A Review on Improve The Bioavailability of BCSS Class II Drug Baloxavir and  Efavirenz

Shaikh Sadiya Mehmood, Sayyed Simran S. , Pathan Najiya S. , Dr Aejaz Ahemed

J.I.I.U' S Ali Allana College of Pharmacy Akkalkuwa, Dist. Nandurbar (425415), Maharashtra, India

Abstract: The various traditional and novel techniques that that can be used for solubility enhancement of BCS Class II drugs are briefly discussed in this article. Based on their solubility and permeability, drugs are typically divided into four classes (Classes I–IV) according to the biopharmaceutics Classification system (BCS). Of these classes, BCS class II drugs have high permeability and low solubility; not only do these characteristics constitute The rate-limiting step in the formulation of these drugs but the low solubility in water results in low bioavailability. Thus, methods for improving their solubility have been developed using lipid carriers such as  niosomes, The Traditional techniques that has been use of co-solvents, Hydrotropy, Micronization, amorphous forms, use of surfactants, inclusion complex , use of soluble prodrugs, functional polymer technology, controlled precipitation technology. Niosomes technique is use to increase the bioavailability of Baloxavir and Efavirenz. Keywords: Biopharmaceutics, Solubility, Permeability, Niosomes.

Corresponding Author: Shaikh Sadiya Mehmood   Email ID: sksadiya0986@gmail.com

Article History Received:        27/09/2023 Revised:          04/10/2023 Accepted:        22/10/2023 Published:       06/11/2023

 

 

 

 

 

 

 

 

 

 

 

INTRODUCTION

General definition broadly includes Absorption, Distribution, Metabolism and Excretion. The very important property of any non-intravenous dosage form is the ability to deliver the active ingredient to the blood stream to cause pharmacologic response. This property of a dosage form has historically been identified as bioavailability. Bioavailability captures two essential features namely rate and extend of absorption. In principle these two properties of non intra venous dosage forms are important in identifying the response to a drug dose.

As bioavailability is concerned with the rate and extent of drug absorption, the drug with poor bioavailability is the one with

1)      Poor aqueous solubility and/or slow dissolution rate in the biological fluid.

2)      Poor stability of the drug at physiologic pH.

3)      Inadequate partition coefficient and thus poor permeation through the bio membrane.

4)      Extensive presystemic metabolism.

Therapeutic effectiveness of a drug depends upon the bioavailability and Ultimately upon the solubility of drug molecules. Solubility is one of the important Parameter to achieve desired concentration of drug in systemic circulation for Pharmacological response to be shown. It is important to improve the solubility And/or dissolution rate of poorly soluble drugs because these drugs possess low Absorption and bioavailability. As solubility is an important determinant in drug Liberation hence it plays a key role in its bioavailability. Actually, only solubilized Drug molecules can be absorbed by the cellular membranes to subsequently reach The site of drug action (vascular system for instance). Any drug to be absorbed Must be present in the form of an aqueous solution at the site of absorptio.

 

BIOPHARMACEUTICS CLASSIFICATION SYSTEM (BCS)

Based on aqueous solubility and intestinal permeability drug substances can be classified and the scientific frame work for this classification is known as Biopharmaceutics Classification System (BCS). It allows for the prediction of in-vivo pharmacokinetics of oral immediate release drug products by classifying Drug compounds into four classes based on their solubility related to dose and intestinal permeability in combination with the dissolution properties of the dosage form.

 

BSC CLASSIFICATION

CLASS	SOLUBILITY	PERMIABILITY
Class l	High	High
Class ll	Low	High
Class lll	High	Low
Class lV	Low	Low

 

Class I: High permeability and solubility

Formulation independent: The bioavailability of class I compounds is Determined only by delivery of the drug solution to the intestine.

Examples: Loxoprofen, Benzapril, Sumatriptan etc.

 

Class II: High permeability but low solubility

Formulation dependent: The bioavailability of class II compounds is limited by Drug Solubility/dissolution.

Examples: Piroxicam, Valsartan, Nimesulide, Loratadine et

Class III: Low permeability but high solubility

Dependent on barrier properties: The bioavailability of class III compounds Is limited by intestinal permeability.

Examples: Atropine, Gabapentine, Topiramate etc.

 

Class IV: Low permeability and low solubility

Formulation and barrier properties dependent: The bioavailability of class IV Compounds is limited both by solubility/dissolution and intestinal permeability.

Examples: Hydrochlorothiazide, Meloxicam, Furosemide etc.

 

Fig.1 BCS Classification

Class Boundaries And Determination

The solubility, permeability, and dissolution are the main class boundary parameters useful in the Identification of drug products.

 

i)         SOLUBILITY: A drug substance is considered highly soluble when the highest dose strength is Soluble in 250 ml or less of water over a pH range of 1-7.5 at 37˚C. The volume 250 ml estimate By bioequivalence study, drug product administered the fasting healthy volunteers with a glass of 8 ounces of water.

ii)       PERMEABILITY: A drug substance is considered highly permeable when the extent of absorption In humans is greater than 85% of an administered dose, based on mass-balance or compared with An intravenous reference dose.

iii)     DISSOLUTION: A drug product is considered rapidly dissolving when 85% or more of the Labeled amount of drug substance dissolves within 30 min using USP apparatus 1or 2 in a volume Of 900 ml or less of buffer solutions

Bioavailability

The term bioavailability is one of the principal pharmacokinetic properties of the drug, is used to Describe the fraction of an administered dose of unchanged drug that reaches the systemic circulation. By definition when a medication is administered intravenously its bioavailability is 100%. However, when a medication is administered via another route (such as oral), its bioavailability decreases due to incomplete absorption or first-pass metabolism

Methods for enhancement of bioavailability

Classical and highly employed approaches to enhance the aqueous solubility and thus bioavailability of poorly soluble drugs especially BCS class II drugs involve solubilization by application of principles like pH adjustment, co-solvency, micro emulsification, self emulsification, micelles, liposomes, etc. Each method is dealing with some merits and demerits. Hence the decision of the method is a crucial step in the formulation process.

 

1)        Surfactants: Conventional approach to solubilize a poorly soluble substance is to reduce the interfacial tension between the surface of solute and solvent for better wetting and salvation interaction. A wide variety of surfactants like tweens, spans, polyoxy ethylene stearates and synthetics block copolymers, etc. are very successful excipients and carriers for dissolution Enhancement.

2)        pH adjustments: Adjustment of micro-environmental pH to modify the ionization behavior is the simplest and most commonly used method to increase the water solubility of Ionizable compounds. As per pH–partition hypothesis and Henderson- Hasselbach equation, Ionization of compound is dependent on the pH of media and pKa of the drug.

3)        Salt formation: Salt formation of poorly soluble drug candidates has been a strategy for Several decades to enhance solubility. It is an effective method in parenteral and other liquid Formulations, as well as solid dosage forms. The pH dictates whether the compound will form Suitable salts. The pH solubility interrelationships also dictate what counter ions would be necessary to form salts, how easily salts start or may dissociate into free acid or base forms, what their dissolution behavior would be under different gastrointestinal pH conditions, and whether the solubility and dissolution rate of salts would be influenced by common ions.

4)        Co-solvents: Co-solvents system is a mixture of miscible solvents often used to Solubilize lipophilic drugs e.g. polyethylene glycol 400, ethanol, propylene glycol, glycerin, etc

5)        Particle size reduction: Micronization or nanonization is one of the most potent Approaches to improve the bioavailability of lipophilic drugs by an increase in surface area and saturation solubility employing the reduction of the particle size to the submicron level. Particle Size is a critical parameter that would be strictly controlled during the preformulation studies of any formulation. Although the reduction in the particle size is a successful way to enhance the solubility, if uncontrolled and un- optimized, it can lead to re-crystallization and re-aggregation of the drug on storage. Size reduction to submicron cannot be achieved by milling techniques. Patented engineering processes have come up based on principles of pearl milling high-pressure Homogenization, solution enhanced dispersion by supercritical fluids(SEDS), rapid expansion from supercritical to an aqueous solution (RESAS), spray freezing into liquid (SFL), and evaporative precipitation into an aqueous solution (EPAS).

6)        High-pressure homogenization: Dispersing a drug powder in an aqueous surfactant solution and passing through a high-pressure homogenization, subsequently, Nano suspension is obtained, the particle size is dependent on the hardness of the drug substance, the processing Pressure, and the number of cycles applied

7)        Spray freezing into liquid (SFL): This technique involves atomizing an aqueous, Organic, aqueous-organic co-solvents solution, aqueous-organic emulsion or suspension Containing a drug and pharmaceutical excipients directly into a compressed gas (i.e. CO2, helium, Propane, ethane), or the cryogenic liquids (i.e. nitrogen, argon, or hydro-fluoro ethers). The frozen particles are then lyophilized to obtain dry and free- flowing micronized powders. Using Acetonitrile as the solvent increased the drug loading and decreased the drying time for Lyophilization. The dissolution rate was remarkably enhanced from the SFL powder contained Amorphous nanostructured aggregates with high surface area and excellent wettability.

8)        Co-precipitation: Weak basic drugs contain good solubility in acidic pH but in alkaline pH, solubility is significantly reduced and when conventional formulation containing weak base Is given orally precipitation of poorly soluble free base occurs within formulation in intestinal Fluids. The precipitated drug is no longer capable of releasing from formulation leading to a Decrease in bioavailability of the drug. The problem can be solved by the use of a co-solvent Evaporation method which incorporates a carrier with solubilizing effect in the alkaline intestinal Fluid which may operate in the microenvironment. Immediately surrounding the drug particle and Polymers for controlling the dissolution rate ensures maximum bioavailability with the controlled Release of a weak base.

9)        Microwave irradiation method: Drug and cyclodextrins mixture is reacted in a Microwave oven to form an inclusion complex. It is a novel method for industrial-scale Preparation due to its major advantage of shorter reaction time and higher yield of the product.

10)    Nanoparticles formation: Nanoparticles have been used for the development of Processing techniques for consistent and economical production of nanoparticles, in either Suspension form or powders form, represents a significant challenge because of the physical Limitation for submicron sizing, physiochemical stability, purity, and concerns about the large-Scale cGMP-compliant manufacturing of such products. Pharmaceutical manufacturing of Nanoparticles can be achieved through a variety of methods. Each method can result in materials With different properties depending on the route chosen to produce them. They are wet chemical process, media milling, high- pressure.

BALOXAVIR

Baloxavir , sold under the brand name Xofluza, is an antiviral medication for treatment of influenza A and influenza B.^[4] It was approved for medical use both in Japan and in the United States in 2018, and is taken as a single dose by mouth. It may reduce the duration of flu symptoms by about a day, but is prone to selection of resistant mutants that render it ineffectual. Baloxavir was developed as a prodrug strategy, with its metabolism releasing the active agent, baloxavir acid (BXA). Baloxavir acid then functions as enzyme inhibitor, targeting the influenza   virus' cap-dependent endonuclease activity,    used    in    "cap    snatching"    by the virus' polymerase complex, a process essential to its life-cycle.^[11]The most common side effects of baloxavir marboxil include diarrhea, bronchitis, nausea, sinusitis, and headache. The US Food and Drug Administration (FDA) considers baloxavir marboxil to be a first-in-class medication.

Baloxavir marboxil is an influenza medication, an antiviral, for individuals who are twelve years of age or older, that have presented symptoms of this infection for no more than 48 hours. The efficacy of baloxavir marboxil administered after 48 hours has not been tested. In October 2019, the FDA approved an updated indication for the treatment of acute, uncomplicated influenza in people twelve years of age and older at risk of influenza complications. In November 2020, the FDA approved an updated indication to include post-exposure prevention of influenza (flu) for people twelve years of age and older after contact with an individual who has the flu. In August 2022, the FDA approved an updated indication to include post-exposure prevention of influenza (flu) for people five years of age and older after contact with an individual who has the flu. In the EU, baloxavir marboxil is indicated for the treatment of uncomplicated influenza and for post-exposure prophylaxis of influenza in individuals aged twelve years of age and older.

Structure

IUPAC:-({(12aR)-12-[(11S)-7,8-Difluoro-6,11-dihydrodibenzo[b,e]thiepin-11-yl]-6,8-

dioxo-3,4,6,8,12,12a-hexahydro-1H-[1,4]oxazino[3,4-c]pyrido[2,1-f]                 [1,2,4]triazin-7- yl}oxy)methyl methyl carbonate.

Molucular Formula:- C27H23F2N3O7S

 

Molucular weight:- 571.552 g/mol

 

Site of Action:- Baloxavir inhibits the endonuclease activity of the polymerase acidic (PA) protein found in influenza virus to ultimately inhibit virus replication.

EFAVIRENZ

 

Efavirenz (EFV), sold under the brand names Sustiva among others, is an antiretroviral medication used to treat and prevent HIV/AIDS.^[1] It is generally recommended for use with other antiretrovirals. It may be used for prevention after a needle stick injury or other potential exposure It is sold both by itself and  in combination as efavirenz /emtricitabine /tenofovir. It is taken by mouth.

Common side effects include rash, nausea, headache, feeling tired, and   trouble sleeping.^[1] Some of the rashes may be serious such as Stevens–Johnson syndrome. Other serious side effects include depression, thoughts of suicide, liver problems, and seizures. It is not safe for use during pregnancy.It is a non-nucleoside reverse transcriptase inhibitor (NNRTI) and works by blocking the function of reverse transcriptase.

Efavirenz was approved for medical use in the United States in 1998,^[1] and in the European Union in 1999.^[3] It is on the World Health Organization's List of Essential Medicines.^[4] As of 2016, it is available as a generic medication. Efavirenz is also used in combination with other antiretroviral agents as part of an expanded post-exposure prophylaxis regimen to reduce the risk of HIV infection in people exposed to a significant risk (e.g. needlestick injuries, certain types of unprotected sex, etc.).

Structure:-

IUPAC:- (4S)-6-chloro-4-(2-cyclopropylethynyl)-4-(trifluoromethyl)-1H-3,1-benzoxazin-2- one

Molecular Formula:- C14H9ClF3NO2

 

Molecular weight:- 315.68 g·mol⁻¹

 

Site Of Action:- Efavirenz falls in the NNRTI class of antiretrovirals. Both nucleoside and non-nucleoside RTIs inhibit the same target, the reverse transcriptase enzyme, an essential viral enzyme which transcribes viral RNA into DNA.

NIOSOMAL TECHNIQUE USED TO IMPROVE BIOAVAILABILITY OF BALOXAVIR AND EFAVIRENZ

Niosomes

 

Niosomes are microscopic layered structures of 10–1000-nm size, and their core is environmentally friendly and non-reactive toward the human immune system and biocompatible surfactants [22]. The niosomes are amphipathic, i.e., a water-soluble drug can be locked in their core cavity region and water-insoluble drugs in the non polar region are present inside their bilayer; hence, both water-soluble and water-insoluble drugs can be added into niosomes as shown in fig. 2. Structurally, niosomes are similar to liposomes: they possess the same drug delivery potential and offer more chemical stability than liposomes at lower production costs. Both vesicles comprise a bilayer, which is composed of uncharged surfactants in the case of niosomes and of phospholipids in the case of liposomes.

 

Fig. 2: Structure of noisome

Preparation methods

Ether Injection Method:- The primitive step in niosome formulation via the ether injection method involves surfactant dissolution in any volatile solvent such as diethyl ether, chloroform, or methanol. The solution is then incorporated into an aqueous drug solution via injection using a 14 Gauze needle maintained at 60 °C on a water bath or on a magnetic stirrer. Consequently, monolayered vesicles with sizes ranging from 50 to 1000 nm are produced through the volatile solvent’s atomization.

Hand-Shaking Method:-

The hand-shaking method, also known as the thin-film hydration technique, involves the dissolution of the surfactant and cholesterol in a volatile organic solvent and subsequent transfer into a rotary evaporator. Following evaporation, a thin layer of solid remains on the wall of the flask. This dried layer is then rehydrated using an aqueous phase of the drug of interest. Alternatively, this procedure can be performed at room temperature via light agitation.

Microfluidization

Microfluidization is another duplicable method that yields size uniformity via operating, i.e., two fluidized streams flowing forward and intersect with each other at ultrahigh speeds through an accurately defined microchannel .

 

Reverse-Phase Evaporation Method

The reverse-phase evaporation method utilizes an amalgamation of surfactant and cholesterol in a 1:1 ratio in addition to ether and chloroform. An aqueous phase containing the target drug is incorporated into the concoction followed by sonication at a

temperature of 4 °C–5 °C. Sonication is continued for about 5 min after incorporating about 10 ml of phosphate-buffered saline into the concoction. The organic solvent is atomized at 40 °C under low pressure, and the persisting suspension is thinned using phosphate buffered saline. The amalgamation is heated at 60 °C for 10 min, and the ultimate product of niosomes is attained [24, 25, 8]. Fig. 3 shows a schematic of this method.

Fig. 3: Reverse-phase evaporation method for the preparation of niosomes

 

The Bubble Method

Niosomes can also be fabricated in the absence of organic solvents through the bubble method, wherein a bubbling unit containing a round bottomed flask with three necks is placed in a water bath; a water-cooled reflux condenser and thermometer are placed in the first and second necks, respectively, whereas nitrogen gas is introduced through the third neck. Surfactant and cholesterol amalgamated at 70 °C in a buffer are blended and bubbled at 70 °C by introducing nitrogen gas into the apparatus [24, 9]. Fig. 4 shows a schematic of this method.

 

Fig. 4: The Bubble Method for Preparation of Niosomes

Multiple Membrane Extrusion Method

 

In the multiple membrane extrusion method an amalgamation of surfactant, cholesterol, and dicetyl phosphate is dissolved in chloroform, and the resulting concoction is vaporized to form a thin film. This film is dampened with an aqueous drug solution, and the resulting suspension is extruded using polycarbonate membranes, which are inserted in series to create a maximum of 8 passages .

Proniosomal Method

In this niosome fabrication method, a water-soluble transporter such as sorbitol is sprayed with a surfactant to form a dry formulation in which each water-soluble particle is laminated with a thin layer of dry surfactant. This formulation is labeled as a proniosome. The proniosome powder thus formed is subsequently loaded into a screw-capped vial, and blended with water or saline at 80 °C by vortexing. This is followed by stirring for about 2 min, thus producing the final niosomal suspension.

CONCLUSION

BCS is the base upon which drugs are classified into respective classes according to their solubility in water and permeability through the GIT; thus, through BCS, the problems of drugs can be identified potentially resolved. BCS employs various methods for determining solubility and permeability. Various drug delivery systems are available for BCS class II drugs, of which niosomes are more economical and safer carriers than liposomes. This review forms an insightful reference base for the various preparation methods together with evaluation parameters and applications of niosomes in various fields of medicine.

 

 

ACKNOWLEDGMENT

Authors are thankful to Principal and Management J.I.I.U' S Ali Allana College of Pharmacy Akkalkuwa, Dist. Nandurbar for providing moral support and necessary facilities for completion of this work.

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