A Review on Applications of Hydroxy Propyl Methyl Cellulose and Natural polymers for the development of modified release drug delivery systems

 

Rahul Khiste¹*, Nilkanth Bhapkar¹, Nilesh Kulkarni²

¹Department Department of Pharmaceutical Chemistry, Marathwada Mitra Mandal’s College of Pharmacy, Thergaon, Pune-411033, Maharashtra, India. 

 

ABSTRACT:

This review summarizes applications of Hydroxy Propyl Methyl Cellulose along with Natural polymers for the development of modified release drug delivery systems. The HPMC was available in variety of grades which show different applications in drug delivery. The various grades of HPMC utilized for the variety of action e.g. Coating agent, Adhesion promoter, Targeted release of drug etc. The modified release drug delivery system one of the highly researched field in pharmacy. Even though it is researched and various modified release formulations available in market. The developing more safer approach for drug release is still area of research, which contain easier routes, safer excipients, highly specific target selective materials. Natural polymer show very less side effects as well as it achieves the desired release of drug, so they are the choice of majority of formulations. e.g. Guar gum, Chitosan and Xanthan gum used in various drug delivery systems. Guar gum Cefapodoxime proxetil floating tablet prepared Guar gum, Xanthan gum ophthalmic preparation. Chitosan used in waste water treatment and various biomedical fields like tissue engineering, buccal drug delivery, anticancer treatment etc. Pollulan nanocrystals were studied for the anticancer drug delivery. The review solely based on HPMC-Natural polymer application in Modified release of drug. The various grades of HPMC utilized for the variety of action.

 

 

 

INTRODUCTION:

The oral solid unit dosage form, it is the most preferred route for administration of dosage form due to its patient compliance, ease of administration, optimal amount of drug is delivered, But still it need to be improved a lot (controlling the release, drug delivery at desired site, shielding of drug from biological fluid of body, avoiding the multiple dosing are some of the aspects expected to improve)^1,2, To meet that various modifications are made in conventional drug delivery system which is known as modified drug delivery system or modified release drug delivery system. A modified release drug delivery addresses, delayed release, extended release, and oral drug delivery system as well as system which are changed in order to achieve modified release effect.

 

Definition by USP - A modified-release dosage form is defined “as one for which the drug release characteristics of time course and/or location are chosen to accomplish therapeutic objectives which are not obtainable by conventional dosage forms. A modified release drug delivery address both³.

 

Following must be considered for modified release dosage form:

·       Small dose

·       Short half-life (Long half-life drugs already have the desired kinetics)

·       Wide Therapeutic Window

·       Absorbed through the GI

·       Modest to rapid absorption

·       Highly stable in the GI

 

Advantages:^3,4

1.   Reduce dosing frequency

2.   Improve patient compliance

3.   Reduce gastric irritation and side effects

4.   Possible to enhance the bioavailability

5.   Alleviate the risk of dose dumping

6.   Reduce fluctuation in circulation drug level

7.   Avoidance of night time dosing 10. More uniform effect.

 

Disadvantages:^3,4

1.   If a toxic dose will stay toxic for a long time

2.   Strong first pass effect

3. Risk of Dose Dumping (failed device) a higher immediate dose

4.   Inflexible dosing schedule

 

Criteria for drug to be formulated as modified drug delivery system:^3,4

A.    Desirable half-life:

The half-life of a drug directly shows of, its residence time in the body. If the drug has a short half-life (less than 2 hours), relative to that the dosage form will have large amount of drug or larger dose need to be given. On the other hand, drug with half-life of 8 hours or more are easily sustained in the body, when administered in conventional dosage from, and sustained release drug delivery system is generally not necessary in such cases. Ideally, the drug should have half-life of 3 to 4 hours.

B.    High therapeutic index:

Drugs with less therapeutic index are not able for incorporation in sustained release formulations. If the system fails in the body, possibility of dose dumping occurs, leading to hazard eg. Digitoxin

C.    Small dose:

Drug must have potency enough to give therapeutics effect at smaller dose. If the drug need to be administered at high dose or in conventional delivery system, dose of drug is high then it is very difficult to form sustained or modified release system for such drug, and also size of unit dose of drug is too big.

D.    Desirable absorption and solubility characteristics:

The poorly water soluble drug are less suitable to formulate as modified release drug delivery system. As its absorption is dissolution limited also drug with extreme aqueous solubility, It is very difficult to control release of such drug the drug which solubility is limited or depend on pH of GI are also the less preferred for modified release.

E.    Desirable absorption window :

Sometime drugs which are administered orally requires particular site of absorption, known as absorption window of that drug. The drugs with such absorption window are unsuitable for the modified release system.

F.    First past clearance :

If the drug undergoes high hepatic first pass metabolism then it very hard to formulate modified release drug delivery system for such drug

 

Types of modified release system:

A) Diffusion type system (Insoluble, slowly eroding, or swelling matrices) :

·       Reservoir type

·       Matrix type

B) Dissolution type system (Insoluble, slowly eroding, or swelling matrices) :

·       Reservoir type

·       Matrix type

C) Methods using Ion-exchange

D) Methods using osmotic pressure

E) Other technology:

·       pH independent formulations.

·       Altered density formulations

 

Table I Different types of Modified release system ^{3, 4, 19}

 

The hydrophilic matrices were one of the choices for the modified drug delivery system. Hydrophilic matrices occurred as compressed powder mixtures of drug and excipients including one or more water swellable hydrophilic polymers which are generally regarded as safe excipients. It use polymers with flexible chemistry that offers an opportunity to design modified release dosage forms for wide range of drugs with varying solubility and doses. Swellable matrices can be administered in various routes such as oral, buccal, vaginal, rectal drug delivery system⁵. Drug release from tablets is controlled by formation of a hydrated viscous layer around the tablet which acts as a barrier to drug release by opposing penetration of water into tablet and also movement of dissolved solutes out of the matrix tablets. The overall drug release process is influenced not only by drug solubility but also by the physical and mechanical properties of the gel barrier that forms around the tablet. The extent of matrix swelling, erosion, and diffusion of drug determines the kinetics as well as the mechanism of drug release⁶. There is many high molecular weight water soluble or water swell able polymers used in hydrophilic matrices such as HPMC, hydroxyl propyl cellulose, sodium carboxyl methyl cellulose, sodium alginates, carbomer etc. HPMC is most chosen polymer in matrix applications because of its ability to obtain desired release profiles for wide range of drugs, provides optimal formulation, global availability, cost friendly manufacture, wide regulatory acceptance etc.

 

HPMC (Hydroxyl Propyl Methyl Cellulose):

Hydroxypropyl methylcellulose, empirical formula is C₈H₁₅O₈-(C₁₀H₁₈O6)n-C₈H₁₅O₈，and molecular weight is about 86000. In the material of this product is a semisynthetic part of methyl cellulose and Hydroxypropyl ether. HPMC is an odorless and tasteless, white or creamy-white fibrous or granular powder. It can be dissolved in water, and formed a transparent to milky white and has a certain viscosity colloidal solution. Due to difference in the composition of the Methoxy and Hydroxyl substitution the different grades of HPMC are available. Range of Hydroxypropyl methyl cellulose products called methocel, there are series, that is, E, F series and K series, each series has a variety of models of products to choose from. E series for thin film coatings, coating for tablets, closed core; E, and F series for adhesion promoter and release resistance of eye ophthalmic preparation, suspending agent and thickener of liquid preparation and adhesive of tablet and granule; K series for release resistance and hydrophilic gel matrix of sustained-controlled preparation^5,6. Along with the Pharmaceutical application HPMC is the choice of material or the research on different aspects like Food materials e.g. bread⁷, also as the packaging material for food materials⁸, Radio pharmaceutical e.g. Barium sulfate used along with the HPMC and CMS, it was found that HPMC show good gastric protection property and used in colon targeted preparation⁹, Fertilizers e.g. Chitosan-HPMC based film coating on conventional fertilizers for prolonging their actions¹⁰. A Dexibuprofen nanocrystal prepared by HPMC-PVP and HPMC- EUD was found best polymer combination to stabilize Dexi nanocrystals. The Dexi nanocrystals exhibited significant dissolution, solubility and analgesic effect compared to the raw Dexi and the control standard diclofenac sodium evaluated both in silico and in vivo¹¹.

 

 

Fig.1: Grades of HPMC and their applications ^{12, 13}

 

Table II: Chemistry of HPMC

 

Table III Different grades of HPMC and their Substitution ¹³:

 

From above grades of HPMC, HPMC – K 100 M, HPMC K4 and HPMC K15 polymers^{12,13,14,15,16} found to be more useful for the modified release formulation. There was greater degree of entanglement at high molecular weight would reduce the effective molecular diffusion area and hence drug permeation across the matrix gel.

 

Natural Polymers:

Natural polymers were most recent trend in pharma industry for drug delivery purpose. They are biodegradable, biocompatible and relatively safer when compared to synthetic polymers¹⁷. The various sources of natural polymers include plants, animals and microbes like bacteria and fungi^17,18. Carbohydrates have been widely used in various forms. Carbohydrate polymers are being extensively studied for biomedical and pharmaceutical applications.

 

Polysaccharides like pectin, guar gum etc. are used for the preparation of different types of dosage forms of drugs. Controlled release preparations of isoniazid and diltiazem have been prepared with the help of guar gum^18,19 also used in colon specific drug delivery of Indomethacin²⁰.

 

Xanthan gum, polysaccharide produced from fermentation of the simple sugar. It is a highly branched glucamannan and It is a hydrophilic polymer, which show limited use as thickening, suspending and emulsifying agent in water-based systems¹⁸, which in turn has its application in food, pharmaceutical and cosmetic formulations. It is found in number of drug preparations including cefdinir oral suspension and nitazoxanide tablets. Xanthan gum controls the drug release, but can provide time independent release kinetics with added advantage of compatibility and inertness. We present here a review of the most widely studied and researched polymers with respect to their roles in improving the availability and efficiency of drug delivery systems.

 

Table IV Polymer according to their origin

 

Guar gum:

It is obtained from seed endosperm of Cyamopsis tetragonolobus^20,21. Guar gum is odorless and with bland taste. Its appearance is off-white to very light-yellow color. Fine finished GG powder is available in different viscosities and granulomeres depending on the desired viscosity development and applications. Chemical structure of guar gum has a linear series of β-(1→4)-linked D- mannose pyranose units connected to (1→6)-linked α-D- galactopyranose remains as side series in the company of galactose: mannose ratio is roughly 1: 2²². GG has been making a wide usage in the biomedical field, as a modified drug delivery, in treatment of diabetes, in treatment of cancer²², other uses modified Guar gum hydrogel used as Water treatment and Biosensor²³. In general, Guar gum plays leading roles as thickening, gelling, and emulsifying, hydrating, suspending, coagulating, and flocculating agent²⁴. Also Guar gum found various advantages in drug delivery of Antihypertensive, Transdermal drug delivery, Protein drug delivery. In addition Guar gum found useful in sustained release of drug²⁰.

 

Agar gum:

Agar is Natural polysaccharide extracted form seaweed, biocompatible material that contains a rich variety of essential elements of human body like iodine, calcium, iron, sodium and magnesium. Now a days the research was focused on Oral e.g. Agar – Gelatin based oral preparation containing Lidocaine, which show optimization over marketed preparation Copalon 6%, with quite smaller surface for application²⁵, controlled release preparation of Agar thermosensitive control of release²⁶. In Injectable preparation, the MoS2/Bi2S3-PEG, Doxorubicin, Agar (AMD) hydrogel formed, solution was able to be intra-tumorally (I.T.) administrated into tumor. After the formation of an Agar/MBP/DOX (AMD) hydrogel which can act as a macro-vessel to remain as the MBP nanosheet and DOX to restrict their access to body circulation. Also, the photoacoustic and computed tomography imaging capacity, as well as the photothermal and chemotherapy efficiency of MoS2/Bi2S3-PEG nanosheets and Drug remain intact due to AMD hydrogel²⁷.

 

Sodium Alginate:

Alginates are natural polysaccharide polymers isolated from brown seaweed, It is linear polymer consisting of D-mannuronic acid and L-guluronic acid polymer chains. Hydration of polymer leads to the formation of a high-viscosity gel due to intermolecular binding²⁸. Whenever gelation is completed, the molecules of water are entrapped physically in the alginate matrix but are still free to migrate. This is of great importance in many applications (e.g., alginate gels for cell immobilization/encapsulation)²⁹. Alginates are widely used in the pharmaceutical, cosmetic, and food industry, e.g. Double walled microsphere of Tomoxifen prepared with Sodium Alginate and HPMC³⁰, (the present microsphere formulation prepared by single coating of the polymer) combining these layers yielded the optimized formulation when compared to single walled microsphere. Another example the occuserts of sodium cromoglycate prepared with HPMC and Sodium Alginate the occusert showed sustained action about to 5 hrs. i.e. the drug release was controlled in manner comparative to marketed formulation³¹.

 

Chitosan:

Chitosan is a natural cationic copolymer. It is the alkaline deacetylated product of chitin, derived from the exoskeleton of crustaceans, insects and fungal cell walls. Chitin consists of a sugar backbone with β1, 4-linked glucosamine units and a high degree of acetylation. Many pharmacologically useful properties have been suggested for chitosan due to its biocompatibility, non-toxicity, biodegradability, antibacterial activity, and antioxidant activity and mucoadhesive properties. Chitosan found most beneficial for targeted drug delivery, various modified nanomaterial of chitosan used along with sugars, carbohydrate, protein, Hormone, Vitamin to target intestinal mucosal layer, Epithelial cell or folate receptor, CD44 cell³², As well as Chitosan used in treatment of Inflammatory and Infectious diseases, Because of its easy derivatization of drug property, Its hydrophilic nature prevents its interaction with the blood, ease in formation of Gel, Films etc.^33,34. Chitosan has wide variety of application it was used for waste water treatment. Chitosan and its derivatives are very important for their availability, cost effectiveness, environment friendliness and biodegradability characteristics. Chitosan derived protonated; biopolymer can adsorb heavy metal ions, dyes and protein molecules. Electrostatic interaction due to amino group leads to the bioabsorption³⁵.  

 

Pollulan:

Pollulan is a maltotriose trimer and it is made up of α- (1 → 6)-linked (1 → 4)-α-d-triglucosides with a chemical formula of C₆ H₁₀ O₅. Due to presence of of both α-(1 → 4) and α-(1 → 6) present in a single compound, and it is seen as a intermediate between the amylose and dextran structure This unique structure is responsible for Pollulans high solubility in water and flexibility³⁶. The Pollulan and its derivatives used in biomedical applications e.g. drug delivery, gene targeting, tissue engineering, Food coatings³⁶, vaccination, plasma substitution, chaperone-like activity, medical imaging, insulin tropic activity³⁷. In drug delivery Pollulan can conjugate interferon and this complex helps in controlling hepatitis C virus disease by directly targeting the liver without any side effects³⁸. One more example is for drug delivery is the novel pH-responsive nanoparticle drug delivery system that contains charge reversible Pollulan-based shell, poly(β-amino ester) and poly(lactic-co-glycolic acid) in a core which is a promising candidate as a carrier for drugs against hepatocellular carcinoma³⁹. Tissue engineering Pollulan hydrogels allow smooth muscle cells (SMCs) adhesion, spreading and proliferation for vascular tissue engineering. They have antiadhesion properties and help in reducing various problems like infertility, postoperative pain, intestinal obstruction⁴⁰.

 

Xanthan gum:

Xanthan is a long-chain polysaccharide having d-glucose, d-mannose, and d-glucuronic acid as building blocks with a high number of trisaccharide side chains. Xanthan gum has an average molecular weight of about 2000 kDa⁴¹. Potential application of the Xanthan gum the use of Xanthan gum based hydrogel for transdermal drug delivery of montelukast nanocrystals yields the formulation comparable to the conventional one⁴². XG has been found suitable for buccal delivery of drugs. XG-based bilayer mucoadhesive buccal patches of zolmitriptan. They performed various studies like swelling index, ex vivo mucoadhesive strength, and in vitro drug release. In vitro drug release studies revealed that 43.15% of the drug was released within 15 min and then it showed a sustained release for 5 hrs⁴³. In advanced drug delivery the mucoadhesive microshpere of the metformin prepared with Xanthan gum show sustained action for the 10hr. The results of stability studies revealed that formulation containing 93.72% - 95.94% was stable up to 3 months during storage without any physical changes⁴⁴. The cosmetic application of Xanthan gum it is used as a thickening agent, emulsion stabilizer, and texture enhancer in cosmetic and personal care. XG generates a gel like structure which is in water and that also can be used along with another viscosity modifier such as guar gum which gives enhanced results. Some patented cosmetic product containing Xanthan gum is available⁴⁵.

 

Table V: HPMC–Polymer combinations and their Role

 

Applications with HPMC:

Drug Delivery:

The natural polymer posses the very much potential for the drug delivery of various type like targeted drug delivery, modified drug delivery, sustained release etc. HPMC when combined with the natural polymers like Chitosan, Xanthan gum, Agar, Sodium alginate it showed, better result and good optimization of the formulation.

 

CONCLUSION:

HPMC and along with the other alternative polymers showed great potential of application in pharmacy industry. Particularly, for HPMC K series polymer there was extensive spectrum of activities was possible in field of modified release drug delivery system. The HPMC- Guar gum, HPMC- Sodium Alginate polymer blends, both polymers of the pair help each other in maintaining the integrity of the matrix of tablet. By regulating the viscosity, Hydration layer around the tablet. The HPMC- Chitosan polymer mixture with broad spectrum of application, as same as Alginate and Guar gum the Chitosan also aids in maintaining the HPMC matrix after the contact with fluid. The Pollulan and Xanthan gum when combine with HPMC, it modifies the mechanical properties of matrix tablet which contribute to its adhesion. Here, from above it can be concluded that HPMC possesses lot of potential as a modified release polymer.

 

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Received on 30.01.2020            Modified on 12.04.2020

Accepted on 08.06.2020         © RJPT All right reserved