The rate of dissolution can be determined mathematically as
Q/t = SDC/h
where Q/t = rate of dissolution,
S = surface area of drug particle
D = diffusion cofficient
C = saturation solubility,
H = thickness of hydrodynamic diffusion layer.
The dissolution can be controlled by
A. Formation of Salt or complexes with low aqueous solubility
E.g.:preparation of penicillin G procaine (C=4 mg/ml) and penicillin G benzathaine
(C=0.2mg/ml) from highly water soluble alkali salt of penicillin G.
2. ADSORPTION TYPE DEPOT SYSTEM
This depot preparation is formed by the binding of drug molecule to adsorbents.
The unbound free species of drug is available for adsoption.
To maintain the equilibrium as the unbound drug is absorbed, fraction of bound drug is released.
The equilibrium concentration of free unbound drug species is determined by Langmuir
relationship i.e.,
(Cf/Cb)=1/a(C)b,m+(C)f/(C )b,m
where (C)b = amount of drug adsorbed by 1gm adsorbent,
( C)b,m = maximum amount of drug adsorbed by 1gm adsorbent
E.g.: vaccine preparation in which antigens are bound to highly disprsed aluminium hydroxide
gel to prolong their release and stimulate antibody formation.
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3. ENCAPSULATION TYPE DEPOT SYSTEM
The drug solid is encapsulated within a permeation barrier or dispersing drug particle in a diffusion
matrix.
The both permeation barrier and diffusion matrix are fabricated from biodegradable or
bioabsorbable macromolecules such as gelatin, Dextran, polylacytate, phospholipid etc.
E.g.: Naltrexone pamoate releasing biodegradable –macrocapsules.
The release is controlled by rate of permeation across permeation barrier and rate of biodegradation
of barrier macromolecule.
4. ESTERIFICATION TYPE DEPOT SYSTEM
This is produced by esterifying a drug to form bioconvertible prodrug type ester and then
formulating into injectable preparation .
The rate of absorption is controlled by intra-facial partitioning of drug esters from reservoir to the
tissue fluid and rate of bioconvertion of ester drug to regenerate active drug .
E.g: fuluphenazine enanthate in oleginous solution.
APPROACHES
Various approaches have been made in formulation of parenteral formulation which can be broadly
classified as
A. Injectable:-
1. Solution
2. Coarse dispersion:-Emulsion, Suspension
3. Colloidial /nanometric dispersion
a. Liposomes
b. Niosomes
c. polymeric mixed micelle.
d. Nanoparticle
4. Microparticle
a. Microsphere
b. Microcapsules
5. Resealed Erythrocytes
B. Implants:-
1. in-situ Forming Implants
2. Solid Implants
3. Vapour pressure powered pumps
4. Battery powered pumps
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SOLUTIONS
Both aqueous as well as oil solution can be used for parenteral controlled drug release formulation.
By the use of aqueous solution (i.m.)the release of drug can be controlled in following ways.
4. By increasing the viscosity of vehicle
Using methyl cellulose, carboxy-methyl cellulose and thus decreasing molecular diffusion and
4ocalizing the injected drug.
2. By forming complex (dissociation)
Complex with macromolecules like MC, CMC or PVP from which drug dissociates at controlled
rate( only free drug will get absorbed)
3. By forming complex (solubility change)
With macromolecules that control the release of drug by reducing the solubility of parent drug e.g.
protamine zinc insulin.
4. Oil suspension
It control the release of drug by partitioning the drug out of oil in surrounding aqueous biofluids.
Veg. oil like arachis oil, cottonseed oil are used.
COARSE DISPERSIONS
Dispersed system like emulsion OR suspension can be administered by i.m., s.c. or i.v. routes.
1. Emulsion
The o/w system have not been used successfully because absorption drug in the oil phase is
rapid due large interfacial area and rapid partitioning.
Multiple emulsion like w/o/w and o/w/o are being used more conveniently because additional
reservoir is present for partitioning which can retard drug release.
2. Suspension
Suspension control of drug release from suspension is easier and predictable.
Drug dissolution and subsequent diffusion is main rate-controlling steps.
Release of water soluble drug can retard by formulating it as oil suspension vice-versa for
oil soluble drugs.
Factor consideration
Solid content-0.5-5.0%.
Particle size-larger the particle size slower is the dissolution.
Greater particle size cause difficulties like irritation at site of injection, poor syringibility
and rapid sedimentation.
Particle size should be below 10 μ for optimum activity.
Generally crystalline and polymorphic forms of drugs are selected to delay release.
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COLLOIDAL DISPERSION
There are different types of colloidal dispersion
1. Liposomes
2. Niosomes
3. Polymeric/ mixed micelle
4. Nanoparticles
Nanocrystals
Nanoemulsion
Nanocapsule
Polymeric Nanoparticles
Solid lipid nanoparticle
Nanostructured lipid carrier
5. Microparticles
Microsphere
Microcapsule
6. Resealed erythrocytes
LIPOSOMES:
Water soluble drugs are trapped in aqueous compartment.
Lipophilic ones are incorporated in the lipid phase of liposomes.
Can be given by I.M., S.C., for controlled rate release.
E.g. progesterone, cisplatin.
Can be given by I.V. for targeted delivery.
Advantages
1. Type of drug: It can incorporate both hydrophilic and hydrophobic drugs.
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2. Surface activity: The surface treatment is possible, so that the pharmacokinetic profile can be
altered.
3. Release at high temperatures: It enables the ability in some cases to deliver and release the
drug at higher temperatures.
4. Targetted treatment: It can be safely used for the targettting of cancer, etc. whose drugs are
higly toxic if given by conventional way.
5. Bypassing Macrophages: If treated with polymers like PEG, then such grafting can enable it
to reduced effects by macrophages.
Disadvantages
1. Production cost is high
2. Leakage and fusion of encapsulated drug / molecules.
3. Sometimes phospholipid undergoes oxidation and hydrolysis like reaction
4. Short half-life
5. Low solubility
6. Fewer stables
NIOSOMES:
It is defined as ……
“the non-ionic surfactant vesicles ,bilayered structure which can entrap both hydrophilic and
lipophilic drug either in aqueous layer or vesicular layer, made up of lipids.”
Advantages:
Low cost
Greater chemical stability
Low toxicity due to its non- ionic nature.
Biodegradable, bio-compatible and non-immunogenic.
Can improve the performance of drug via better availability and controlled delivery at a
particular site.
Disadvantages:
Aqueous suspension of niosomes may exhibit fusion, aggregation, leaching or hydrolysis of
entrapped drug, thus limiting the shelf-life.
Time consuming process
Requires specialized equipments
In-efficient drug loading
POLYMERIC/MIXED MICELLE:
These are nano-sized core/shell assemblies of amphiphillic block copolymer that are suitable for
delivery of hydrophilic and amphiphillic agent.
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Copolymer with PEO as shell –forming block and poly (l-amino acid)s are most popular in drug
development.
Hydrophobic core of polymeric micelle provide an excellent host for incorporation and
stabilization of anticancer agent that are hydrophobic.
NANOPARTICLES:
Nanoparticles are called as nanospheres or nanocapsules depending upon the position of drugs.
Polymer used are biodegradable ones.
Eg: Polyacrylic acid, Polyglycolic acid
For selective targeting therapy.
Advantages………
Disadvantages ……
MICROPARTICLES:
Microparticles are defined as particulate dispersions or solid particles with a size in the range of
1-1000 μm. The drug is dissolved, entrapped, encapsulated or attached to a microparticle matrix.
Depending upon the method of preparation, microparticles, microspheres or microcapsules can
be obtained.
TYPES:
1. Microsphere
Each microsphere is basically a matrix of drug dispersed in a polymer from which release
occurs by first order process.
Polymers used are biocompatible and biodegradable.
Eg: Polylactic acid, Polylactide co-glycolide, etc.
Drug release is controlled by dissolution degradation of matrix.
Small matrices release drug at a faster rate.
Drug is centrally located within the polymeric shell.
Release is controlled by dissolution, diffusion or both.
For potent drugs such as steroids, peptides and antineoplastics.
2. Microcapsule
Microcapsules contain an active agent and surrounded polymeric shell or dispersed in
polymeric matrix.
Microcapsule size : 1 to 1000 micron
Microcapsules can be of different structures.
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RESEALED ERYTHROCYTES
Biodegradable, biocompatible, nonimmunogenic.
Can circulate intravascularly for days and allow large amounts of drug to be carried.
Drug loading in erythrocytes is easy.
Damaged erythrocytes are removed by liver and spleen.
EXAMPLES OF INJECTABLE CR FORMULATIONS
1. Long-acting Penicillin Preparations
2. Long-acting Vitamin B12 preparations
3. Long-acting Adrenocorticotropic Hormone Preparations
4. Long-acting Steroid preparations
5. Long-acting Antipsychotic Preparations
6. Long-acting Antinarcotic Preparations
7. Long-acting Contraceptive Preparations
8. Long-acting Insulin Preparations
LONG-ACTING PENICILLIN PREPARATIONS
Penicillin in the form of water-soluble Na+
or K+
salt is rapidly absorbed from subcutaneous &
intramuscular sites of parenteral administration.
Intramuscular route of administration is preferred because of its rapid absorption & high peak
serum levels.
The high serum penicillin concentrations then declines rapidly as a result of the rapid urinary
excretion, following its absorption from the site of injection.
APPROACHES:
Earliest approach was to reduce the aqueous solubility of penicillin by converting
water soluble Na+
or K+
salt into extremely low aqueous solubility, such as penicillin
G procaine.
Intramuscular administration of penicillin G procaine in vegetable oil produces a
depot effect that sustain the therapeutic blood level of penicillin for 24-48 hours.
Gelation of this oil suspension with 1% aluminium monostearate further sustain the
therapeutic blood level of penicillin to 96 hours.
The therapeutic concentration of penicillin is prolonged approximately five times and
peak plasma level is suppressed sevenfold when suspension is gelled with 1%
aluminum monostearate.
Approach
1
Approach
2
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Serum concentration of penicillin is maintained over minimum effective
concentration longer than 168 hours when gelled with 2% aluminum monostearate.
Depot effect is due to a reduction in aqueous solubility of penicillin G by formation
of procaine salt with low aqueous solubility and retardation in drug absorption by
formation of compact cohesive depot within muscular tissue following i.m. injection.
Scientist at Abbott laboratories discovered that therapeutic concentration of
penicillin can also be prolonged by formulating the same in aqueous thixotropic
suspension by maintaining high solid –vehicle ratio(40-70% of e milled and
micronized penicillin Gprocaine particles).
NOTE: To form a spherical depot aqueous suspension of penicillin G procaine must
possess structural breakdown point of 1000000dyn-cm
LONG-ACTING INSULIN PREPARATIONS
Due to its extensive 1st
pass metabolism, it is given by parenteral administration via sub cutaneous
route.
Improper injection techniques have been found to be responsible for poor bioavailability of insulin.
APPROACHES:
Approach
3
Approach
4
Effect of particle size of penicillin G procaine on the blood profile of penicillin following
i.m.50,000 units/kg in rabbits:
▲ 150-175µm,
□ 45-60µm,
● <5µm in peanut oil gelled with 2% aluminium monostearate.
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Insulin molecule reacts with zinc ion & precipitates as a water insoluble Zn-insulin complex.
Depending upon pH of solution, it may precipitate as an amorphous or a crystalline solid.
7 - parts of crystalline insulin and three parts of amorphous insulin zinc insulin
complex preparation is called LENTE INSULIN.
It provides intermediate acting form of insulin.
It provides minimum effective concentrations within 1-1.5hrs.
It reaches peak level within 8-12 hrs and has duration of action 24 hrs.
Other modified types:
i. Ultra-Lente Insulin
Insulin crystals can be precipitated from acetate buffer at pH 5-6.
This crystalline insulin-zinc complex is absorbed very slowly & has a prolonged
normo-glycaemic activity.
After s.c injection of these Zn-Insulin crystals as a suspension in buffer, the insulin
is slowly released, absorbed & retains its activity for more than 36 hrs.
ii. Semi-Lente Insulin
Amorphous Zn-Insulin complex is precipitated at higher pH (6-8)
This amorphous insulin has low Zn content & is absorbed more readily & achieves
duration of action shorter than that of ultre-lente.
When administered subcutaneously, the Insulin in amorphous Zn-Insulin suspension
is quickly released, absorbed & has shorter duration of normo-glycaemic activity (12-
16hrs).
LONG-ACTING VITAMIN B12 PREPARATION
By oral administration the systemic bioavailability of vitamin B12 is limited & variable.
Vitamin B12 is rapidly & quantitatively absorbed from intramuscular & subcutaneous sites of
injection.
Approach
1
Approach
2
Approach
3
Comparative normoglycemic activity of ultralente, semilente,
regular insulin preparation in 26 rabbits by crossover tests.
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On administration of intramuscular or deep subcutaneous injection, the peak plasma level of
Vitamin B12 reaches its peak concentration within 1 hr, which is the choice of medication in case
of pernicious anemia & other vitamin B12 deficiency states.
Unfortunately, much of the injected doses is lost in the urine. For these reasons, it becomes
necessary to develop a parenteral controlled-release formulation for Vit-B12.
APPROACHES:
The development of a parenteral controlled vitamin B12 release formulation was to
formulate the Vitamin B12 in a controlled partially hydrolyzed gelatin 32% solution.
However, no sustained-release behavior was observed in human testing.
Crystalline Vitamin B12 was suspended in sesame oil gelled with 2% aluminum
monostearate.
This approach achieved a significant prolongation of the absorption of Vitamin B12
compared to an aqueous solution of Vitamin.
Synthesize an insoluble derivative of Vitamin B12, the Vit-B12 zinc-tannate complex,
& then suspend it in sesame oil gelled with aluminum monostearate 2%.
This preparation achieved a significant prolongation of the absorption of Vitamin B12
& urinary loss was significantly reduced.
LONG-ACTING ACTH PREPARATION
ACTH is a polypeptide hormone that stimulates & regulates the secretion of adrenal steroids,
mainly the corticosteroids, from the adrenal cortex.
The adrenocorticotropic activity of ACTH is easily destroyed by proteolytic enzymes in the
gastrointestinal tract, exogenous ACTH is therefore ineffective when given orally.
On the other hand, ACTH is readily absorbed from parentral sites of administration & is usually
administered by intramuscular injection & occasionally by i.v infusion.
APPROACHES: (Approach-1)
Gelatin was found to inhibit the protein binding of ACTH.
Addition of a partially hydrolyzed gelatin into the injectable ACTH solution was
found to enhance adrenal ascorbic acid responses in hypo-sectomized rats.
The results of this investigation provided the foundation for the development of a
repository corticotropin injection, a long acting injectable formulation that contains
a highly purified preparation of ACTH in 16% gelatin solution.
This preparartion is active for 24hr, over the regular corticotropin injection, which
has a duration of action of only 8 hr.
LONG-ACTING ANTI-PSYCOTICS PREPARATION
The major problem in the management of psychotic disorder treatment is patient compliance.
Approach
1
Approach
2
Approach
3
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Development of long acting antipsychotic preparation certainly provide a practical solution to
minimize this non-compliance problem.
Prolongation of antipsychotic activity of fluphenazine can be achieved by esterification,
E.g.: development of fluphenazine enanthate and fluphenazine deconate.
Parenteral administration of either ester in sesame oil produces antipsychotic action for average
duration of 2 weeks and onset of action appears within 24-72 hrs following injection
Esterification approach has been utilized to render longer duration of action for other neuroleptic
drugs.
LONG-ACTING ANTI-NARCOTICS
Narcotic addicts become psychologically dependent upon the drug.
Believe that the effects produced by self-administration of narcotics are necessary for maintaining
optimal state of well-being.
At peak concentration, brain –serum ratio is only 0.1for morphine where as it is 15times greater
for naloxone.
As serum level declines the ratio become greater for morphine (0.5), but remains within a narrow
range 1.5-2.0 for naloxone.
APPROACHES:
First approach : to form insoluble salt of naloxone and forming ionic complex.
The formation of Zn –tannate naloxone complex prolonged the antinarcotics activity
up to 24hrs, whereas the formation of water soluble naloxone –HCl salt shows
antinarcotics activity up to only 4 hrs.
The antinarcotic activity of naloxone tannate and pamoate was found only up to 8hrs
following i.m.
Second approach: The incorporation of zinc reduce the dissociation of tannate from
53.3 to13.9 %.
The naltrexone Zn –tannate complex showed three times more prolonged action than
the naltrexone HCl salt.
Third approach: When pea nut oil suspension of naltrexone Zn –tannate complex
gelled with 2%aluminium monostearare was administered i.m., the antagonistic
analgesic effect of morphine was prolonged up to 19 days in 70% rats.
Fourth approach: The use of polymeric drug delivery system such as microcapsule,
microsphere for antinarcotics preparation has been successfully used.
E.g long term bioavailability of naltrexone from lactide –glycolide copolymer
is constant for 53 days and 0.83% of drug was released daily.
LONG-ACTING STEROID PREPARATION
13. Worked by: Mukesh (RE-edited by: Suraj C)
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Androgenic steroids:
Testosterone is rapidly absorbed orally, but such administration is ineffective orally due to
pre-systemic metabolism by liver before reaching systemic circulation.
Testosterone is also quickly metabolized and excreted after parenteral administration in an
oleaginous solution.
APPROACHES:
First Approach: for prolong androgenic activity was achieved by esterification of
testosterone.
The effect was related to oil /water partition of these fatty acid ester.
The androgenic activity was prolonged by acylation of 17-β hydroxy group in
testosterone molecule and was administered via i.m.
This was due to the reduction in water/oil partition coefficient.
Second Approach: The enanthate ester of testosterone prolong androgenic action up
to 4 weeks.
Estrogenic steroids:
APPROACHES:
First Approach: prolong action was achieved by the benzoylation of the 3-hydroxy
group of estradiol which is oil soluble ester from which release of active beta
esteradiol is slow
Second Approach: prolong estrogenic effect is also achieved by esterifying estadiol
at both 3and 17 position by treatment with valeryl chloride (in pyridine and removing
3-Valerate by treating with potassium carbonate (in aqueous methanol).
LONG-ACTING CONTRACEPTIVE PREPARATION
Progesterone in high doses suppress the pituitary release of luetenizing hormone and
hypothalmic release of LH –releasing, hence prevent ovulation.
The following APPROACHES have been made for long acting progesterone preparation:
o Medroxyprogesterone acetate in aqueous suspension (Depo-provera, Upjohn)
o Dihydroxy-progesterone acetophenide and estradiol enanthate in oleaginous solution
(Deladroxate, Squibb).
o Norethindrone in a biodegradable polymer beads.
NOTE: The long term contraceptive action of medroxy-progesterone acetate is due to:
1. Inhibition of secretion of luteinizing hormone and follicle stimulating hormone.
2. Reducing the penetration of spermatozoa into the uterus by increasing the viscosity
of cervical mucus.