Oral Drug Delivery System

Oral administration is favored for its simplicity of ingestion, avoidance of pain, versatility in handling different types of drugs, and, most importantly, high patient compliance. Additionally, solid oral delivery systems do not need sterile conditions, making them more cost-effective to produce.

Noval Drug Delivery System

Several new technologies for oral drug delivery have emerged recently, aimed at addressing the physicochemical and pharmacokinetic properties of drugs while enhancing patient compliance. Innovations like electrostatic drug deposition and coating, along with computer-assisted 3D printing for tablet manufacturing, have also been introduced. The development of oral modified drug delivery systems has allowed for extended drug release over several hours, reducing dosing frequency, minimizing side effects, improving therapeutic outcomes, and increasing bioavailability, making it more favorable than conventional dosage forms.

Challenging Oral Drug Delivery Via Nano-Carriers

The Vesicular drug delivery systems offer several benefits over conventional and prolonged-release dosage forms, such as:

• Enhanced drug permeation into cells.
• Extended presence of drugs in systemic circulation.
• Reduced toxicity due to selective uptake.
• Lower therapy costs.
• Improved bioavailability
• Ability to incorporate hydrophilic and lipophilic drugs.
• Function as a sustained-release system.
• Delayed elimination of drugs that are rapidly metabolized.
• Overcoming issues related to drug insolubility, instability, and rapid degradation.

Conventional chemotherapy for treating intracellular infections is often ineffective due to limited drug permeation into cells. Vesicular drug delivery systems improve bioavailability at the disease site, minimize harmful side effects associated with conventional and controlled-release systems, and address issues of drug degradation and loss.

Liposome

Liposomes are composed of one or more concentric lipid bilayers that enclose internal aqueous compartments. For drug delivery purposes, liposomes are typically unilamellar and have diameters ranging from approximately 50 to 150 nm. Larger liposomes are quickly removed from the bloodstream. Liposomes are distinctive in their capacity to encapsulate drugs with varying physicochemical characteristics, including polarity, charge, and size. Drugs can localize in different regions within liposomes: the hydrophobic hydrocarbon chain core of the bilayer, the large polar surface (which can be neutral or charged), and the internal aqueous space. Liposomes offer selective passive targeting to tumor tissues (e.g., liposomal doxorubicin), enhanced drug efficacy and therapeutic index (e.g., Actinomycin-D), stability through encapsulation, biocompatibility, complete biodegradability, non-toxicity, flexibility, and lack of immunogenicity for both systemic and non-systemic administrations. They also reduce the toxicity of encapsulated agents (e.g., Amphotericin B, Taxol) and limit the exposure of sensitive tissues to toxic drugs. Additionally, liposomes provide a site-avoidance effect and the flexibility to be coupled with site-specific ligands for active targeting.

Cochleate And Nano-Cochleats

Various modifications to liposome formulations have led to the creation of a new class of drug carriers known as "cochleates." Cochleates are solid particles composed of large, continuous lipid bilayer sheets rolled into a spiral structure without an internal aqueous phase. This technology addresses the challenges of orally delivering various biological molecules, particularly hydrophobic ones. Unlike liposomes, cochleates have a water-free interior, rod-like shape, and rigid, stable structure. Cochleates and nanocochleates are spiral rolls formed from negatively charged phospholipid bilayers, rolled through interactions with multivalent counter ions (Ca2+ or Zn2+) that act as bridging agents between the bilayers. Nanocochleates feature both hydrophilic and hydrophobic surfaces, making them suitable for encapsulating hydrophobic drugs like amphotericin B and clofazimine, as well as amphipathic drugs like doxorubicin. This technology excels at encapsulating drugs within the nanocochleate structure, which remains intact even when exposed to harsh environmental conditions or enzymes.

Components Of Nano-Cochleate Drug Delivery System

The three primary components used to prepare nano cochleates are atmospheric pressure ionization (API), lipids, and cations.

1. Lipids: Phosphatidyl serine (PS), phosphatidic acid (PA), dioleoyl PS, phosphatidylinositol (PI), phosphatidyl glycerol (PG), phosphatidyl choline (PC), dimyristoyl PS, phosphatidyl ethanolamine (PE), diphosphatidyl glycerol (DPG), dioleoyl phosphatidic acid, distearoyl phosphatidyl serine, and dipalmitoyl PG.

2. Cations: Zn?2;?, Ca?2;?, Mg?2;?, or Ba?2;?.

Objective

- Conduct preformulation studies of lenvatinib.

- Enhance the solubility of lenvatinib.

- Target cancer cells by improving drug delivery.

- Increase entrapment efficiency.

- Utilize drug and polymer carriers.

- Improve the stability of the drug.

Nano cochleates encapsulate anticancer drugs and deliver them directly to the target site. This enhances the solubility and permeability of BCS Class II drugs, thereby increasing drug efficacy.

MATERIAL AND EQUIPMENTS

List Of Materials

Preformulation Study

The primary objectives of preformulation studies are to identify the physicochemical properties of the new drug entity and to determine its compatibility with common excipients¹⁹.

Organoleptic Properties:

The visual assessment included examining the physical appearance, color, and odor of the Lenvatinib sample²⁰.

Melting Point Determination:

The condition refers to its melting point. Moreover, the purity of the substance influences its melting point, which provides insights into its characteristics. This method identifies the temperature at which the medication begins to melt. The experiment was to ensure accuracy. The observed melting point was recorded and documented for reference.

Fourier Transforms Infrared Analysis:

To identify potential structural changes, the atorvastatin sample was analyzed using Fourier Transform infrared spectroscopy (Agilent Technologies Cary 630 FTIR)²¹.

Preparation of Phosphate buffer pH 6.8

To prepare the solution, sodium hydroxide (28.80 g) and potassium dihydrogen ortho phosphate (11.45 g) were dissolved in a sufficient amount of distilled water, then diluted to a total volume of 100 ml in a volumetric flask.

Preparation of lenvatinib loaded liposomes

Multi-lamellar vesicle (MLV) liposomes were created using the thin film hydration method. The lipid phase comprised mixtures of cholesterol and phosphatidylcholine in various molar ratios (refer to the table). In brief, the lipid mixture and 50 mg of lenvatinib were dissolved in a 3:3 v/v chloroform solution, then evaporated under vacuum at 45°C. This resulted in a thin, dry lipid layer on the flask wall, produced using a rotary flash evaporator. The film was hydrated by adding phosphate buffer (pH 7.4) and vigorously shaking with a vortex mixer until vesicles formed after all solvent traces were removed. The liposomes were further reduced in size using a sonicator to create small unilamellar vesicles²¹.

Preparation of lenvatinib loaded nanocochleates

Lenvatinib-loaded nanocochleates were prepared using the trapping technique. The resulting liposomes were vortexed, and 50 microliters of a 0.1 M calcium chloride solution was added drop by drop. This immediately caused the lenvatinib liposomal phase to become turbid, indicating the formation of nano cochleates. These nano cochleates were then evaluated for drug content, encapsulation efficiency, zeta potential, and particle size.

In efforts to improve nano cochleate formulations, researchers have tried creating dry powder using lyophilization technology. Dry powder formulations offer several advantages over liquid forms, including improved physicochemical stability and reduced risk of microbial contamination. The lyophilized powder was analysed using FTIR, PXRD, and DSC techniques²².

Optimization of Liposome Preparation:

A thin, uniform coating is crucial for determining the final product of the liposomal preparation. During the hydration and film formation processes, the rotational speed was maintained between 60 and 100 rpm.

The ratio and volume of solvent system

The solvent system was adjusted by mixing varying amounts of methanol and chloroform, the two organic solvents. The film was tested at ratios of 3:1, 3:2, and 3:3, and its homogeneity was evaluated.

pH of the hydrating media 

The effect of the phosphate buffer's pH on the formulation was studied, as pH influences drug entrapment in liposomes. Entrapment efficiency was measured by adjusting the hydration buffer's pH to levels near the drug's pKa. Distilled water and phosphate buffer with pH values of 5.2, 6.8, and 7.4 were used as hydrating media. The entrapment efficiency of each formulation was then analyzed²³.

Optimization of nanocochleates preparation by change in molarity of calcium chloride solution:

The influence of the calcium chloride solution's concentration on the batches of nanocochleates was investigated. Prior to evaluating how calcium ions affect entrapment efficiency, practical yield, and in vitro drug release within the nanocochleates, the synthesis of these liposomes was optimized using multiple criteria.

RESULTS AND DISCUSSION:

Preformulation study:

The preformulation studies of the medication produced the following results, based on spectral and melting point analyses.

Organoleptic properties:

The powder was found to be without odor and had a color ranging from white to off-white.       

The documented melting point of Lenvatinib ranged from 216 to 231°C, with the observed melting point specifically noted at 226°C. This confirms the purity of the powdered drug and verifies its identity as Lenvatinib.