INTRODUCTION:

Biopharmaceutics Classification System (BCS) is a scientific categorization of a drug substance on the basis of its aqueous solubility and intestinal permeability. After oral ingestion of a drug, it gets dissolved into the gastric (hydrophilic) fluid initially, and then permeated across the biological membranes (lipophilic) and finally reaches in the blood. Many synthetic and herbal drugs are associated with the problem of either poor absorption or poor permeation through the biological membrane, thereby limiting their absorption and overall availability to the body system.

Poor absorption may be due to their poor water solubility, whereas poor permeation may be due to the poor miscibility with the lipids, thereby severely limiting their ability to pass across the lipid-rich outer membranes of the small intestine. Therefore, a large number of strategies including soluble pro-drug, solid dispersions, cyclodextrin and phospholipids, and vesicular drug delivery systems, etc have been investigated to improve the absorption and permeation of biologically active molecules^1-3.

Vesicular drug delivery systems (VDDS) are important systems used for drug targeting, increasing the bioavailability, and stability. These systems have an aqueous core normally surrounded by a lipid bilayer. The system is used as an excellent vehicle for the delivery of both hydrophilic and hydrophobic types of drugs. The hydrophilic drugs are entrapped in the inner aqueous core, while lipophilic drugs are encapsulated in a lipid bilayer. The various advantages offered by VDDS are high drug entrapment, long retention time, tissue targeting, reduced side effects, and increased bioavailability. Furthermore, the system can deliver a drug to the target site at a predetermined rate^4-6.

However, beneficial VDDS have certain limitations. The chief limitations of VDDS are related to their method of preparation, loading efficacy, stability, sterilization, scale-up, cost-effectiveness, burst release, and short half-life. Therefore, the pharmacosomes were developed to overcome various shortcomings associated with the conventional vesicular delivery systems. The pharmacosomes are reported as self-assembling conjugates of lipophilic prodrugs.

In this review, we overview in a very comprehensive manner, the pharmacosomes as an important vesicular delivery system, different components and techniques of preparation and characterization of pharmacosomes, and their applications. In addition, we have analyzed the pharcosomes of different drugs prepared using a variety of lipids and their effects on physicochemical properties and pharmacokinetic performance of the drugs. Finally, we conclude by outlining future perspectives for the development of pharmacosomes drug delivery.

Pharmacosomes:

Pharmacosomes are colloidal dispersions where the drug is covalently bound to lipid which gives rise to an amphiphilic block. Based on chemical structure of drug lipid complex, they exist as ultrafine vesicular, micellar, and hexagonal aggregates. The development of vesicular pharmacosomes originates from the surface and bulk interactions of drugs and lipids. The drug possessing the active functional groups (–COOH, -OH, -NH₂) can be covalently linked to lipids with or without spacer chain by esterification or any other suitable conjugation strategy leads to the formation of prodrugs. These prodrugs behave like amphiphilic molecules and get self-assembled in one or more layers in contact with the aqueous medium. These layers further self-assembled in the form of vesicles, resulting formation of pharmacosomes. In pharmacosomes the drug molecules act as a polar head and attached lipids as a non-polar tail. Pharmacosomes avoid problems such as drug leakage, drug incorporation, and reduced shelf life. They can improve drug bioavailability due to the reduction of interfacial tension, increased area of contact. The stability of pharmacosomes depends on the physical and chemical characteristics of the conjugate system. It posses several advantages over other vesicular systems such as transferosomes, niosomes, liposomes and hence serves as an alternative to this vesicular systems⁷.

Pharmacosomes plays a vital role in the improvement of the drugs dissolution in gastrointestinal fluid and enhancement of their permeation through the lipophilic membrane. Besides, they can improve the bioavailability of drugs having either low lipid or/and water solubility. The prodrug strategy offers high entrapment efficacy of the drug and practically prevents leakage from the vesicles and burst release. This, in turn, helps to skip the step of removal of the free or unentrapped drug from the formulation process, which is considered as a key limitation of liposomes. The stability of pharmacosomes mainly depends upon the physiochemical properties of drug-phospholipid conjugate like solubility, melting point, phase transition temperature, and lipid composition^8,9.

The degradation rate of pharmacosomes into active drug molecules is related to types of functional groups present in the drug molecule, fatty acid chain length in lipids and presence or absence of spacer groups. All these factors can be specifically varied to accomplish the desirable in vivo pharmacokinetic behaviour. It is reported that a lot of drugs including anti-cancer, cardiovascular drugs, non-steroidal anti-inflammatory drugs (NSAIDS), proteins, and herbal products are delivered through pharmacosomes. Pharmacosomes can be given through different routes like topical, oral and extra vascular routes^10,11.

The various advantages of pharmacosomes includes higher and predetermined drug entrapment efficiency due to its conjugation with lipid, lowest drug leakage due to covalent bonding, delivery of both hydrophilic and lipophilic drugs, improved bioavailability and stability of drugs, and can be given through different routes like oral, topical, intra and extravascular, etc. On the other hand certain disadvantages of pharmacosomes are aggregation and chemical degradation due to storage, surface bulk interaction, covalent bondings are essential for inhibition of drug leakage^12,13.

Components of Pharmacosomes:

The three main components of pharmacosomes are drug, lipid and solvents.

Drug:

A drug having active hydrogen atom (-COOH, -OH, -NH₂) esterified with a lipid moiety to get amphiphilic block. This amphiphilic block facilitates drug transport via cell membrane, tissue and cell wall. Pharmacosomes of several drugs such as diclofenac, aceclofenac, geniposide, aspirin etc were prepared.

Solvent:

Solvents with high polarity and solubility used for preparation of pharmacosomes. The solvents used must be of high purity and volatile. Generally solvents with intermediate polarity such as acetone, dichloromethane, ethanol, methanol, tetrahydrofuran etc. were preferred for preparation of pharmacosomes.

Lipid:

The major component of the biological membrane is phospholipids. There are two types of phospholipids such as phosphoglycerides and spingolipids which are majorly used. Phosphatidylcholine is the most commonly used lipid for the preparation of pharmacosomes. It is an amphiphilic block in which pair of hydrophobic acyl hydrocarbon chains binds with a hydrophilic polar head group of phosphocholine with glycerol bridge. Phosphatidylcholine helps to maintain cell membrane integrity and involved in various biological processes. It acts as a source of protein and hepatoprotective agent and used in the management of liver disorders. Besides, it prevents fibrosis and cirrhosis by enhancing collagen breakdown. Furthermore, it is used to treat different brain conditions such as memory loss, Alzheimer disease, and tardive dyskinesia, and in cancer management^14,15. The chemical structure of different lipids used for pharmacosomes preparation is shown in Figure 1.

Fig. 1: Chemical structure of some phosphorlip

Methods of Pharmacosomes Preparation^10-13

The pharmacosomes can be prepared by different methods (Figure 2). The methods of pharmacosomes preparation are discussed below.

Figure 2: Pharmacosomes preparation techniques

1. Hand shaking method:

It is one of the simple methods of pharmacosomes preparation where the drug lipid mixture dissolved in a volatile organic solvent in a round bottom flask. Then, the solvent is allowed to evaporate using a rotary vacuum evaporator that leads the formation of a thin film in a flask. Finally, the thin film is hydrated using an aqueous medium which gives a vesicular suspension.

2. Ether injection method:

In this method, drug lipid complex is dissolved in a definite quantity of ether. This ether solution is then injected in hot buffer or aqueous medium, where vesicles get formed. Vesicles may be in different forms such as round, cylindrical, cubic, or hexagonal type. The shape of vesicles depends on the amphiphilic nature of conjugate and its concentration.

3. Anhydrous co-solvent lyophilyzation method:

The drug and phospholipid is dissolved in a solution of dimethyl sulfoxide and glacial acetic acid. Then, this mixture is agitated to form a clear liquid solution and freeze-dried overnight at condenser temperature. The complex obtained is flushed with nitrogen and stored at 4⁰C.

4. Solvent evaporation method:

It is a conventional method of pharmacosomes preparation where the drug is firstly acidified to get an active hydrogen atom which is necessary for complexation. An acid solution of drug extracted with chloroform and recrystallized. The drug lipid complex is dissolved in the organic solvents in a round bottom flask at different ratios. The resultant mixture then refluxed for 1 or 2 hours and dried under vacuum evaporator at 40⁰C. This dried residue was placed in a vacuum dessicator for complete drying. It is time-consuming and involves multistage processing.

5. Supercritical fluid process:

This method is used to overcome shortcomings associated with the solvent evaporation technique. The main drawbacks of solvent evaporation technique, time-consuming and involve multistage processing. Besides, the dissolution of pharmacosomes does not improve ideally. Parameters allied to solid morphology, including the particle size, the crystal habit, and crystal pattern, influence the dissolution rate of a compound and thus can affect their bioavailability significantly. The two main techniques used in the supercritical process are gas anti-solvent and solution enhanced dispersion by supercritical fluid. In this method drug lipid complex is dissolved into a supercritical fluid of CO₂ and mixed by using a nozzle mixing chamber. Pharmacosomes formed by fast mixing of dispersion due to the turbulent flow of solvent and carbon dioxide.

Characterization of Pharmacosomes:

Characterization of drug-lipid complex (prodrug):

1. Chromatography:

The simple chromatographic technique like thin layer chromatography (TLC) is primarily used for the confirmation of prodrug. The purity of starting materials and product as well as the progress of drug-phospholipid conjugate synthesis can be confirmed by this technique. Nowadays, advanced techniques such as high-performance thin layer chromatography (HPTLC) and high-performance liquid chromatography (HPLC) are widely used over TLC due to rapid separation, better resolution, and higher sensitivity. The conjugation of lipids to the drug molecule leads to an increase in the lipophilic character of parent drugs and therefore, results in a change in the retention time¹⁴.

2. Melting point:

The melting point is an important parameter that gives information regarding any structural changes in the organic compound. The prodrug formation is characterized by a change in melting point which is normally notably different from that of either pure drug or lipid. The incorporation of lipid moiety to the drug molecule has been reported to either increase or decrease the melting point of the original drug. A technique like differential scanning colorimetry (DSC) is widely used to determine the melting point of compounds¹⁶.

3. Ultraviolet spectroscopy:

It is one of the preliminary spectroscopy techniques used to identify the changes in the absorption peaks that occur due to a change in molecular structure. The UV-visible spectrum for pure drug, phospholipid, physical mixture, and prodrug is recorded. The absorption peaks in physical mixtures usually appear at the same wavelength as observed in pure drug and phospholipid. Prodrug synthesis can be confirmed by shifting of peaks which may be attributed to the formation of new bonds and newly introduced neighbouring groups.

4. Fourier transform infrared spectroscopy (FTIR):

The prodrug formation is confirmed using FTIR by comparing the infrared spectrum (IR) of prodrug with individual components and physical mixture. The spectrum of a prodrug is commonly different from individual components or physical mixture due to chemical interactions between drug and phospholipid which leads to the formation of new bonds¹⁷.

5. Nuclear magnetic resonance (NMR):

The prodrug formation can also be confirmed by NMR. This technique provides information regarding magnetic properties of nuclei such as hydrogen, carbon, and phosphorous. The signals of various nuclei may exhibit an upfield or downfield shift in the NMR which may be attributed to shielding or deshielding effect of neighbouring nuclei in the phospholipid derivative¹⁸.

6. X-ray diffraction (XRD):

X-ray diffraction analysis is also performed to confirm the formation of the drug-phospholipid conjugate. In X-ray diffraction pattern the crystalline drugs demonstrate characteristic intense peaks while phospholipid which is amorphous, shows wide peaks. The physical mixtures display both sharp and wide peaks due to the presence of both free drug and phospholipids. The disappearance or reduction in the intensity of sharp peaks indicates the formation of drug-phospholipid conjugate¹⁹.

7. Solubility studies:

The solubility is also one of the criteria used in the characterization of drug-phospholipid conjugate. The formed drug-phospholipid conjugate will affect the solubility profile of the drug. The conjugation of drug with lipophilic moieties decreases solubility and increases the membrane permeability. The solubility studies are performed in water and buffer solutions of different pH values. An excess amount of sample beyond saturation is added in vials containing different solvents and equilibrated in shaker bath at 37⁰C for 24 hrs at controlled rpm. After completion of 24 hrs, a known volume of sample is withdrawn and the amount of drug solubilized is determined by UV-visible spectroscopy²⁰.

Characterization of vesicles^21,22

1. Surface morphology:

The size and shape of pharmacosomes are altered by certain parameters such as purity of phospholipids, speed of rotation, method of preparation. Surface morphology can be studied by using scanning electron microscopy (SEM) and transmission electron microscopy (TEM), etc technique.

2. Drug content:

For the determination of drug content, an equivalent amount of drug-lipid complex is measured and transferred to a volumetric flask containing solvent. Then flask is sonicated to achieve solubilization for 24 hrs. Finally, the solutions are diluted and drug content is determined using UV-visible spectroscopy or HPLC.

3. In vitro drug release study:

The equilibrium reverse dialysis bag technique is used to perform in vitro drug release study. Dialysis bag containing donor phase (an emulsion of drug, drug lipid complex) suspended in a vessel containing continuous phase outside and stirred. At definite time interval dialysis bag is removed and analyzed for drug release. This method has certain advantages as the increased surface area available for donor and receiver phase and increased efficiency due to reduction in the number of steps.

4. In vivo characterization:

Specific study models were selected based on the expected pharmacological activity of the drug in the pharmacosomes. For evaluating in vivo hepatoprotective activity, the effect of test pharmacosomes on animals against alcohol or paracetamol-induced hepatotoxicity can be observed.

5. Stability:

FTIR spectrum of drug lipid complex in solid form is compared with the FTIR spectrum of its micro-dispersion in water after lyophilization at different time intervals. This spectrum data tells about the stability of pharmacosomes.

Applications of Pharmacosomes:

Nowadays, pharmacosomes have shown wide applications in the delivery of different types of drugs to treat a variety of diseases. The various kinds of drugs given through the pharmacosomes include NSAIDs (aceclofenac, aspirin, diclofenac, etodolac, ibuprofen, ketoprofen, and naproxen, etc), anti-cancers (camptothecin, cytarabine, gemcetabine, paclitaxel, etc), anti-viral (acyclovir, adefovir, didenosine, zidovudine, etc), anti-hypertensive (amlodipine, losartan), diuretics (furosemide), and anti-tubercular (isoniazid)²³. The pharmacosomes prepared by using different drugs and lipids with improved physicochemical properties and pharmacokinetic performance are presented in Table 1.

Table 1: Pharmacosomes prepared using different drugs, lipids and preparation techniques with improved physicochemical properties and pharmacokinetic performance

Drug	Lipid used	Preparation Technique	Therapeutic Application	Significance
Aceclofenac (ACF)	Soya phosphatidylcholine (Lipoid S-80)	Solvent evaporation	NSAIDs	Improved bioavailability of ACF ²³
Aspirin (ASP)	Soya phosphatidylcholine (Lipoid S-80)	Solvent evaporation		Controlled release of ASP²⁴
Diclofenac (DCF)	Soya phosphatidylcholine (Lipoid S-80)	Solvent evaporation		Improved solubility and loading of DCF²⁵
Etodolac (ETD)	Soya lecithin	Thin film hydration		Improved solubility and Entrapment efficiency of ETD, and sustained release of ETD²⁶
Ibuprofen (IBF)	Phosphatidylcholine	-		Improved bioavailability of IBF²⁷
Ketoprofen (KTP)	Soya phosphatidylcholine (S-80)	Solvent evaporation		Increased solubility and dissolution of KTP²⁸
Naproxen (NP)	Soya lecithin	Ether injection		Exhibited controlled release of NP²⁹
Geniposide (GP)	Phospholipid	Solvent evaporation	Anti-inflamatory	Improved lipophilicity, absorption and permeation of GP³⁰
Acyclovir (ACV)	Phosphatidylcholine	Tetrahydrofuran injection	Antiviral	Improved solubility of ACV³¹
Didanosine (DDS)	Soya lecithin	Tetrahydrofuran injection	Antiviral	Enhanced dissolution profile and bioavailability of DDS³²
Losartan (LST)	Soya phosphatidylcholine (S-80)	Solvent evaporation	Antihypertensive	Improved bioavailability of LST³³
Pindolol (PDL)	Soya lecithin	Tetrahydrofuran injection	Antihypertensive	Improved bioavailability of PDL³⁴
Furosemide (FRS)	Soya phosphatidylcholine (Lipoid S 75-3)	Solvent evaporation	Diuretics	Showed sustained release of FRS³⁵
Ornidazole (ODZ)	Soya lecithin	Solvent evaporation	Antibiotic	Showed sustained release of ODZ³⁶
Rosuvastatin (RSV)	Soya lecithin	Hand shaking	Antihyperlipidemic	Demonstrated sustained release, and improved bioavailability of RSV³⁷

Conclusions and Future Perspectives:

Amongst, the vesicular delivery systems, pharmacosomes is a stepping stone to improve delivery of drugs containing active hydrogen atom (-COOH, -OH, -NH₂). In pharmacosomes drug is bound to the lipid by covalent, van der Waal and hydrogen bonding. The drug-lipid conjugate (prodrug) is amphiphilic in nature and get self-assembled in vesicles in an aqueous medium. Both hydrophilic and lipophilic drugs are easily delivered through the pharmacosomes. In contrast to conventional liposomes, pharmacosomes are characterized by an unusually high drug loading, amenability to sterilization, higher in-vitro stability, and a low burst release. A large variety of drugs formulated as pharmacosomes using different lipids and preparation techniques have shown improved physicochemical properties and pharmacokinetic performance of the drug, but no formulations have yet reached the clinical stage.

The continued development of advanced methodologies is crucial to the advancement of pharmacosomes as a drug delivery system. Although different methods to confirm the formation of prodrug have been reported, still there is a need to develop some innovative tools and techniques for their characterization. Moreover, the main challenge remains to develop safe drug derivatives capable of self-assembly and high targeting efficiency in vivo. The interaction between drug molecules chemical structure, the unprompted self-assembly of these amphiphilic conjugates, and their drug delivery potential pave an exciting way for future investigations.

Abbreviations:

BCS: Biopharmaceutics Classification System; VDDS: Vesicular drug delivery systems; ACF: Aceclofenac; ASP: Aspirin; DCF: Diclofenac; ETD: Etodolac; IBF: Ibuprofen; KTP: Ketoprofen; NP: Naproxen; GP: Geniposide; ACV: Acyclovir; DDS: Didanosine; LST: Losartan; PDL: Pindolol; FRS: Furosemide; ODZ: Ornidazole; RSV: Rosuvastatin; NSAIDS: Non-steroidal anti-inflammatory drugs; TLC: Thin layer chromatography; HPTLC: high-performance thin layer chromatography; HPLC: High-performance liquid chromatography; DSC: Differential scanning colorimetry; FTIR: Fourier transform infrared spectroscopy; NMR: Nuclear magnetic resonance; XRD: X-ray diffraction; SEM: Scanning electron microscopy; TEM: Transmission electron microscopy.

ACKNOWLEDGMENTS:

We are greatly thankful to our institute’s head and management for their support of the writing of this review article.

CONFLICT OF INTERESTS:

The authors declare that they have no any conflict of interests.

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Received on 17.05.2020 Modified on 26.08.2020

Research J. Pharm. and Tech. 2021; 14(8):4485-4490.

DOI: 10.52711/0974-360X.2021.00779