Liquisolid Technology for Anticancer Drug Delivery: Mechanisms, Benefits and Challenges

In every nation on the planet, cancer is one of the main causes of death and a significant obstacle to raising life expectancy. In 2019, the World Health Organization (WHO) estimated that cancer ranks first or second in 112 out of 183 nations for causes of mortality before the age of 70 and third or fourth in another 23. In many countries, the mortality rates of stroke and coronary heart disease have significantly decreased in comparison to cancer, which contributes to the disease's increasing status as a major cause of death.[1] "Cancer is a disease in which some of the body's cells grow uncontrollably and spread to other parts of the body "Cancer was initially identified as a tumor, a growing mass of tissue. They could see what it looked like, how quickly it grew, and how frequently it appeared[2]. Cancer is the second biggest cause of death worldwide and one of the major public health issues. According to the American Cancer Society, by the end of 2021, there will likely be 1.9 million additional cases. Surgery, chemotherapy, radiation therapy, targeted therapy, immunotherapy, and hormone therapy are the traditional therapeutic modalities used to treat cancer. Despite their capacity for cryostasis and cytotoxicity, chemotherapy and radiation therapy are frequently associated with severe adverse effects and a significant chance of recurrence. The most typical Neuropathies, bone marrow suppression, skin and gastrointestinal issues, hair loss, and exhaustion are among the adverse effects that are brought on by it. Additionally, certain drugs have side effects that are peculiar to them, like anthracyclines and bleomycin-induced pulmonary and cardiotoxicity.[3] The treatment windows are further limited by the more universal modes of action of earlier anticancer drugs. These medications are often tiny compounds. 200–500 Daltons, roughly. Since the more recent agents are made entirely of proteins, they are somewhat larger—roughly 150 kilodaltons. They are primarily given parenterally have considerable variations in pharmacokinetics with small molecules, target their sites of action more precisely, and have fewer adverse effects.[5] Many cancer treatments and drug delivery systems are being developed these days. Adoptive cell therapy, cytokines, cancer vaccines, therapeutic antibodies and nano-based drug delivery systems are all part of the fast evolving and promising cancer immunotherapy paradigm. It improves the drugs' pharmacokinetic behavior in vivo, improves their solubility and bioavailability, lengthens their circulation duration, and enhances their therapeutic impact.[4] Because of its cost-effectiveness, convenience of administration, and high patient compliance, oral drug administration is a legitimate delivery method. Lack of appropriate plasma drug levels is the primary issue with the oral route. Furthermore, the drug must be present in solution at the gastrointestinal level in order to provide the necessary concentration of the drug in the systemic circulation. Because hydrophobic medications have a limited bioavailability due to their dissolution rate, poorly water-soluble pharmaceuticals have an incomplete systemic availability. The primary obstacle for hydrophobic medications is increasing their bioavailability and rates of dissolution.

The liquisolid strategy is a novel approach used to improve the bioavailability and dissolvability of medications that are ineffectively water insoluble.[6] The rate-controlling phase for BCS class II medicines is the dissolution process, which establishes the absorption rate and extent. The "Liquisolid compact technique" is an effective method for increasing the solubility and dissolving of medications that are not very soluble in water, as well as their bioavailability. Formulations created by converting liquid medications, drug suspensions, or drug solutions are referred to as Liquisolid systems. in non-volatile liquids, by mixing the suspension or solution with a chosen carrier and coating material, producing a dry, non-adherent, free-flowing, and compressible powder combination.[10] Using coating materials (Eudragit RL) not only improves solubility or dissolution but also prolongs medication release, which follows zero-order kinetics.[7] whether making tablets with pH-independent medication release using this method can be advantageous. Therefore, the purpose of this study was to investigate the theory that the liquisolid compact approach could be used to reduce the impact of pH changes on the pace at which various medications dissolve.[11]

1. RISK FACTORS FOR CANCER:[5,35,36,37]

It is commonly known that in high-income nations, smoking, and to a lesser extent, alcohol use, poor diet, obesity, and inactivity, can all lead to cancer.

2.1 Alcohol consumption

Alcohol has been identified as a carcinogen for humans. Although its general mechanism of action is unclear, alcohol can exacerbate the carcinogenic effects linked to smoking or other variables. Indeed, ethanol has been believed to have some promoting effects in addition to its main co-carcinogenic effect. Here, we make a clear distinction between promoters and co-carcinogens. A co-carcinogen is a chemical that can intensify or activate the effects of a carcinogen, such as a promoter or mutagen. However, regardless of whether the cells are altered or not, a promoter is a molecule that promotes cell division and may aid in the induction of death and loss of differentiation.

 Drinking alcohol can cause the depletion of detoxifying molecules like glutathione and the stimulation of the hepatic cytochrome P450 2E1 (CYP2E1) enzyme, which activates genes into carcinogens, are cocarcinogenic consequences of alcohol. In contrast, there has been a suggestion that alcohol promotes immune-suppression. However, relevant epidemiological and toxicological research has never supported this theory. Furthermore, because ethanol may be converted to acetaldehyde via the liver's activation of CYP2E1, which could result in the generation of some mutagenic free radicals,[5]

2.2Tobacco smoking

As one of the main risk factors for human carcinogenesis, smoking is undoubtedly a severe concern. This mixture is equivalent to what is known as a full carcinogen since tobacco smoke and tar include hundreds of chemicals, including numerous mutagens like nitrosamines and polycyclic aromatic hydrocarbons (PAH), as well as other promoters. Smoking is a risk factor for various types of cancers mainly lung cancer , upper digestive track, and certain extra in to pancreas, liver, kidney, stomach and cervical cancer.

2.3  Overweight and obesity

Hormone and growth factor levels are altered by excess weight. It has serious negative effects on health as well. Numerous cancers, such as colorectal, postmenopausal breast, endometrial, kidney, and esophageal cancers, are brought on by being overweight or obese. cancer, ranging from 9% (postmenopausal breast cancer) to 39% (endometrial cancer) in terms of population-attributable risk. Along with these cancers, obesity may also affect non-Hodgkin's lymphoma myeloma and cancers of the prostate, liver, gallbladder, pancreas, stomach, ovary, and cervix. In general, obesity may result in 120% of female cancer deaths and 14% of male cancer deaths.[35,36]

1. 4. Dietary issue

Finding a link between nutrition and cancer has been the subject of extensive investigation, and numerous factors have been discovered. examined. A diet low in red meat and animal fat, high in fruits and vegetables, and supplemented with a daily multivitamin containing folate is considered good for preventing cancer and chronic diseases. Although early research indicated a substantial correlation between fruits, vegetables, and the risk of cancer, more current data from prospective cohort studies only point to weak relationships. Pancreatic, bladder, lung, colon, mouth, pharynx, larynx, esophageal, and stomach cancers may be impacted by total intake.

1. 5. Sun UV rays

Malignant melanoma, squamous cell carcinoma, and basal cell carcinoma are all made more likely by exposure to the sun. In the United States, the incidence of melanoma is increasing at a faster rate than that of any other cancer. Focusing just on the segment of the population that possesses high-risk traits, such fair skin or a family history.

2.6 Air pollution[37]

Mutagens are polycyclic aromatic hydrocarbons (PAH), which are produced when organic materials burn. In addition to tobacco smoke, they can be found in any combustion product, including smoke from factories, waste incinerators, and automobile exhaust. They have the ability to stick to tiny carbon particles. floating in the atmosphere, allowing the particles to more thoroughly enter the organism because they gather close to the ground at the level we.

The air pollutant nitrogen [NO2] may potentially be involved, in addition to PAH and fine and ultra-fine carbon particles. NO2 is a marker of a mixture of gases and particles associated with emissions from power plants, traffic, and waste incinerators. According to experimental research, NO2 can help induce lung cancer and promote the spread of the disease to other areas. It also has been shown that when NO2 and benzo[a]pyrene combine, the resultant compound, nitrobenzoic[a]-pyrene, has a higher mutagenicity than benzo[a]pyrene alone. According to the European epidemiological study mentioned above, non-smokers who are exposed to more NO2 have a higher risk of developing lung cancer. Compared to adults, they breathe in more pollutants per kilogram of body weight due to their faster rate of respiration.[5,36]

2.7 Physical activity

It has been demonstrated that engaging in physical activity helps prevent the development of breast cancer. This significant factor impacts all women, premenopausal and postmenopausal, and is not limited to those with a family history of BC. This activity could be caused by a variety of processes, including a decrease in oxidative stress, a change in the immune system's response, a reduction in exposure to endogenous sex hormones, and an effect on low-level chronic inflammation. While the ideal amount of physical activity to prevent BC has not yet been determined, moderate to intense physical activity yields the best outcomes.

Following table shows the drug name, class, mechanistic class, and main adverse effects.[5,9,12]

2. CONCEPT OF LIQUISOLID TECHNIQUE [6,8,14]

Adsorption and absorption occur when a medicine that has been dissolved in a liquid medium is mixed with a porous carrier material, like cellulose, that contains densely entangled fibers. Fluid initially held within the molecule is captured by the molecule's internal structure. The inner and exterior surfaces of the porous carrier particles are where liquids are adsorbed. as soon as this process is saturated. Second, covering materials with large explicit surface regions and high adsorption qualities give fluid strong frames good stream features. Within the Liquisolid framework, the drug is now dispersed within the fluid medium and is transported by the powder.

One of the factors suggested to explain the increased disintegration rate from fluid pellets is the wettability of the pellets in the disintegration media. By lowering the interfacial pressure between the tablet surface and the disintegration medium, the non-unstable dissolvable found in the Liquisolid framework aids in the wetting of the drug particles. It may be anticipated that liquisolid compacts of water-insoluble materials will exhibit improved drug release properties, leading to increased oral bioavailability. Since the rate-limiting stage in gastrointestinal absorption is frequently the dissolution of a non-polar drug, an oral water-insoluble drug's bioavailability is improved when the drug is already in solution, resulting in increased dissolution rates. For this reason, when compared to traditional oral solid dose forms, soft gelatin elastic capsules containing solutions of such drugs have better bioavailability.

4. CLASSIFICATION OF LIQUISOLID SYSTEM[13 ]

The Liquisolid compact technique classified   according to formulation technique and type of liquid medication

Liquisolid Medication: Lipophilic liquid drug, suspension or solution of water soluble or water insoluble drugs in the non-volatile solvent system are called Liquisolid medication system

Liquisolid Compact: Refers to the "liquisolid systems" that are defined as instant sustained-release tablets or capsules.

Liquisolid Microsystems: Describes the use of "liquisolid systems" to produce capsules and the addition of an resulting in unit size that might be up to five times smaller than a liquisolid compact.Liquisolid Microsystems describes the use of liquisolid systems to produce capsules, resulting in a unit size that may be up to five times smaller than a liquisolid compact.Liquisolid Microsystems describes the use of liquisolid systems to produce capsules, resulting in a unit size that may be up to five times smaller than a liquisolid compact.Liquisolid Microsystems describes the use of liquisolid systems to produce capsules, resulting in a unit size that may be up to five times smaller than a liquisolid compact.

Based on a liquisolid technique it can be classified in subgroups such as:

[i]  “Powdered drug solution”

[ii]  “Powdered drug suspension”

[iii]  “Powdered liquid drug”

1. PROCEDURE:[13,16,17]

The superior dissolving profiles displayed by these preparations are mostly due to the similar concept that highlights the process of drug distribution from liquisolid compacts. One of the hypothesized mechanisms for the increased dissolution rate from the liquisolid compacts is the wettability of the compacts by the dissolution media.[13] By reducing the interfacial tension between the tablet surface and the dissolving media, the nonvolatile solvent in the liquisolid system makes it easier for drug particles to moisten.[10,16]

A mathematically determined quantity of pure medication is first weighed and dissolved in an appropriate amount of solvent in a molecularly dispersed form as part of the liquisolid tablet production process. Trial and error techniques, such as altering the carrier, were employed to achieve favorable flow characteristics. coating material ratio using new mathematical formulas from 50:1 to 5:1. Liquid medication is mixed with cellulose, a carrier substance with a porous surface and closely matted fibers inside. Both adsorption and absorption occur; that is, the liquid that is absorbed into the particles' interior is trapped by their internal structure, and once this process is saturated, the liquid is adsorbed onto the porous carrier particles' exterior and interior surfaces.

The best excipients for this step are those with fine, extremely adsorptive particles, including different kinds of amorphous silicon dioxide (silica). To create liquisolid compacts in the dosage form of tablets or capsules, different chemicals, such as lubricants, disintegrants, polymers, and binders (as illustrated in the figure), may be included with the completed liquisolid systems prior to compression or encapsulation.

First Stage: The aqueous medicament was able to concentrate in the powder by mixing the weighted components at a rate of one rotation per second or minute.

Second Stage: The aforesaid mixture should be soaked on the mortar's surface for around five minutes to guarantee that the liquid is fully absorbed into the spaces between the powder particles

Finale Stage: To provide compression, blend the aforementioned mixture with super disintegrant for 30 seconds at blending speed. final combination ready for[16]

Fig. Procedure of Liquisolid Technique

6.CALCULATION: [15,17]

A simple mathematical model for motif formulation was presented by Spirease. A system that is liquisolid. This model states that by preserving effective flow and compressibility, powder excipients utilized in a liquisolid system can retain a given amount of liquid vehicle.[15]

This model aids in determining the required amount of excipients. It is also tested on the retention potentials of compressible and flowable liquids. With respect to a specific powder/liquid (P/L) combination, these values remain constant. The maximum portion of the liquid vehicle (non-volatile) that is retained in the bulk (w/w) while maintaining admissible flow is known as the flowable liquid retention potential (value). On the other hand, the maximum amount of liquid vehicle trapped in the bulk (w/w) while maintaining an acceptable compression in terms of effective friability and hardness is known as the compressible liquid retention potential, or P-value. A novel model called pacrisity theory, which evaluates the compaction behavior of powder, can be used to explain this compactness. In mathematics, the "ratio of carrier and coating material is termed the excipient ratio" is represented by R.

                             R= Qq

Where R= ratio of carrier& coating material

Q=quantity of carrier materials

q= quantity of coating materials

The mathematically flowable liquid retention potential (Φ-value) could be calculated as follows:

?-Value=weight of liquid medication weight of carrier material

Only when a suitable amount of the liquid vehicle is retained can the liquisolid technique be used to particles with acceptable flowability. This attribute, according to Spirease theory is termed, the liquid load factor and can be described as the ratio of the weight of liquid medication (drug and liquid vehicle) and the weight of carrier material.

Lf=wQ

Where,

Lf=load factor

Q=weight of carrier material

To produce a acceptable flowability, the load factor is determined as by:

φLF=∅+φ/R

Whereas ∅=liquid retention potential of carrier material.

        Φ=flowable liquid retention potential of coating material

        R=excipients ratio

To produce powder with acceptable compressibility, it is determined as follows:

ψLf=Ψ+ΨR

Where, ? is compressible liquid retention potential for carrier & coating material_.

7. ADVANTAGES [18,19,11,20]

1.  Drug release can be modified using proper formulation ingredient.

2. Many solid medications that are insoluble in water can be made into liquisolid  system.
3. It is possible to achieve improved bioavailability in comparison to traditional tablets.
4. Capability of  industrial production is also possible.
5. Maximum of liquid or solid 'water-insoluble drug may be formulated into immediate release or sustained release 'Liquisolid compact.
6. Lower production cost than that of soft gelatin capsules.
7. pH-dependent solubility of various drugs that can be overcome by Liquisolid compact technique.

LIMITATIONS:[17,18,19]

1.  Required high Solubility of drug in non-volatile liquid vehicle
2. This technique was introduced on an industrial scale to solve the challenges of combining small amounts of viscous liquid solutions. It might not be possible to transfer onto a lot of carrier material.
3. Since the liquid medication may be squeezed out of the liquid-solid tablet throughout, it may not acquire the appropriate compression qualities, leading to tablets with insufficient hardness.
4. This technique is not applicable for high  dose.

8.APPLICATION OF LIQUISOLID TECHNIQUE:

8.1 Liquisolid compact technique used in sustained drug release:

The original purpose of the liquidsolid approach was to speed up the dissolution of medications that were not very soluble  in water. Numerous research conducted in the last few years have suggested that the liquisolid technique may be applied as a viable way to create prolonged release formulations of various medications.[21]

With excellent efficacy, great patient compliance, and few adverse effects, sustained release formulations are made to release the medication gradually over a predefined length of time at a predefined pace. The potential to achieve a liquisolid system with zero order release kinetics is one of the primary benefits of using the liquisolid technology to extend medication release. Its primary drawback, though, is the large tablet weight, which is caused by the high medication dosage in extended release liquisolid formulations. The liquisolid technique's basic premise is that by using hydrophobic carriers (such as Eudragit RL and RS) rather than hydrophilic ones, medication release can be sustained.[21,24,27] 8.2 Liquisolid technique for enhance solubility: This procedure first introduced by spireas et al. by the liquisolid delivery system poorly soluble drugs are made to soluble. By using various grades of disintegration agent microcryastalline cellulose [MCC],sodium starch glycolate which helps in tablet dissolution. Drug is soluble in inorganic vehicles PG 400 [22]. Higher drug surface area, higher drug solubility, and enhanced wetting qualities are the three potential methods of dissolution enhancement for liquisolid systems that have been suggested in the literature. The medication is either delivered in a solubilized or disseminated condition, despite being stored in a solid dosage form. Therefore, the drug surface area available for dissolution is markedly increased[27] 8.3 Liquisolid technique to minimize the influence of PH variation on drug release: The ionization constant (pka) of the chemical and the pH of the surrounding environment determine how soluble weak acids and bases are. Therefore, the pH of gastrointestinal fluids has a significant impact on the solubility and bioavailability of these medications. Additionally, this results in a significant degree of intra- and inter-variability in the therapeutic effects and drug bioavailability. El-Hammadi et al. initially investigated the potential use of the liquisolid approach to reduce the impact of pH change on loratadine release. Propylene glycol was used as a liquid vehicle, MCC as a carrier, and silica as a coating material to create a number of liquisolid compositions.[11] 8.4 Liquisolid technique to minimize photosensitivity in solid dosage form:

The photostability research is an essential component of Preformulation studies for photosensitive pharmaceuticals since a decrease in medication potency during the photodegradation process may produce toxic degradation products and could cause adverse effects. This deterioration can occur when their dosage form goods are handled, produced, stored, distributed, and used clinically. The anticipated photosensitivity eventually results in unfavorable outcomes, including the loss or alteration of the active pharmaceutical ingredient, the excipients, the release of unwanted by-products that may be toxic, and a dose reduction of the active drug that results in a decrease in efficacy. Patients who consume these deteriorated products may be at risk. To guarantee the stability, safety, and effectiveness of the finished commercial products, pharmaceutical preparations should be examined for the potential presence of photo-degradation products.[23,26]

9.EVALUATION OF LIQUISOLID SYSTEM:

9.1 Flow behavior:

In the manufacturing of tablet dosage forms, a powder's flowability is crucial for minimizing large dose fluctuations. Particle size, shape, density, moisture content, and surface roughness all influence a powder's flow characteristics. To guarantee the flow characteristics of the liquisolid systems, Hausner's  ratio, Carr's index, and angle of repose are employed.(16)

9.2 Pre-compression study:

before the formulations are compressed into tablets to guarantee the appropriateness of the chosen excipients. Differential scanning calorimetry (DSC), X-ray diffraction (XRD), and scanning electron microscopy (SEM) are among the tests carried out.(25)

9.3 Differential Scanning Calorimetry(DSC) :

DSC is used to identify the drug's thermal behavior and thermotropic properties, as well as those of the excipients employed in the formulation and the prepared liquisolid system. Additionally, it provides any potential interactions between the formulation's excipients. Additionally, it will show that the stability studies were successful. The drug's distinctive peak is missing from the DSC thermogram if the drug is in the form of a solution in a liquisolid (7,15)                   

9.4 X-ray Diffraction(XRD) :

X-ray diffraction (XRD) patterns are obtained for the drug, excipients, physical mixing of drug and excipients, and finally for the resulting liquisolid system in order to characterize the crystalline state. The absence of the drug's distinctive peaks in the liquisolid XRD shows that the drug has completely changed into an amorphous or soluble form. The drug's apparent solubility and, consequently, its rate of dissolution are improved as a result of this amorphization or solubilization in the liquisolid system.(10,15)

9.5 Scanning Electron Microscopy(SEM):

The morphological properties of the drug-carrier systems and raw materials are evaluated using scanning electron microscopy (SEM). This investigation determines whether crystals are present or if the substance is present in a fully soluble form.(10)

9.6 Dissolution Testing:

The liquisolid compacts exhibit higher dissolving rates than the pure one since the medication is in the solution form and is also transported by the powder particles. When a nonvolatile solvent is used in the formulation, water-insoluble medications become more wettable. Its significantly enhanced wettability and surface availability to the dissolving liquid thereby accelerates release. In the case of liquisolid formulation, researchers found that many people see an improvement in the rate of disintegration(10,11,15,21)

10. Solubility enhancers:

By putting the medicine in suspension or solution form in a hydrophilic, non-volatile solvent, liquisolid techniques have been used to enhance the dissolving characteristics of poorly soluble medications, as was previously mentioned. The solution or suspension was then adsorbed onto a sizable surface area of the coating and carrier material. Mesoporous clays and silica could be utilized in place of the coating and carrier materials that were employed in significant amounts.          

Pharmaceutical excipients with very high surface areas and high capability to adsorb liquids. using this  reduces the number of excipients, therefore decreasing the liquisolid dosage form weight. List the drugs formulated into liquisolid systeme based on mesoporous silica.

Here we can see in the table by improving the dissolution properties of anticancer drug”“erlotinib “through the use of selected (Neusilin US2) and florite PS 200 in preparing of liquisolid tablet. That was associated with excluding the use of coating material.The mixture of mesoporous silica having an extraordinary high liquid load factor.Mesoporous silica is highly porous and adsorptive nature. Formulation shows excellent flow & compressibility.Liquisolid compact technique enhances the “antineoplastic drug erlotinib” solubility and dissolution.[28]

Using the carriers like microcrystalline cellulose[MCC] inhances the tablet disintegration result in improve solubility and dissolution.Walnut is a omeg-3 fatty acids also used in cancer. various types of vehicles Tween 80,PEG 400 are the inorganic solvents in which walnut is dissolved and improving the solubility and dissolution[29]

Non-volatile solvents and sodium starch glycolate also made it possible to create liquisolid systems of celecoxib by combining semi-volatile solvent mixes with non-volatile solvents. In order to decrease the viscosity and surface tension of the drug solution in the non-volatile solvent, semi-volatile liquid combinations (PEG/PS 80) were introduced. This made it easier to load the medication solution and enhance the solubility and dissolution[33]

Release retardation

Contradictory to release enhancement, liquisolid technique was successfully employed to sustain the release of APIs. The liquisolid technique successfully achieved zero order release rates Dat, exhibiting high patient compliance and minimal side effects .The main principle uses hydrophobic carriers such as Eudragits and hydrophilic retarding agents.