by Dr. Shruti Bhat
For a successful product, there are 2 basic needs; firstly the drug substances and second carrier medium.
Requirement of an ideal drug carrier for injections are as follows-
1. Material of fabrication must be biodegrade in a timely manner and form biologically acceptable degradation products.
2. Carrier must contain an effective dose of active agent.
3. Carrier formulation must have acceptable shelf life stability.
4. Rate of drug release from carrier must occur at an acceptable rate.
5. Carrier system must not cause increased toxicity and must be sterile.
6. Carrier system must be capable of being administered routinely and in a non-offensive manner.
7. Particles must be capable of being produced reliably in amounts that fulfill demand.
8. Carrier system must be cost effective.
Carrier must be manufactured from materials that are biocompatible Various particulate drug carrier systems have been used-
Liposomes :
Incorporating drugs into biodegradable liposome formulation offers several benefits including protection from premature degradation, altered biodisposition and pharmacokinetics alleviating dose limiting toxicity improved solubility if the agent is amphipathic and simultaneous incorporation of multiple reverse compounds delivered to a common site.
Liposomes have been employed as site specific carriers since, on administration, they concentrate in the organs bearing fenostrated capillaries, such as liver, spleen, bone marrow and therefore, form ideal substrate carriers for antineoplastic drugs. Several liposomal formulations of drugs viz. doxorubicin, daunorubicin, 4 epimere of doxorubicin, epirubicin, annamycin, campthothericin, mitoxanrone, paclitaxel, interleukin -2 etc. have already been studied. The liposomal formulations of doxorubicin has been observed to improve the therapeutic index of the drug by changing the drug disposition leading to a decreased occurrence of doxorubicin related cardiac toxicity. Liposomal encapsulation of interleukin -2 decreased overall toxicity while maintaining immuno modulatory activity.
With the recent discovery of different stealth lipid formulations, liposomes may now avoid the RES for prolonged periods and remain in the circulation for many hours. However, it is unclear whether an increased residence time in the circulation will translate into a higher therapeutic index.
Several types of liposomes are now available :
a) Target sensitive immunoliposome: -
Target sensitive immunoliposomes are composed of a contact sensitive phospholipid formulation, engineered to deliver and release a variety of drugs at the outer cell surface following antibody specific binding of the liposome to the desired cell. The result is a transient high local concentration of drug at the targeted cell surface followed by rapid uptake into the cell.
The primary advantage of these liposomes is that the target cell need not engulf or process the liposomes intracellularly for drug release to occur.
b) pH Sensitive Liposomes :
pH sensitive immunoliposomes circumvent the typical lysosomal inactivation of liposome entrapped drugs, which has caused quite a low efficacy for drugs delivered by conventional liposomes. Acid-labile liposomes are able to release their entrapped contents directly into the cytoplasm of the target cell, presumably because of their inherent pH-dependent instability in the pre-lysosomal membrane compartments such as the endosomes. This type of immunoliposome can be employed to enhance transfection efficiency through its more effective mechanism of DNA injection directly into the cell cytoplasm. Thus, it also has the potential for highly efficient and targeted delivery of smaller nucleic acid assemblies, such as antisense DNA.
c) Multiple Vesicle Liposome :
Multiple Vesicle Liposomes is a liposome as vesicle-within-a vesicle called a vesosome. In this case, individual vesicles are programmed to release drugs at different times enabling low level sustained release or drugs for treating cancer, gangrene or wounds. Alternatively the vesicles could simultaneously release “toxic cocktail” of drugs at the site of a tumor.
For inquiries please contact 1-514-6159 or email at drshrutibhat@gmail.com
by Dr. Shruti Bhat
Targeting with drug-carrier systems can be divided into three types:
Passive, active and physical. Passive targeting relies on the natural distribution pattern of the drug-carrier system. For example, particles 5 m or smaller are readily removed from the blood by macrophages of the Reticulo Endothelial System (RES) when administered systemically. This neutral defense mechanism of the RES thus provides an opportunity to target drug, encapsulated in or conjugated to an appropriate carrier system, to macrophages. Mechanical filtration of large carriers by capillary blockage can also be exploited to target drugs to the lungs by the venous supply and to the organs through the appropriate arterial supply. By controlling the rate of drug release, once can achieve the desired therapeutic action in the targeted organ. Passive targeting also includes delivery of drug-carrier systems directly to a discrete compartment in the body (e.g. different regions of the GI tract, eye, nose, knee joints, lungs, vagina, rectum, respiratory tract, or other). This offers the opportunity for the treatment of diseases that require a persistent and sustained presentation of drug at that site.
Active targeting employs a deliberately modified drug-drug-carrier molecule capable of recognizing and interacting with a specific cell, tissue, or organ in the body. Modifications of the carrier system may include a change in the molecular size, alteration of the surface properties, incorporation of antigen-specific antibodies, or attachment of cell receptor-specific ligands.
Physical targeting refers to delivery system that releases a drug only when exposed to a specific macroenvironment, such as change in pH or temperature or the use of an external magnetic field.
Particulate Drug Delivery Systems:
The concept of using particles to deliver drugs to selected sites in the body originated from their use as radio diagnostic agents in medicine in the investigation of the RES (liver, spleen, bone marrow and lymph nodes), gastrointestinal examination, and so on. Particles ranging in sizes from 20 up to 300 m have been proposed for drug targeting. Because of the small size of the particles, particulate drug delivery systems can be introduced directly into the central circulation by intra-articular or intravenous injection, or delivered to a given body compartment, for example, by injection into a joint or by administration by an aerosol to the lungs and nose. Subcutaneous and intraperitoneal administration route have also been used to deliver drugs to the lymphatic system and regional lymph nodes.
Particulate drug delivery system can be monolithic (i.e. containing an intimate mixture of drug and the core material), capsular (in which the drug is surrounded by the carrier material), or emulsion (in which the drug is dispersed in a suspension of the carrier material) types. The biofate (passive targeting of particulate drug delivery systems depend on the size and shape, charge and surface hydrophobicity of the particles.
For inquiries please contact 1-514-6159 or email at drshrutibhat@gmail.com
by Dr. Shruti Bhat
Targeted drug delivery systems are designed to maximize therapeutic response by delivering drug selectively to its pharmacological site(s). There are several factors that determine the availability of drug at the target site. These include the rate of (a) input of targeted drug into the body plasma, (b) distribution of targeted drug to the active site, (c) release of active drug from the targeted drug at the site of action, (d) removal (elimination) of targeted drug and free drug from the target site, (e) diffusion or transport of targeted drug and free drug from the active site to non-target sites, and (f) blood and lymph flow to and from the target site.
APPROACHES TO TARGETED DRUG DELIVERY SYSTEM:
A) Pro-drug :
A prodrug is pharmacologically inert form of an active drug that must undergo transformation to the parent compound in vivo by either chemical or an enzymatic reaction to exert its therapeutic effects.
B) Drug Carrier Delivery System:
Drug-carrier delivery systems employ biologically inert macromolecules to direct a drug to its target site in the body. These are divided into two types: Particulate and soluble macromolecular. Depending on the carrier system, the drug can either be molecularly entrapped within the carrier matrix or covalently linked to the carrier molecules. The major advantage of drug-carrier delivery systems is that the distribution of drug in the body depends on the physiochemical properties of the carrier not those or by alterations in the physiochemical properties of the carrier. There are however several other factors that must be considered in the pharmaceutical development and clinical use of both soluble macromolecular and particulate bio-technical and synthetic site-specific systems.
For inquiries please contact 1-514-6159 or email at drshrutibhat@gmail.com
by Dr. Shruti Bhat
Various biological processes and events govern drug targeting. They are as follows:
1) Cellular Uptake and Processing:
Following administration, a drug frequently passes through various cells, membranes and organs to reach its target sites. These pathways offer opportunities for cell selection and access by targeted drug delivery.
Low-molecular-weight drugs can enter into, or pass through, various cells by simple diffusion processes. Targeted drug delivery systems often comprise macromolecular assemblies, and are unable to enter into cells by such simple processes. Instead, they are captured by a process called endocytosis. Endocytosis is defined as a phenomenon that involves internalization of the plasma membrane, with concomitant engulfment of the extra cellular material (particulate or fluid). This process can be constitutive or nonconstitutive. Other methods of gaining access to cells include passive diffusion, membrane fusion, and binding to either specific or nonspecific regions of the cell.
Endocytosis is divided into two types: phagocytosis and pinocytosis. The former refers to the capture of particulate matter, whereas the latter represents engulfment of fluids. Phagocytosis is carried out by specialized cells of the mononuclear phagocyte system (MPS), called phagocytes. It is mediated by the absorption of specific blood components [e.g. immunoglobulin (Ig) G, complement C3b, and fibronectin], called opsonins, and relevant receptors located on macrophages. The extent to which a drug is opsonized, and by what plasma protein depends on the size and surface characteristics of the particles. This, in turn, determines the engulfment mechanism.
Following ingestion, the phagocytic vacuole (or phagosome) fuses with one or more lyososomes to form phagolysosomes (or secondary lyososomes); It is here that the digestion of particles by lyososomes acid hydrolases (e.g. protemases, glycosidases, nucleases, phospholipases, phosphatases, and sulfatases) occurs, making the drug available to exert its therapeutic effect. The internal pH of lysozomes is between 4.5 and 5.5.
Unlike phagocytosis, which is mediated by the serum opsonin, pinocytosis does not require any external stimulus. Pinocytosis is divided into two types; fluid phase pinocytosis and adsorptive pinocytosis. Fluid-phase pinocytosis is a nonspecific, continuous process, and is a general process for transporting macromolecular constructs through epithelia, some endothelia, and into various blood cells. Adsorptive pinocytosis, in contrast, refers to internalization of macromolecules that bind to the cell surface membrane. If the macromolecule adheres to a general cell surface site, then uptake is referred to as simply nonspecific pinocytosis. However, if it binds to a specific cell receptor site, then the process is called receptor-mediated pinocytosis.
Once internalized the pinocytosis vesicles interact among themselves or with vesicles of other intracellular origins such as endosomes and lysozomes.
B. Transport across the epithelial barrier:
The oral, buccal, nasal, vaginal and rectal cavities are all internally lined with one or more layer of epithelial cells. The transport of macromolecules across the intestinal epithelium may occur by cellular vesicular process by either fluid-phase pinocytosis or specialized (receptor-mediated) endocytotic process.
C. Extravasation :
Many diseases are known that result from the dysfunction of cells located outside the cardiovascular system. Thus, for a drug to exert its therapeutic effects, it must egress from the central circulation and interact with its extravascular-extracellular or extravascular-intracellular target(s). This process of transvascular exchange is called extravasation, and it is governed by the permeability of blood capillary walls. The main biological features that control permeability of capillaries include the structure of the capillary wall, under normal and (patho) physiological conditions, and the rate of blood and lymph supply. Physicochemical factors that are of prohydrophilic-lipophilic balance (HLB) characteristics.
D. Lymphatic Uptake:
Following extravasation, the drug molecules can either reabsorb into the blood stream directly by the enlarged postcapillary interendothelial cell pores found in most tissues or enter into the lymphatic system and then return with the lymph to the blood circulation.
For inquiries please contact 1-514-6159 or email at drshrutibhat@gmail.com
by Dr. Shruti Bhat
The Novel Parenteral Controlled Drug Delivery Systems - Targeted approach to disease management would be dealt with in Part III of this series.
A target oriented DDS by definition - supplies drug selectively to its site(s) of action(s) in a manner that provides maximum therapeutic activity (though controlled and predetermined drug release kinetics), presents degradation or inactivation during transit to the target sites and protects the body from adverse reactions because of inappropriate disposition.
For drugs that have a low therapeutic index, targeted drug delivery proves an effective treatment at a relatively low drug concentration.
There are several other reasons/ benefits cited for site-specific delivery . For inquiries contact 1-514-6159.
CLASSIFICATION OF DRUG TARGETING:
Drug targeting has been classified into three types:
(a) First-order targeting --- this describes delivery to a discrete organ or tissue;
(b) second-order targeting----this represents targeting to a specific cell type(s) within a tissue or organ (e.g. tumor cells versus normal cells and hepatocytic cells versus Kupffer cells);
c) third-order targeting ---- this implies delivery to a specific intracellular compartment in the target cells (e.g. lyososomes).
Basically, there are three approaches for drug targeting. The first approach involves the use of biologically active agents that are both potent and selective to a particular site in the body (magic bullet approach of Ehrlich). The second approach involves the preparation of pharmacologically inert form of active drugs that when they reach the active sites become activated by a chemical or enzymatic reaction (prodrug approach). The third approach utilizes a biologically inert macromolecular carrier system that directs a drug to a specific site in the body where it is accumulated and affects its response (magic gun or missile approach).
Regardless of the approach, the therapeutic efficacy of target drug delivery systems depends on the timely availability of the drug in active form at the target site(s) and its intrinsic pharmacological activity. The intrinsic pharmacokinetic properties of the free drug should be the same, irrespective of whether or not it is introduced into the body attached to a carrier. A drug can selectively access to, and interact with, its pharmacological receptors, either passively or by active processes. Passive processes rely on the normal distribution pattern of a drug-drug-carrier system, whereas the active routes use cell receptor-recognizing ligand(s) or antibodies (“homing” or “vector” devices) to access specific cells, tissues, or organs in the body.
For inquiries please contact 1-514-6159 or email at drshrutibhat@gmail.com
by Dr. Shruti Bhat
Pulsating polymer Gel for Episodic Drug Delivery:
In the field of controlled release, constant rate of zero order delivery of drugs is often considered to be the gold standard. This philosophy reflects the notion that drug effect is directly related to the instantaneous concentration of drug in an appropriate biosphere. However, in recent decades evidence has accumulated that certain clones of drugs particularly hormones are best administered with a periodic pulsatile program. Such a program will mimic the normal endogenous pattern of hormone release from endocrine glands. In fact, hormone replacement therapy using zero order delivery has been shown to fail in some cases with the target endocrine fraction restored only when the normal pulsatile pattern of release is imitated by the delivery system.
Research workers then geared towards developing an implantable, autonomously pulsing drug delivery system which can be used for such hormones and whose pulse pattern is controlled by device design. No external energy source, such as electricity, magnetism or heat is required to activate the system. The system is based on a cross-linked poly (N-isopropyl acrylamide - co - methacrylic acid) hydrogel (HG) and the enzyme glucose oxidase (GO). GO is situated in a chamber and communicates with body fluids through the HG membrane. Glucose, at constant activity in the body permeates through the HG and causes the latter to collapse by neutralizing pendant carboxylic acid groups. By this means, glucose permeation is sharply reduced, and is subsequent proton production. Eventually the protons are released from the HG membrane and the latter re-swells, restoring glucose permeability. This process can be repeated indefinitely, provided the system maintains its integrity and the external glucose concentration remains constant. Drug release from the chamber will follow the pulsatile swelling of membrane.
Here, we conclude part II of our series.
In the next posting, we shall begin with a new part, III and shall deal with new subjects of CRDDS, primarily, novel parenteral CRDDS, targeted approach of drug delivery etc.
For inquiries contact me at 1-514-743-6159 or email at drshrutibhat@gmail.com .
by Dr. Shruti Bhat
Dosage forms with a prolonged gastric residence time (GRT) i.e. gastro-remaining or gastro retentive dosage forms (GRDF) have brought new and important therapeutic options. For instance, they significantly extend the period of time over which drugs may be released and thus prolong dosing intervals and increase patient compliance beyond the compliance level of existing controlled release dosage forms. Also, GRDF’s greatly improve the pharmacotherapy of the stomach itself through local drug release, leading to high drug concentration at the gastric mucosa, which are sustained over long period of time. For example, the eradication of helicobacter pylori which today requires the administration of various medication several times a day according to a complicated regimen and which frequently fails as a result of insufficient patient compliance, could perhaps be achieved more reliably using GRDF to administer smaller drug doses fewer times. Finally GRDF will be used as carriers for drugs with so called “absorption windows”, these substances are taken up only from very specific sites of the gastro-intestinal mucosa, often in a proximal region of the small intestine. Conventional controlled release dosage forms pass the absorption window while they still contain a large and rather undefined portions of the dose which is consequently lost for absorption. In contrast an appropriate GRDF would slowly release the complete dose over its defined GRT and thus make it continuously available to the appropriate tissue regions for absorption.
The controlled gastric retention of solid dosage forms may be achieved by the mechanism of mucoadhesion, floatation, sedimentation, expansion or by the simultaneous administration of pharmacological agents which delay gastric emptying.
1) Mucoadhesive Systems :
Muco adhesion tends to be not strong enough to impart dosage forms, the ability to resist the strong propulsive forces of the stomach wall. The continuous production of mucous by the gastric mucosa to replace the mucous which is lost through the peristaltic contraction and the dilution of the stomach content also seem to limit the potential of muco adhesion as a gastro-retentive force. Flotation as a retention mechanism requires the presence of liquid on which the dosage form can float and it also presumes that the patient remains in an upright posture during the GRT; in a supine position the pylorus is located above the stomach body and allows the accelerated emptying of floating material.
Sedimentation on the other hand has been successfully employed by few research workers as a retention mechanism for pellets which are small enough to be retained in the rugae or folds of the stomach body near the pyloric region, which is the part of the organ with the lowest position in an upright posture. Dense pellets (approximately 3g/cm3) trapped in rugae also tend to withstand the peristaltic movements of the stomach wall.
Expansion has been shown to be a potentially reliable retention mechanism. Several devices features which extend, unfold or which are inflated by carbon dioxide generated in the device after administration. These dosage forms are excluded from the passage of the pyloric sphincter if they exceed a diameter of approximately 12-18 mm in their expanded state. Various mechanisms ensure the full reversibility of the expansion. Prototypes have already achieved the desired expansion and release profiles with model drugs in pilot clinical trials in which ultrasound and magnetic resonance imaging were employed as methods to visualize the gastric residence of the dosage form. There are few pharmacological approaches to achieve a moderately increased GRT of oral dosage forms. However, the concept of simultaneous administration of a drug to delay gastric emptying together with a therapeutic drug will most likely not receive the favor of clinicians and regulatory agencies because of the questionable benefit to risk ratio associated with these devices.
For inquiries contact me at 1-514-743-6159 or email at drshrutibhat@gmail.com
by Dr. Shruti Bhat
Technology in the field of controlled delivery has gone forward at a rapidly accelerating pace and promises many new and exciting developments.
Research on novel oral controlled release delivery systems focuses on increasing gastric retention or gastro-intestinal absorption. Currently, retention time is quite variable and depends on the individual. Gastric platforms have been developed that adhere to the stomach wall, thereby increasing gastric residence time and allowing for prolonged duration of therapy.
Latest Advances in Oral Transmucosal Delivery:
The controlled delivery of macromolecular drugs represents one of the greatest challenges in drug delivery. Transmucosal delivery across the tissues of the oral cavity is an attractive means for non-invasively administering such drugs. Oral transmucosal (OTM) administration offers several advantages for controlled drug delivery. Viz. bypass hepatic first pass effect. The oral mucosa can be generally divided into two categories: Keratinized tissues (gingiva and palate) and non-keratinized epithelial tissues (sublingual & buccal). The non-keratinized oral mucosa is highly permeable and blood flow to the oral mucosa is exceptionally high. In addition, an oral mucosal tissue is readily accessible and localization of dosage form with a defined surface area over extended periods should maximize absorption and provide higher degree of control and reproducibility relative to other mucosal delivery routes. These factors combined with the relatively rugged nature of the oral mucosa to physical and chemical injury make OTM an attractive mode for macromolecular drug administration.
One example of OTM based DDS is a bilayered tablet, which consists of a biocompatible adhesive layer that adheres to the gingiva and an active layer containing drug and optionally a tissue permeation enhancer. The active layer contacts the inner surface of the upper lip opposite the gingival application site and delivers the drug as the entire tablet dissolves. The choice of formulation components of the adhesive and active layers of the OTM system is dependent on the desired release characteristics of the active compound, dissolution time can be varied based on the physicochemical properties of the drug and the profile desired by the glucagon-like peptide (GLP-1) containing tablet for NIDDM therapy. Potentially therapeutic plasma levels of GLP-1 were achieved after administration of a single OTM tablet in type 2 diabetic patients. The peptide had marked glucose lowering effect during the first two hours. The bioavailability of GLP-1 after oral transmucosal administration was estimated as 47% relative to subcutaneous administration.
For inquiries contact me at 1-514-743-6159 or email at drshrutibhat@gmail.com
by Dr. Shruti Bhat
Quality parameters such as assay, content uniformity, and dissolution rate test along with the already established destructive & non-destructive tests for physical parameters need to be carried out for the controlled release systems as well.
In order to gain FDA approval of New Drug Application for a new chemical entity initially marketed in Controlled Release Dosage forms (as with all other similar products), clinical studies in patients establishing the safety and efficacy of each particular dosage form are required. For drugs that have been previously approved as safe and effective in controlled release dosage forms, data are required to establish bioavailability / bioequivalence to an approved controlled release drug product. Single dose bioavailability studies are acceptable for determining the fraction of the amount absorbed, lack of dose dumping, lack of food effects etc. Pharmacokinetic studies, performed under steady-state conditions are acceptable to demonstrate comparability to an approved immediate release drug product, occupancy time within a therapeutic window, percent fluctuation etc. The specific types of in-vivo studies include:
1) Fasted single dose studies
2) Post prandial study
3) Multiple dose steady-state studies.
Regulatory Considerations for Specialized CRDDS:
Novel CRDDS evolved in recent years viz. Ocusert, Oros, Copper and Progesterone releasing IUD’s and transdermal systems are considered new drugs requiring full new drug applications (NDA) as a basis of drug approval. In addition to safety and efficacy considerations which includes an understanding of the drug input function, plasma blood level oscillation and the drug’s pharmacodynamics, there are biopharmaceutic and pharmacodynamic issues that need to be addressed by the manufacturer such as :
1) Reproductivity of the new drug delivery system by in-vivo or in vitro studies.
2) A defined bioavailability profile which rules out dose dumping.
3) Demonstration of reasonably good absorption relative to an appropriate standard and which considers important elements e.g. obviating of first pass gut or liver metabolism.
4) A well-defined pharmacokinetic profile to support drug labeling.
5) In vitro characterization (when possible)
For inquiries contact me at 1-514-743-5159 or email at drshrutibhat@gmail.com
by Dr. Shruti Bhat
The intravenous, subcutaneous, intramuscularly, intraperitoneal and intrathecal routes are examples of parenteral routes of drug administration. Up to the present, efforts in developing controlled release parenteral dosage forms seem to have concentrated on the subcutaneous and intramuscularly routes, resulting in products such as aqueous and oily suspensions and oily solutions.
There are a number of injectables depot formulations on the market e.g. Penicillin & Procaine suspensions (Duracillin Squibb); medroxyprogesterone acetate suspension (Depo-Provera, Upjohn) ; Fluphenazine enanthate and decanoate in oil solutions (Prolixin enanthate and Prolixin decanoate; Squibb) ; ACTH - Zn tannate / gelatin preparation (H.P. Acthar, Armour); Microcrystalline deoxycorticosone pivalate in oleaginous suspension (Percortan pivalate; Ciba); Testosterone enanthate (Delasteryl; Squibb); Testosterone enanthate / estradiol valerate in ethyl oleate BP repository vehicle (Ditate - DS, Savage); Nandrolone decanoate injection (Decadurabolin, Organon) and Insulin Zinc suspensions (Utralente, Lente and semi-lente, Novo)
The rate of drug absorption and hence duration of therapeutic activities will be determined by the nature of the vehicle, the physico-chemical characteristics of the drug or its derivatives and the interactions of drug with vehicle and tissue / fluids.
Biopharmaceutics of CR Parenteral Products :
When a CR drug formulation is administered parenterally into a tissue space, muscle or adipose tissue, a depot is formed. Before the drug can exert its therapeutic action, it must first be released from the formulation into the general circulation and then to the site of drug action.
Generally, the release rate of a drug is affected by the dissolution, partitioning or absorption step. However, in many cases, the rate-limiting step is dissolution of drug particles in the formulation and / or partitioning of drug molecules from the vehicle to the surrounding tissue fluid. Thus, factors that affect the dissolution step and / or the partitioning step will affect parenteral drug absorption.
Details on CRDDS of parenteral delivery systems, drug targetting shall be dealt with soon in the forth coming chapters.
For inquiries contact me at 1-514-743-5159 or email at drshrutibhat@gmail.com
|
