INTRODUCTION:

Pharmacosomes are amphiphilic complexes of lipid drugs (which contain an active hydrogen atom). The drugs bind to lipids either covalently, electrostatically, or by hydrogen bonds. Pharmacosomes are the spherical particles of drugs directly binds to lipids, which can exist as super-fine vesicular, micellular or hexagonal aggregates depending on the chemical structure of the drug-lipid complex. Improving the absorption and minimizing gastrointestinal toxicity has been found to develop drug pharmacosomes. A drug with a free carboxyle group or an active hydrogen atom (-NH2, OH, -COOH) may be esterified to the hydroxy group of a lipid molecule with or without a spacer chain, thus producing an amphiphylic prodrug.

Such a prodrug incorporates hydrophilic and lipophilic properties, and thus shows amphiphilic properties. Pharmacosomes are formed from these when diluted with water Prodrugs amphiphilic. The idea to create the vesicular pharmacosome is based on interactions between the surface and bulk of the lipid-drug. Amphiphilic compounds are pharmacosomes that promote membrane, tissue, or cell wall movement within the organism. The amphiphilic characters support pharmacosomes lower the interfacial stress and exhibit higher mesomorphic action concentrations. This decrease in the interfacial tension results in an increase in the contact area thus increasing drug bioavailability.²

Fig.1: Structure of Pharamacosome

· Importance of Pharmacosomes^3,4:

1. Pharmacosomes have some value in escaping formulation from the repetitive steps of extracting the free unentrapped material.

2. Pharmacosomes can provide an effective delivery system the medication directly to the infection site, leading to a reduction in drug toxicity without adverse effects and also reducing therapy costs by improving drug bioavailability, particularly for poorly soluble drugs.

3. Pharmacosomes are suitable for both lipophilic and hydrophilic drug incorporation.

4. Efficiency in entrapment is not only high but predetermined, because drug itself forms vesicles in conjunction with lipids.

5. No need to follow the tedious, time-consuming step to remove the formulation of the free, untrapped drug.

6. Since the drug is covalently linked, there is no loss due to drug leakage.

7. No drug-incorporation issue.

8. Encaptured volume and drug – bilayer interaction, in the case of pharmacosomes, do not affect entrapping efficiency.

9. The pharmacosomal physicochemical stability depends on the physicochemical properties of the drug-fat complex

· Advantages^1,7:

1. Drug loading high and predetermined

2. Deliver the medication directly to the infection site.

3. Reducing toxicity and adverse effects.

4. Stable and efficient because of covalent bonding

5. Scale, functional groups (drug molecule), chain length (lipids), and spacer dictates the rate of degradation into the active molecule of drugs

6. No drug-incorporation issue

7. Pharmacosomes are complexes of PLs of the zwitter ionic, amphiphilic, stoichiometric and polyphenolic compounds. In many ways pharmacosomes show better results than other lipid-based delivery systems.

8. Encaptured volume and drug-bilayer interactions, in the case of a pharmacosome, do not affect the effectiveness of trapping. In the case of liposomes, on the other hand, these factors have a great influence on the efficiency of trapment.

9. Entrapment efficiency is not only high, but also predetermined, as the drug itself forms vesicles in conjunction with lipids, and is covalently linked together.

10. Reduced Therapy costs

11. No need to separate the free unentrapped drug from the formulation that is needed for liposomes.

12. Improves bioavailability particularly in the case of drugs which are not very soluble.

13. Reducing toxicity and adverse effects

· Disadvantages⁸:

1. The synthesis of a compound is determined by its amphiphilic nature.

2. This requires lipid surface and bulk contact with drugs.

3. For the protection of drug leakage it requires covalent bonding.

4. Pharmacosomes undergo fusion and aggregation upon storage, as well as chemical hydrolysis.

Pharmacosome material^5,6:

Drug: any drug possessing (-COOH-OH-NH2,) is esterified to the lipid, with or without a spacer chain, resulting in complexes of both hydrophilic and lipophilic. They are directed in such a form of compound synthesis as how it effectively leads to both a compound's hydrophilic and lipophilic nature, which can promote cell, tissue, or plasma membrane transfer within the organism.

Lipid: The main molecular strength of the cell membranes is lecithin, lipid, or phosphatidylcholine. Phospholipids are the drug forming both hydrophilic and lipophilic merchandise that makes hydrophilic phospholipids and lipid-soluble drugs as well.

Solvents: The solvents help to demonstrate more purity for the creation of pharmacosomes and the essence is volatile. The intermediate polarity solvents are selected for pharmacosome preparation.

Pharmaceutical Carriers of Pharmacosomes^11,12,13:

Pharmaceutical carriers are classified as carriers of particulates, polymeric, macromolecular, and cellular. Particular types of carriers are also known as colloidal carriers which include low- and high-density lipoprotein lipid particles, low-density lipoproteins and high-density lipoproteins. A wide variety of drug carriers are being studied and each of them has unique benefits and ill effects. More prominent type of drug carriers are niosomes, liposomes, polymeric micelles, microspheres, and nanoparticles. The different methods present in binding the drug with carrier include adsorption, encapsulation and covalent bonding. Various drug carriers use various forms of attachment systems.

Fig No.2: Pharmaceutical Carriers

Formulation of pharmacosomes¹:

Drug salt has been converted into acid form to provide the complexation of an active hydrogen site. Drug acid was prepared by acidification of a drug salt aqueous solution, chloroform extraction and recrystallization afterward. Drug-PC complex was prepared by mixing product acid with a PC concentration of equimolar. Equimolar pc and drug acid concentrations were placed in round bottomed flask and dissolved in dichloromethane. The solvent was evaporated in a rotary vacuum evaporator at 40°C under vacuum.

Different evaluation techniques used for Pharmacosomes:

Table No. 2: Different evaluation techniques used for Pharmacosomes

Parameters	Techniques and Instruments
Size and size distribution	For measurement of drug lipid complex
Shape and surface Morphology	Scanning electron Microscopy, Transmission electron microscopy
Conformation of complex Formation	Atomic force microscopy
State of Phospholipid Complex	Differential scanning colorimetry, X- ray Powder diffraction study
In vitro dissolution study	Dissolution test apparatus, Shake Flask method
Solubility study	Infra- red spectroscopic analysis
Formation of Complex	Nuclear magnetic resonance
Drug Content	UV visible spectrometer

Method for preparation of pharmacosomes⁸:

Hand-shaking method:

The dried film of drug lipid complex deposited on hydration with aqueous medium in a round bottom flask readily gives vesicular suspension in hand-shaking method. Typically, lecithin is added several times in the drug lipid complex to the complex's surface tension, so good surface wetting properties are provided when reconstituted in an aqueous medium. In general, water is used as an aqueous phase.

Ether injection method:

Organic solution of the drug lipid complex was slowly injected into the aqueous medium by ether injection method, whereby the vesicles were readily formed. Here the complex of product lipids is combined with ether, which serves as a solvent and is then gradually injected into the aqueous medium and spontaneous vesicle formation.

Fig. 3: Ether injection method

Supercritical fluid process:

The complex supercritical fluid helps to increase solution dispersion, it combines into a nozzle intermixture chamber before this complicated drug and lipoid are dissolved in a very supercritical carbon dioxide fluid.

Anhydrous co-solvent lyophilization method^11,12:

Product and phospholipids are diluted in glacial acetic acid-containing dimethyl sulfoxide solution.

The above mixture is then agitated to produce transparent liquid and then freeze-dried at condenser temperature overnight. The resulting complex is nitrogen-flushed and deposited at 4cc.

Solvent evaporation method^13:

The drug is first acidified in the solvent evaporation process used to prepare the pharmacosomes so that the active hydrogen may be usable for complexation. The therapeutic acid is then dissolved into chloroform and recrystallized. The complex of drug-PCs is prepared by associating drug acid with PC in different molar ratios. PC and drug acid weighed precisely are put in a 100ml round bottom flask and dissolved in adequate quantities of dichloromethane. The mixture is refluxed for one hour. Then the solvent is evaporated off under vacuum at 40°C in a rotary vacuum evaporator. The dried residues are then collected for full drying and put in a vacuum desiccator.

Recent approaches:

A biodegradable micelle containing a drug conjugate has been synthesized with a polymer consisting of polyoxyethylene glycol and Adriamycin polyaspartic acid hydrophobic in nature. Dilution of the micelle without precipitation of the active constituent in the monomeric conjugate¹³. Diluting lyotropic liquid crystals of amphiphilic drug by Muller-Goymann and Hamann.¹⁴nPhosphotidylethanolamine with different molar ratios of Phosphotidylecholine and cholesterol which significantly increased cytoprotection by encapsulating amoxicillin Singh et al. formulated “vesicular constructs “using aqueous domain.¹⁵

Characterisation of pharmacosomes^1,5,8:

Complex Determination:

Fourier's assistance transforms infrared spectroscopy, whereby correlating spectrum discovered in a complicated sample will determine the formation of the complex or conjugate with their mixture and with separate components.

Stability of Pharmacosomes:

This association of the solid-state continuum indicates a varied point of time with the dispersion continuum being studied in water composed of tiny particles, this helps to assess the steadiness of the system when the sample is lyophilized.

Solubility:

As this process results in complexation and this is due to the change in solubility which can be evaluated by the technique of shake flasks. In this process, two phases are used in this one is octanol and aqueous phase is used, at a temperature of 37°C for one day and constant shaking is required in this time period. Using ultraviolet high-performance liquid chromatography technique, the concentration is calculated using liquid portion which is separated by solution.

Scanning electron microscopy/transmission electron microscopy:

SEM of the complex was recorded on a scanning electron microscope to detect the pharmacosomal surface morphology. Scanning electron microscopy detects pharmacosomal surface morphology.

Drug- liquid compatibility:

Differential calorimetry scanning is a thermoanalytical method used to assess compatibility of the drug-lipid and their interactions, if any. The thermal response will be analyzed using separate samples, and heated in a closed sample bath. The nitrogen gas is purged, and a specific heating rate keeps the temperature within a definite range.

Crystalline structure management:

Using X-ray diffraction technique, the crystalline structure of the substance is determinable. In the X-ray generator, the tube voltages and tube current can be controlled. Copper lines may serve as the radiation source. The angle of scan may be adjustable. The overall combined intensity of all peaks of reflection is projected by area under X-ray powder diffraction pattern curve which specifies the specimen attributes.

Dissolution studies:

Studies of dissolution, in vitro are carried out using various available models for the purpose. The results are assessed therapeutically on the basis of apprehended activity of the active constituents.

X-ray powder diffraction:

Determining the degree of crystallinity was performed using the relative, integrated intensity of peaks of reflection. The integrated intensity is given by the area under XRPD pattern curves, and it represents the characteristics of the specimen.

In vivo and in vitro evaluations:

Depending upon the expected therapeutic activity of biologically active constituents, models of in-vivo and invitro evaluations had been carried out.

Marketed preparations^9,10:

Human Iron Dextran is produced by Pharmacosmos as an Iron Dextran low molecular weight. As the only injectable iron product, CosmoFer ® offers iron replenishment flexibility through total dose iron infusion, intravenous and intramuscular iron injection. Veterinary Iron Dextran is used as an iron supplement in piglets to prevent iron deficiency anaemia. Uniferon ® Iron Dextran drug products are commercialized in a number of countries. Pharmacosmos Dextran polymers are made in line with Good Manufacturing Practice (GMP). Our Dextran products include the Dextran and GPC standards for GPC chromatography in clinical and reagent grade.

Table No. 3: Comparing Various Methods and Their Outcomes of Drugs Using Pharmacosomes

S. No.	Drug	Polymer	Solvent	Bonding
1	Naproxen	Soya lecithin	Diethyl ether, ethanol, acetone	Covalent bond
2	Aspirin	Soya phosphotidylecholine	Dichloromethane	Covalent bond
3	Aceclofenac	Soya phosphotidylecholine	Dichloromethane	Covalent bond
4	Ketoprofen	Soya phosphotidylecholine	Dichloromethane	-
5	Etodolac	Soya lecithin	Acetone, dichloromethane, methanol
6	Ibuprofen	Phosphotidylecholine	Dichloromethane, chloroform	-
7	Etodolac	Soya lecithin	Acetone, dichloromethane, methanol	-
8	Diclofenac	Phosphotidylecholine	Dichloromethane	Covalent bond

Continew Table 3

S. No.	Drug	Technique used	Result	Final product
1	Naproxen	Ether injection method	Solubility enhanced and achieved controlled drug release	Pharmacosomes gel
2	Aspirin	Solvent evaporation	Improved drug delivery controlled drug delivery	Pharmacosome
3	Aceclofenac	Solvent evaporation	Enhancement of solubility and dissolution profile and improved bioavailability	Pharmacosome
4	Ketoprofen	Solvent evaporation	Improved solubility, dissolution profile	Pharmacosomes
5	Etodolac	Thin film hydration	Increased solubility, entrapment efficiency and sustained relaese	Pharmacosomes gel
6	Ibuprofen	-	Increased bioavailability	Pharmacosomes
7	Etodolac	Thin film hydration	Increased solubility, entrapment efficiency and sustained relaese	Pharmacosomes gel
8	Diclofenac	Solvent evaporation	Improved solubility and drug loading	Pharmacosomes

Application of pharmacosomes^{1,25,26,27,28,29}:

1. Pharmacosomes show wider stability profile and longer shelf life.

2. Pharmacosomes have the capacity to increase drug absorption and conveyance. Using response surface design, the formulated geniposidepharmacosomes were optimized and their attributes examined by colleagues. Phospholipid-to-drug ratio, temperature of the reaction mixture, and concentration of drugs were 3, 50 C, and 5.5 mg / mL respectively.

3. Pharmacosomes prepared for various anti- inflammatory medications, which are poorly soluble, non-steroidal, i.e. Aceclofenac, Diclofenac, Aspirin, and Fenoprofen. These studies show that pharmacosomes can enhance the ability to dissolve and permeate a substance. Drug permeation across the skin also increased when tested with percutaneous in vitro absorption by using fenoprofen flow through the diffusion cell.

4. Pharmacosomes can increase the permeation rate by improving the fluidity of the membranes. The transition temperature of vesicles in the form of vesicles and micelles could have an obvious effect on the vesicular interaction with the biomembrane, thus improving the transfer of drug across the membrane.

5. Pharmacosomes' phase transition temperature in the vesicular and micellar state may have a major effect on their membrane interaction and interact with bi membranes, thus allowing better transfer of active ingredients. This interaction leads to changes in the temperature of bio membranes in phase transition, thus improving the fluidity of the membranes.

6. The approaches have successfully improved therapy, performance, and various drugs such as pindolol diglyceride, amoxicillin, taxol, cytarbin, dermatansulfate, bupranolol hydrochloride, and so on.

7. The process of injection of tetra hydro furan is the negatively charged pharmacosomal nanometer Acyclovir succinyl glyceryl monostearate. They found that centrifugation and heating effect on stability of pharmacosomes very weekly, whereas freezing and lyophilization disturbed the structure of the pharmacosomes.

8. Tetra hydrofuran injection technique and concluded that in target tissue, pharmacosomes provoke liver targeting and sustained release effect.

9. Isoniazid pharmacosomes have increased permeability and are targeting the macrophage. Pharmacosomes also enhance the biopharmaceutical properties of bioactive phytoconstituents, including flavones, glycosides and xanthones.

Future Prospects:

It is hoped that with more and more research endeavours being focused into this Pharmacosomes, in near future, a large portions of the conventional dosage forms would be replaced by these NDDS system like Pharmacosomes and an overall betterment of health care delivery is expected with that change over. These system having more advantages over other system. Moreover development and implementation of new branches like Pharmacovigilance will ensure availability of safer medicines to our people. This system will provide cost effective health care, which may help to extend the health care to the underprivileged

REFERENCES:

1. Thakur Sonam, Tibrewal Richa, et alPharmacosomes: An Overview, international journal of Pharmaceuticals and Biological science archive,2017; 5(2): 1-7.

2. Jangam Payal R, Thombre Nilima A, Gaikwad Pallavi N. A Review: Proniosomes as a Novel Drug Delivery System Asian J. Pharm. Tech. 2017; 7 (3): 166-174.

3. Sonam Ranga, Amit Kumar., et al A Review on Pharmacosomes. Research and Reviews: Journal of Pharmaceutics and Nanotechnology, 2014; 2(1): 8-14

4. Selvaraju K., Vengadesh Prabhu K., Karthick K., Padma Preetha J. and Arul Kumaran K.S.G. Pharmacosomes- An Immense Potential Vesicular Constructs Research J. Pharma. Dosage Forms and Tech. 2011; 3(3): 84-86.

5. Nagasamy V. D, Kalyani K, Tulasi K, Swetha P, Shaik A. A, et alPharmacosomes: a potential vesicular drug delivery system, International Journal of Pharmaceutical Science and Drug Research. 2014; 6(2): 90-94.

6. Pavan Kumar, Debnath S, Babu N et al “Pharmacosomes as a novel vesicular drug delivery system”, Int J of Novel Trends in Pharm. Sci.2013; 3(3): 46- 52.

7. D. Nagasamy Venkatesh, K. Kalyani, K. Tulasi, V. Swetha Priyanka, Shaik Abid Ali, S. Shashi Kumar, et alPharmacosomes: A Potential Vesicular Drug Delivery System; International Journal of Pharmaceutical Sciences and Drug Research 2014; 6(2): 91-92

8. PreetiKhulbe, Deepa Mohan Rajput, Tahseen Khan et alPharmacosomes: An Effective Approach for Drug Delivery; SGVU Journal of Pharmaceutical Research and Education, 2019; 4(1): 352-358

9. Mantelli S, Speiser P, Hauser H. et al Phase behaviour of a diglyceride prodrug: spontaneous formation of unilamellar vesicles Chem. Phys Lipids 1985; 37: 329–343.

10. P. H. Sharma, P. V. Powar, S. S. Sharma et alPharmacosomes: A novel drug delivery system; The Pharma Innovation Journal 2014; 3(10): 94-100

11. Drug carrier Wikipedia, sevenson, sonke, carrier based drug delivery, 2004.

12. Biju SS, Talegaonkar S, Mishra PR, Khar KR. Vesicular System: An overveiw. Indian J. Pharm Sci, 2009; 71(4): 421-427.

13. Bommala Supraja, Saritha Mullangi, An updated review on pharmacosomes, a vesicular drug delivery system, Journal of Drug Delivery and Therapeutics. 2019; 9(1-s): 393-402

14. Solanki D, Patidar A, Kukde D, Pharmacosomes – A Review, International Journal of Pharmacy, Eng and Life Sci. 2016; 12(3): 70-78.

15. Lawrence MJ. Surfactant Systems: Their use in drug delivery. Chem Soc Rev, 1994; 23: 417–424.

16. Muller-Goymann CC, Hamann HJ. Pharmacosomes: Multilamellar vesicles consisting of pure drug. Eur J Pharm Biopharm, 1991; 37: 113–117.

17. A. Singh and R. Jain, “Targeted Vesicular Constructs for cryoprotection and treatment of H. Pylori infections,” US Patent 6576, 2003, 625.

18. Kolar kusuma, D. Priyanka, J. Sundaraseelan. Formulation and evaluation of pharmacosomal gel loaded with NSAID. WJPMR2018; 4 (7): 81-88.

19. Semalty A, Semalty M, Rawat BS, Singh D, Rawat MSM. Development and characterization of aspirin- phospholipid complex for improved drug delivery. IJPS 2010; 2(2): 940-947.

20. Semalty A, Semalty M, Rawat B S, Singh D, Rawat MSM. Development and evaluation of pharmacosomes of aceclofenac. IJPS 2010;72: 576-81.

21. Kamalesh M, Baviskar D, Wagh K, Baviskar K. Formulation and evaluation of pharmacosomes of Ketoprofen. Indo Am J Pharm Res. 2014; 4(3): 1363-1368.

22. Raikhman L M, Ivanov V E, Moshkovskii Y S. Development of Ibuprofen pharmacosomes for enhancing the bioavailability. Drug Dev Indian Pharm. 2002; 28(5): 473-482.

23. Letha S, Shammika P, Viswanand V. Formulation and evaluation of etodolac pharmacosomes: A novel approach towards rheumatoid arthritis. IJPT 2017; 9(2): 29665-29680.

24. Semalty A, Semalty M, Rawat BS, Singh D, Rawat MSM. Development and physicochemical evaluation of pharmacosomes of diclofenac. IJPS 2010; 59: 335-344.

25. Raval, Madhabhai M. Patel Techniques to Improve Bioavailability of Poorly Water Soluble Drugs – A review Amit J. Research J. Pharma. Dosage Forms and Tech. 2011; 3(5): 182-192.

26. Kanti Sahu, Rishita Pathak, Naveen Agrawal, Pinkesh Banjare, Harish Sharma, Gyanesh Sahu, Review of the Novel Drug Delivery System used in the Treatment of CancerRes. J. Pharma. Dosage Forms and Tech.2019; 11(3): 199-205.

27. Selvakumar Kalimuthu and AV Yadav, Nanobased Drug Delivery System: A ReviewResearch J. Pharm. and Tech. 2(1): Jan.-Mar. 2009; Page 21-27.

28. Shiva Kumar Yellanki, Jeet Singh, Naveen Kumar Nerella, Sambit Kumar Deb and Sharada Goranti, Nanotechnology for Poorly Soluble Drugs, Research J. Pharm. and Tech.3 (3): July-Sept. 2010; Page 688-693.

29. Sunder Raj Manvi, V. R. M. Gupta, K. Srikanth, N. Devanna, Formulation and Evaluation of Candesartan Niosomal Suspension, Research J. Pharm. and Tech. 5(12): Dec. 2012; Page 1570-1572.

Received on 19.09.2020 Modified on 25.12.2020

Asian Journal of Pharmaceutical Research. 2021; 11(2):122-127.

DOI: 10.52711/2231-5691.2021.00023

Sr. No	Component	Requirement
1	Drugs	Functional hydrogen atom from amino, or hydroxyl group that can be esterified
2	Lipid	Phospholipid-phosphoglyceride / sphhingolipids
3	solvents	High purity, volatile, and intermediate polarity