Mucoadhesion Based Solid Dosage Form: The Next Generation

 

Nagpal Navneet1*, Arora Manisha1, Rahar Sandeep1,  Swami Gaurav2, Sharma Dinesh3 and Kapoor Reni 4

1B.I.S. College of Pharmacy, Gagra, Moga-142103, Punjab, India

2C.T. College of Pharmacy, Jalandhar-144001, Punjab, India

3Department of Pharmaceutical sciences, University of Kashmir, Srinagar-190001, J&K, India

4Akal College of Pharmacy, Mastuana Sahib, Sangrur-148001, Punjab, India

 

 

ABSTRACT:

This review reveals the potential of mucoadhesive polymers and tablets for gastrointestinal administration. Prolonged contact time of a drug with a body tissue through the use of mucoadhesive polymers can significantly improve the performance of many drugs. These improvements lead to better treatment of local pathologies, improved drug bioavailability and control release of the drug to enhanced patient compliance. This review highlights the role of next generation mucoadhesive polymers and the benefits likely to occur with these improved polymeric systems. New mucoadhesive materials with optimal adhesive properties are now being developing and explored to enhance the application of this technology.

 

KEYWORDS: Mucoadhesive, polymers, gastroretention, bioavailability.

 

 

INTRODUCTION:

Bioadhesion may be defined as the state in which two materials at least one of which is biological in nature are held together for extended periods of time by interfacial forces. In the pharmaceutical sciences when the adhesive attachment is to mucus or a mucous membrane the phenomenon is referred to as mucoadhesion1. Over the last two decades mucoadhesion has become the point of interest for its potential to optimize localized drug delivery. The need to deliver challenging molecules such as biopharmaceuticals (proteins and oligonucleotides) has increased interest in this area2. Under certain circumstances the gastro- retention delivery system is desired for achieving greater therapeutic benefit of the drug substance; e.g. drugs that are absorbed in the proximal part of the gastrointestinal tract and drugs that are less soluble in or are degraded by the alkaline pH may benefit from prolonged gastric retention3,4. It has been suggested that prolonged local availability of antibacterial agent may augment their effectiveness in treating H. Pylori related peptic ulcer. Moreover, it has been reported that the bactericidal effect of clarithromycin, gracinol, and reveratrol are time and concentration dependent. Mucoadhesive materials could also be used as therapeutic agents in their own right, to coat and protect damaged tissues (gastric ulcers or lesions of the oral mucosa) or to act as lubricating agents (in the oral cavity, eye and vagina). This review will consider the basic mechanisms by which mucoadhesives can adhere to a mucous membrane in terms of the nature of the adhering surfaces and the forces that may be generated to secure them together and specific targeted mucoadhesives material currently in used. The present review will examine progress in the field mucoadhesives in terms of understanding now mucoadhesives polymers work in drug delivery.

MUCOADHESION:

Due to its relative complexity, it is likely that the process of mucoadhesion cannot be described by just one of these theories.

 

a)  Dry or partially hydrated dosage forms containing surfaces with substantial mucous layers (eg. Aerosolised particles deposited in the nasal cavity).

 

 

b) Fully hydrated dosage forms contacting surface with thin ⁄ substantial mucous layers (eg. Particle suspensions in the gastrointestinal tract).

 

c)                    Dry or partially hydrated dosage form contacting  surfaces with thin/discontinuous  mucus layers (eg. A tablet placed onto the oral mucosa).

 

 

d) Fully hydrated dosage forms contacting surfaces withthin / discontinuous layers (e.g. aqueous microparticles administered into the vagina).

Figure 1: Some scenarios where mucoadhesive can occur

In considering the mechanism of mucoadhesion, whole range scenarios for in-vivo mucoadhesive bond formation are possible (Figure. 1).

 

These include:

1. Dry or partially hydrated dosage forms contacting surfaces with substantial mucus layers (typically particulates administered into the nasal cavity).

2. Fully hydrated dosage forms contacting surfaces with substantial mucus layers (typically particulates of many ‘First Generation’ mucoadhesives that have hydrated in the luminal contents on delivery to the lower gastrointestinal tract).

3. Dry or partially hydrated dosage forms contacting surfaces with thin/discontinuous mucus layers (typically tablets or patches in the oral cavity or vagina).

4. Fully hydrated dosage forms contacting surfaces with thin/discontinuous mucus layers (typically aqueous semisolids or liquids administered into the oesophagus or eye).

It is unlikely that the mucoadhesive process will be the same in each case.

In the study of adhesion generally, two steps in the adhesive process have been identified5, which have been adapted to describe the interaction between mucoadhesive materials and a mucous membrane6 (Figure.2).

 

Figure 2: The two stages in mucoadhesion

 

Step 1 — Contact stage: An intimate contact (wetting) occurs between the mucoadhesive and mucous membrane7-10.

Step 2 — Consolidation stage: Various physicochemical interactions occur to consolidate and strengthen the adhesive joint, leading to prolonged adhesion11-23.

 

 

There are essentially two theories as to how gel strengthening/consolidation occurs. One is based on a macromolecular interpenetration effect, which has been dealt with a theoretical basis by Peppas and Sahlin24. This theory is based largely on the diffusion theory described by Voyutskii25 for compatible polymeric systems, the mucoadhesive molecules interpenetrate and bound by secondary interactions with mucus glycoprotein (Figure.3).

 

Figure 3: The interpenetration theory: three stages in the interaction between a mucoadhesive polymer and mucin glycoprotein

 

Evidence for this is provided by an ATR- FTIR study by Jabbari et.al26, 27. In their study a thin cross-linked film of poly(acrylic acid) was formed on an ATR crystal. A mucin solution was placed into contact with this film and ATR-FTIR spectra collected over a period of time. These spectra revealed a peak after 6 min at 1550 cm-1 (which anifested itself as a small shoulder in the original spectrum) which was attributed to mucin dimeric carboxylic CMO stretching and it was proposed that, this indicate the presence of interpenetrating mucin molecules within the poly(acrylic acid) film.

 

The second theory is the dehydration theory. When a material capable of rapid gelation in an aqueous environment is brought into contact with a second gel water movement occurs between gels until equilibrium is achieved. A polyelectrolyte gel, such as a poly(acrylic acid) will have a strong affinity for water, therefore a high osmotic pressure and a large swelling force when brought into contact with a mucus gel it will rapidly dehydrate that gel and force intermixing and consolidation of the mucus joint (Figure 4) until equilibrium is reached28,29. The movement of water from mucus into a poly(acrylic acid) film was observed by Jabbari et al.

 

Figure 4: The dehydration theory of mucoadhesion

 

MUCOADHESIVE MATERIALS:

The most widely investigated group of mucoadhesives is hydrophilic macromolecules containing numerous hydrogen bonds forming groups30-34, the so called ‘first generation’ mucoadhesives. Their initial use as mucoadhesives was in denture fixative powders or pastes. The presence of hydroxyl, carboxyl or amine groups on the molecules favors adhesion. They are called wet adhesives in that they are activated by moistening and will adhere non-specifically to many surfaces35. Once activated, they will show stronger adhesion to dry inert surfaces than those covered with mucus. Unless water uptake is restricted they may over hydrate to form slippery mucilage. Like typical hydrocolloid glues, if the formed adhesive joint is allowed to dry then they can form very strong adhesive bonds. Typical examples are carbomers, chitosan, sodium alginate and the cellulose derivatives36 (Figure 5). Various properties and characteristics of mostly used mucoadhsive polymers used in prepration of mucoadhesion based solid dosage forms are shown in table 1.

 

a)                    Poly(acrylic acid), R = allyl sucrose or allyl pentaerythritol (carbopols); or divinyl glycol (polycarbophil)

 

 

Table 1: Some mucoadhesive polymer and their properties36

S. No.

Mucoadhesive polymer

Propertiesα

Characteristics

1.

Polycarbophil (polyacrylic             acid cross linked with divinyl glycol)

● Mw 2.2 x 105

● η 2000-22,500 cps (1% aq. Soln.)

● κ 15-35 mL/g in neutral and basic media

● Ф viscous colloid in cold   water

 

● synthesized by lightly cross- linking of divinyl glycol

● swellable depending on pH, but insoluble in water

● entangle the polymer with      mucus on the surface of the tissue

● hydrogen bonding between the nonionized carboxylic acid and mucin

2.

Carbopol/carbomer (carboxy polymethylene)

● Mw 1 x 106- 4 x 106

● η 29,400 - 39,400 cps at 25 oC With 0.5% aq. Soln.

● ρ 5 g/m in bulk

● pH 2.5-3.0

● Ф viscous colloid in cold water mucoadhesive dosage forms

● synthesized by cross-linker of allyl sucrose or allyl pentaerythritol

● excellent thickening, emulsifying suspending, gelling agent

● common component in mucoadhesive dosage forms

 

3.

Sodium carboxymethyl cellulose (cellulose carboxymethyl ether sodium salt)

● Mw 9 x 104 – 7 x 105

● η 1200 cps with 1.0% soln

● ρ 0.75 g/cm3 in bulk

● pH 6.5-8.5

● Ф water

sodium salt of a polycarboxy methyl ether of cellulose

● emulsifying, gelling, binding agent

● good mucoadhesive strength

4.

Hydroxypropyl cellulose (cellulose 2- hydroxypropyl ether)

● Mw 6 x 104 – 1 x 106

● η 4000 – 6500 cps with 2.0% aq. Soln.

● ρ 0.5 g/cm3 in bulk

● pH 5.0 – 8.0

● Ф soluble in water below 38oC, ethanol

● partially substituted poly hydroxy propyl ether  cellulose

● granulating and film coating agent for tablet

● thickening agent, emulsion stabilizer, suspending agent in oral and topical liquid soln. or suspension formulation

5.

Hydroxypropylmethyl cellulose (cellulose-2- hydroxypropylmethyl ether)

● Mw 8.6 x 104

● η 15 – 4000 cps (2% aq. Soln.)

● Ф cold water

● mixed alkyl hydroxyl alkyl cellulosic ether

● suspending, viscosity-increasing and film-forming agent

● tablet binder and adhesive ointment ingredient

6.

Hydroxyethylcellulose

● ρ 0.6 g/ml

● pH 6 – 8.5

● used as suspending or viscosity increasing agent

● binder, film former, thickener

7.

Alginate

● pH 7.2

● η 20 – 400 cps (1% aq. Soln.)

● Ф water

●stabilizer in emulsion, suspending   agent, tablet disintegrant, tablet binder

α η : Viscosity ; ρ : density ; Mw : Molecular weight  ; κ : absorption measured at water ; Ф : soluble solvent; pH measured at 0.1 % aqueous solution (aq. Soln.)

 

 

b)                    Chitosan

 

c)             Sodium alginate

 

d)                    cellulose derivetives eg.

Sodium carboxy methyl cellulose-

R1, R4 = CH2OH; R2, R3, R5 = OH; R6 = OCH2CO2Na+

Hydroxy propyl methyl cellulose-

R1CH2OCH3; R2 = OH; R3 = OCH2CHOHCH3; R4 = CH2OH; R5, R6 = OCH3

Figure 5: The structure of some common ‘first generation’ mucoadhesive polymers.

 

 

MUCOADHESIVE DEVICES:

Mucoadhesive dosage forms, such as laminated polymer films37, mucoadhesive tablets38,39 and patches40 are currently being investigated for sustained delivery of drug. Several laminated devices have been developed to achieve sustain/control drugs release. These include devices containing an impermeable backing layer, a rate limitining membrane and an adhesive polycarbophil layer, which remained in place for 17 hrs. in dogs and humans41, two polylaminates consisting of an impermeable backing layer with a hydro gel containing drugs42 and a dosage form comprising a non adhesive backing, a drug core and a peripheral adhesive layer43. Based on the mechanism by which a drug is released the devices can be classified into one of the following two categories-

·         The drug is dissolved or dispersed in the polymer system where diffusion of drug from the dug / polymer matrix controls the overall release from the device.

·         Reservoir (or membrane) system where diffusional resistance across a polymer membrane controls the overall drugs release.

 

NOVEL MATERIALS:

In order to overcome the limitations of first generation off the shelf mucoadhesive materials, new types of materials have been investigated that allow specificity and strengthen the mucoadhesion process. In some cases existing mucoadhesive polymers have been modified, while in others new materials are developed. One approach to produce improved mucoadhesives has been to modify existing materials. For example thiol groups (by coupling cysteine, thioglycolic acid, cysteamine) have been placed into a range of mucoadhesive polymers such as the carbomers, chitosan and alginates by Bernkop-Schnurch et al44-47. The concept is that in-situ they will form disulphide links not only between the polymers themselves thus inhibiting overhydration and formation of the slippery mucilage but also with the mucin layer/ mucosa itself, thus strengthening the adhesive joint and leading to improved adhesive performance. This interesting approach appears to be meeting with some success.

 

The incorporation of ethyl hexyl acrylate into a copolymer with acrylic acid in order to produce a more hydrophobic and plasticized system was considered by Shojaei et al48. This would reduce hydration rate while allowing optimum interaction with the mucosal surface, and the mucoadhesive force was found to be greater with the copolymer than with poly(acrylic acid) alone. The grafting of polyethylene glycol (PEG) onto poly(acrylic acid) polymers and copolymers has also been investigated49–51. These copolymers were shown to have favorable adhesion relative to poly(acrylic acid) alone, in that the polyethylene glycol is proposed to promote interpenetration with the mucus gel52. Poly(acrylic acid) / PEG complexes have also been developed as mucoadhesive materials53. Poloxomer gels have been investigated as they are reported to show phase transitions from liquids to mucoadhesive gels at body temperature and will therefore allow in-situ gelation at the site of interest54. Pluronics have also been chemically combined with poly(acrylic acids) to produce systems with enhanced adhesion55 and retention in the nasal cavity56. Dihydroxyphenylalanine (DOPA), an amino acid found in mussel adhesive protein that is believed to lend to the adhesive process, has also been combined with pluronics to enhance their adhesion57.

 

Problems encountered in mucoadhesive gastrointestinal system:

1)       The mucoadhesive polymer in an aqueous environment can over-hydrate to form slippery mucilage, which is readily removed58.

2)       The drug substances that are unstable in the strong acidic environment of the stomach are not suitable candidates to be incorporated in such system.

3)       These system do not offer significant advantages over the conventional dosage forms for drugs, which are absorbed throughout the gastrointestinal tract59.

4)       Choice of the right mucoadhesive polymer which is added to the normal tablet formulation also a problem when preparing a mucoadhesive tablet.

 

CONCLUSION:

Mucoadhesion is a method, which has great potential for pharmaceutical technology and dosage form design. It can be adapted to almost all the administration routes and the example presented shows that the mucoadhesive technique and mechanism are a function of the administration route considered. The gastrointestinal mucoadhesive drug delivery systems emerge as a tool to overcome the problem associated with the conventional dosage forms. In essence, we can conclude that the mucoadhesive systems have the potential for sustained delivery and controlled release with an additional possibility of targeting.

 

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Received on 22.07.2010

Accepted on 02.08.2010        

© A&V Publication all right reserved

Research Journal of Pharmaceutical Dosage Forms and Technology. 2(5): Sept.-Oct. 2010, 323-328