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Nanocrystals In Drug Delivery

Nanomedicine

Date : 22/12/2021

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Kolsoom

Uploaded by : Kolsoom
Uploaded on : 22/12/2021
Subject : Chemistry

Background

A significant number of the newly discovered drugs are poorly water soluble. Currently, about 40% of the drugs have poor water solubility and also 60% of the newly synthesised drugs that are in the pipeline are expected to be insoluble in water. Poor water solubility of drugs is one of the challenges that formulation scientists face as it leads to poor bioavailability which decreases the therapeutic effect for patients. Nanocrystals are crystalline drug with a mean particle size of <1000nm which have been used to improve drug solubility (1). The main advantages of the nanocrystals (Table. 1) (Figure. 1) are high drug loading, great stability, faster dissolution rate, high solubility as well as the simplicity of the scaling up. Nanocrystals have been shown to improve the pharmacokinetic and pharmacodynamic properties due to their nano-size which contribute to a greater bioavailability. They are prepared by decreasing the crystalline drug particles to less than 1000nm, which accelerate the dissolution rate and results in a greater solubility and consequently improves the oral bioavailability of water insoluble drugs (2).

This technology has shown to improve the rate of absorption, enhance oral bioavailability, rapid therapeutic effect and so reduces the amount of dosage required due to its high drug loading. Nanocrystals offer the flexibility to be administered by numerous routes, including orally, topically and intravenously (3),(4). This review will focus on the usage of the nanocrystals technology and its properties in the delivery of poorly water soluble drugs.

Advantages of Nanocrystals

Cost effective

Enhanced solubility

Delivery through various routes

Faster dissolution rate

Elimination of food effect

Enhanced stability

Scope for targeting

Enhanced Bioavailability

Table 1. Advantages of Nanocrystals in drug delivery (5).

Figure 1. An illustration of micro-size drug material and the usage of nanonization to improve their properties (6).

Nanocrystal Properties

Dissolution Rate

The Noyes Whitney equation (Equation. 1) state as the size of the drug particles decreases the surface area will be increased and this leads to an increase in the dissolution rate (Graph. 1) which is one of the nanocrystals properties that translates in an enhanced bioavailability. This is because small particles lead to a greater surface curvature comparing to the larger ones and so the thickness of the boundary layer is reduced which results in a frequent drug diffusion from the surface of the particle to the bulk (7),(8).

Equation 1. QUOTE

Graph 1. The dissolution rate of Nanocrystals versus Micro-size drugs (9).

Solubility

Reducing the particles to nanosized range results in an increased surface curvature. This way the dissolution will be increased because the drug molecules will leave the particle surface more frequently which leads to an enhancement on the solubility. For nanosized particles <1000nm the solubility is dependent on the particle size where it increases with a decrease in the particle size less than 1000nm. Noyes and Whitney equation states that the increase in the dissolution rate is due to dc/dt which is proportional to the concentration gradient (cs-cx)/h. Hence the concentration gradient between the gut lumen and blood is enhanced as a result of increased rate of the solubility and leads to an absorption by passive diffusion (10),(11).

Enhanced Mucoadhesion and Bioavailability

Nanocrystals drug particles frequently adhere to the biological mucosa which results in high concentration gradient and a longer retention time which results in an enhancement of the bioavailability upon administration. It has been observed that an increase in the surface area of the drug particles is correlated with a higher bioavailability. For instance, decreasing the particle diameter from 10 m to 200nm has increased the surface area by 50 times which translated into a greater dissolution rate. An experimental study was conducted on the impact of the cilostazol s particles size and its bioavailability. It was found that decreasing the diameter of the drug particles from 13 m to 0.22 m has enhanced its bioavailability by 6.55times (Graph. 2), (12).

Graph2. The effect of the crystal size reduction on the bioavailability of Cilostazol (13).

Stability

The stability of the nanocrystals is a function of the size distribution and morphology. Reducing the particle size increases its interaction with the surroundings and produces a thermodynamically unstable system which could promotes aggregation. Aggregation is a phenomenon where nanocrystals grow back to a larger size which will ultimately affect the dissolution, solubility and the bioavailability of the drug. Therefore, stabilisers should be added which are usually polymeric or surfactant based (Figure. 2). Also, an even particle size <1000nm is essential as it reduces the aggregation because of particle size homogeneity. Due to the Ostwald ripening, the maximum amount of the API that can be integrated into a dosage form is about 30% of the tablet weight. This is because the risk of the API particles that interact with each other and aggregates during compression will be greater if the API content increases. Therefore, in the commercial products the amount of the API substance is kept low. For instance, Rapamune has a total weight of 365 mg but only contains about 1 mg of API (14),(15).

Figure2. An illustration of adding stabilisers to nanocrystals to avoid aggregation (16).

NANOCRYSTAL PREPARATION METHODS

The preparation method for nanocrystals can be done via bottom up, top down or combination techniques. The bottom up technique involves dissolving the drug molecules in a solution and growing these molecules to a desired size. However, the top down involves reducing the large particles into smaller ones with the application of mechanical energy. Both of these techniques have their own advantages and disadvantages (Table.2) which will be discussed in some more details in the subsequent paragraphs (17).

Bottom up

This is a precipitation method involves dissolving the drug into a solvent and growing the drug particles on the molecular level which results in precipitation of finely dispersed drug nanocrystals. This is a simple and low cost method. Despite this , there isn t any commercial product available in the market that was manufactured by exploring the precipitation method because some drugs are insoluble in the solvent, solvent should be miscible with a minimum of one non solvent and also , the removal of the solvent residues from the crystals increases the production cost. Additionally, special care should be applied for nano-crystallisation so the crystals don t grow out of the desired nano-size (18).

Top down

Ball milling is a top down technique which is used to reduce the drug particle size. The process of the particle size reduction begins when the milling media start to move and generate forces that hit the drug particles and break them apart. The milling time could take anywhere from 30 minutes to several hours depending on the hardness of the drug, temperature, size of the milling media, size of the batch as well as the surfactant content. Comparing to the high pressure homogenisation, this is a low energy milling method and the milling media which is a ball can be small or large. The main disadvantage of this technique is the erosion of the milling media but this issue can be minimised by coating the milling beads. The adhesion of the drug particles to the inner surface area of the mill is an additional common issue. However, this method is simple, cost effective and can be explored for large scale production (19).

Technology

Advantages

Disadvantages

Precipitation

Finely dispersed drug particles,

Good control of desired size.

Requires to be stabilized,

Results in organic solvent residues,

It is not usually applicable,

Drugs need to have particular properties such as to be soluble in at least one solvent.

Milling

Requires low energy,

Simple, cost effective and can be used for large scale production,

Has been used for 4 FDA approved drugs.

The milling process can take several days,

Need to be stabilised,

The resultant residue from the milling media,

Erosion of the milling media, and

Adhesion of the drug particles to the inner surface area of the mill.

Table2. The advantages and disadvantages of precipitation and milling (20).

Nanocrystals in Topical Delivery

Skin infection diseases demand a great amount of drug concentration at the site of action and so topical delivery is highly favoured. Nanocrystals can be applied in the topical formulations because of their high drug loading, stability, great skin penetration, improved efficacy and low amount of excipients that can be used in the formulations which makes them much safer and well tolerated than other nanotechnologies as they don t cause skin irritation. Nanocrystals high saturation solubility establish a concentration gradient among the skin and the formulation which promote for a higher drug absorption. It has been shown that particles in the size range of 300-600nm penetrate into the hair follicles and diffuse according to the drug concentration present in the skin layers. This finding has been supported by Oswald Freundlich and Kelvin equations, suggesting that nanosizing increases the surface area which improves the saturation solubility of the drugs. Rutin was the first nanocrystal based cosmetic formulation that was introduced to the market by Juvena in 2007, it has shown a 500-fold greater bioactivity and had two times greater photoprotection to the skin in comparison to the rutin glucoside solution (21).

Expert Opinion

Over the past two decades the number of poorly water soluble drugs has increased and at present more than 50% of drug candidates fail to enter the pharmaceutical market due to their poor physicochemical and biopharmaceutical properties. Nanocrystals have the potential to improve the solubility and bioavailability of these insoluble compounds and therefore making them therapeutically more effective. The large surface area of the nanocrystals increases the saturation solubility that improves the dissolution rate and so enhance the drug absorption.

This fact was observed in vitro during preclinical studies in tumour bearing mice. During this observation, 80mg/kg of chemotherapeutic drug Paclitaxel with two different particle sizes which include Paclitaxel nanocrystals and coarse Paclitaxel was given to tumour-bearing mice every 2 days for 20 days. The tumour volume of the mice treated with Paclitaxel nanocrystals was reduced to one third of the mice that was treated with coarse Paclitaxel (22). This suggests that nanocrystals promote a greater drug internalisation into the tumour cells because of the small size of the drug particles into the leaky tumour vasculatures which allows for a higher drug accumulations and therefore a greater efficacy and therapeutic effect. An in vitro study for oral administration showed the dissolution rate of Paclitaxel nanocrystals was greater than the coarse Paclitaxel with a drug release of about 40% from nanocrystals and 12% of coarse PTX over 12 hours which explains the reason for reducing the tumour size of the mice. Approximately, a solubility enhancement of about 9folds was noticed with Paclitaxel nanocrystals than coarse Paclitaxel. This translated into an improvement of 12.6fold in the bioavailability of Paclitaxel nanocrystals which had a greater therapeutic effect in decreasing the tumour volume in comparison to the coarse Paclitaxel (23). Therefore, nanocrystals is a great technology which could be explored in tumour or organ targeting and cancer treatment as it allows for a higher drug absorption by the tumour and therapeutically more effective in reducing tumour size .

The main limitation of this technique is the potential toxicity due to the nano-sized drug particles which promotes a greater drug absorption and high drug loading. Thus, long term toxicity studies should be conducted for a suitable doing schedules that could guarantee patients adherence, particularly in chronic diseases (24).

The concept of the nanocrystals was first introduced in the 1990s and start to gain more attention with the successful launch of the first product, Rapamune. Rapamune is an immunosuppressant poorly soluble drug which is taken to avoid rejection of kidney transplant. Decreasing its particles size has increased its bioavailability to 21% in comparison to the conventional oral solution formulation (25).

With the increased development of the poorly soluble drugs and inadequate solubilisation of other techniques, pharmaceutical companies have started to invest more in the field of nanocrystals which can be used for class II and IV of the biopharmaceutical classification system. However, this technique is not the first choice of the companies as it is a bit more complicated and costly in comparison to other manufacturing techniques such as microemulsion-filled capsules for oral delivery (26).

The main Engineering challenge is to achieve a nanosized crystals <1000nm without destructing the surface of the crystals and converting it to partially amorphous form during milling. This is a well-known phenomenon which happens because of the great shear forces applied to the drug particles. These partially amorphous particles are unstable and will convert back to their original crystalline state. This is one of the stability issues in which can affect the dissolution, solubility and influence its pharmacological efficacy in vivo (27). Also, the precipitation method has its own challenges in order to grow the crystals to the desired size. The nanocrystal development demand a multidisciplinary knowledge of the physical background of the crystal stability, processing engineering as well as biological behaviour of the drug in vivo (28).

Despite this, nanocrystals technology has been successfully applied to some drugs on the market such as Emend , Tricor and shown improvement in their solubility, dissolution rate and bioavailability (29). Also, this technology can also be a successful exploitation for the life cycle management of the product and protecting the market exclusivity for drugs. More companies are expected to use this simple technology in the upcoming years as it is a simple way of gaining market exclusivity and extending the patent life (30). In the future, amorphous nanoparticles are also predicted to join the market because of the emerging technologies for manufacturing amorphous nanoparticles (Nanomorph). The main idea behind the Nanomorphs is that they can increase the saturation solubility because of the combination of the amorphous solid state properties and their exceptionally small size, however, they are unstable are require a stabiliser (31).

Conclusion

Nanocrystals technology can be used for poorly water soluble drugs to improve their solubility, dissolution and bioavailability. They also have shown to be effective in tumour targeting and cancer treatment. The great benefit of this technology is that it can be used in different administration methods such as oral, parental, ocular and even pulmonary delivery. Nanocrystals technology has several advantages like easy production and scaling up, low manufacturing cost which makes it a desirable method for overcoming drug poor solubility, low absorption and bioavailability. However, it can also cause toxicity and so careful toxicity studies should be carried out to reduce the risk of toxicity and improve patients adherence. Similarly, nanocrystals are physically unstable and require suitable stabilisers which are not easy to choose to reduce the risk of aggregation.

In conclusion, despite nanocrystals advantages for improving drug solubility and bioavailability, the number of FDA certified drugs are still limited. This technology is still in the research and development stage for enhancing scalable formulation, manufacturing processes and achieving formulation stability throughout the shelf life of the product.

This resource was uploaded by: Kolsoom

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