Sustained Drug Delivery Using Mucoadhesive

62

Recent Patents on Nanomedicine, 2012, 2, 62-77

Sustained Drug Delivery Using Mucoadhesive Microspheres: The Basic Concept, Preparation Methods and Recent Patents Anupama Singh*, Pramod Kumar Sharma and Rishabha Malviya Department of Pharmaceutical Technology, Meerut Institute of Engineering and Technology, Bypass Road, Baghpat Crossing, NH-58, Meerut-250005, U.P., India Received: 26 January 2012; Revised: 23 February 2012; Accepted: 24 February 2012

Abstract: Mucoadhesion is the most vital concept that is widely utilized in most of the novel drug delivery systems via mucosal membrane of buccal, nasal, digestive tract, etc when administered through oral, nasal or any other route. This review deals with the basic concept of sustained release mucoadhesive microspheres, their preparation methods, recent patents on sustained release microspheres and finally the various marketed formulations of microspheres. The mucoadhesive microspheres prepared by different techniques are widely used in sustained delivery of drugs with improved bioavailability and targeting efficacy. The listed patents contain the methods developed for microsphere preparation along with the encapsulated material that needs to be delivered. In short the patents listed here also gave the information of the polymers utilized for the microsphere preparation along with their therapeutic efficacy.

Keywords: Bioadhesive polymers, bioavailability, mucus, sustained release formulation, targeted delivery. INTRODUCTION The concept of mucoadhesion is most widely utilized in novel drug delivery systems. The term mucoadhesion consists of two words, muco and adhesion, which refers to the adhesive interactions between polymers and mucus or mucosal surfaces [1]. In other words it refers to the state in which two surfaces, at least one biological in nature gets held together in close contact by interfacial forces for an extended duration of time [2]. MECHANISMS OF MUCOADHESION The mechanisms responsible in the formation of mucoadhesive bonds are not fully known, yet certain bond formation is involved as a three step process based on the interrelation between mucoadhesive theories and the material properties [3]. Step 1: Polymer wetting and swelling (Wetting theory) Step 2: Formation of chemical bonds between the entangled chains (Electronic and Adsorption theory) Step 3: Interpenetration between the polymer chains and the mucosal membrane (Diffusion theory) STEP 1 The spreading of polymer over the surface of the biological substrate or mucosal membrane causes wetting and swelling of the polymer that too results in developing an intimate contact with the substrate [4]. This swelling of polymers occurs due to its affinity for water. This can be *Address correspondence to this author at the Department of Pharmaceutical Technology, Meerut Institute of Engineering and Technology, Bypass Road, Baghpat Crossing, NH-58, Meerut-250005, U.P. India; Tel: +91 9720200161; E-mail: [email protected]

1877-9131/12 $100.00+.00

readily achieved for example by placing a mucoadhesive formulation such as microspheres within the gastrointestinal tract or vagina. Mucoadhesives are able to adhere to or bond with biological tissues by the help of the surface tension and forces that exist at the site of adsorption or contact [5]. STEP 2 This step involves the formation of weak chemical bonds including primary bonds such as covalent bonds and secondary interactions such as van der Waals and hydrogen bonds between the entangled polymer chains. Both primary and secondary bonds are exploited in the manufacture of mucoadhesive formulations in which strong adhesions between polymers are formed [6]. STEP 3 The glycoprotein’s, a high molecular weight polymer forms mainly the surface of mucosal membranes. This step involves the intermingling and entangling of the mucoadhesive polymer chains and the mucosal polymer chains thus forming semi permeable adhesive bonds. The strength of these bonds depends on the degree of penetration between the two polymer groups. The strong adhesive bonds can be formed if one polymer group must be soluble in the other and both polymer types must be of similar chemical structure [7]. Theories of mucoadhesion: There are various theories of mucoadhesion which involve different mechanisms for their adhesion. Thus on the basis of all the stated theories the process of mucoadhesion can broadly be classified into two categories: chemical (electron and absorption theory) and physical (wetting, diffusion and cohesive theory) [8-10]. Electronic theory: According to this theory, the difference in electronic structures of polymer and mucus causes electron transfer upon contact of adhesive polymer © 2012 Bentham Science Publishers

Sustained Release Using Mucoadhesive Microspheres

Recent Patents on Nanomedicine, 2012, Volume 2, No. 1 63

with a mucus glycoprotein network [11]. As a result this mucoadhesion leads to the formation of electrical double layer at the interface as shown in Fig. (1) [12]. For example, interaction between positively charged polymer (chitosan) and negatively charged mucosal surface develops the property of adhesive on hydration and provides an intimate contact between the absorbing tissue and dosage form [13].

contact angle of liquids on the substrate surface is lower, then there is a greater affinity for the liquid to the substrate surface. The component that needs to adhere penetrates surface irregularities, hardens and anchors itself to the surface [13]. This adhesive performance of such elastoviscous liquids is expressed in terms of wettability, spreadability and critical parameters that can be determined from solid surface contact angle measurements. The main mechanism defines the energy required to counter the surface tension at the interface between the two surfaces allowing for a good mucoadhesive spreading and coverage of the biological substrate [23]. When such types of substrate surfaces are brought in contact with each other in the presence of the liquid, the liquid may act as an adhesive medium among the substrate surface as shown in Fig. (3) [24]. The work of adhesion (Wa) is denoted by eqn. (1).

Fig. (1). Diagrammatic representation of electronic theory.

Wa = YA + YB Y AB

Absorption theory: This theory is based on the presence of surface forces between the atoms in two surfaces [14]. According to this theory, the material adheres after an initial contact between two surfaces [15]. Two types of chemical bonds that result in surface adhesion are the primary chemical bonds of covalent nature and secondary chemical bonds having many different forces of attraction, such as electrostatic forces, Vander Walls forces, hydrogen and hydrophobic bonds [13, 16].

where,

Diffusion theory: This theory is based on the extent of diffusivity of polymer chains in the mucus layer [17]. According to this theory, a semi permanent adhesive bond is created between the polymer chains and the mucus after their mixing to a sufficient depth as shown in Fig. (2) [18]. This property of penetration of polymer chain to a specific depth to the mucus depends on the diffusion coefficient and the time of contact [19]. However, the diffusion coefficient in turn depends on the value of molecular weight between crosslinking. The diffusion coefficient decreases significantly on increasing the cross linking density [13, 20, 21]. Wetting theory: This theory depends upon the degree of contact angle between the two surfaces in contact. If the

(1)

A & B refers to the biological membrane and mucoadhesion, respectively. Cohesive theory: According to this theory, the phenomenon of mucoadhesion is based mainly on the intermolecular interaction amongst like molecules. The work of cohesion (Wc) is denoted by eqn. (2). Wc = 2YA or YB

(2)

where, A & B refers to the biological membrane and mucoadhesion, respectively. For a material B to spread on a mucosal surface A, spreading coefficient is given by eqn. (3). SA/B = YA (YB + Y AB)

(3)

where, SA/B should be positive for a mucoadhesive material to adhere to a mucosal membrane [13].

Fig. (2). Representation of diffusion theory (a) polymer layer and mucus layer before contact; (b) polymer layer and mucus layer immediately after contact; (c) polymer layer and mucus layer after contact for a period of time [22].

64 Recent Patents on Nanomedicine, 2012, Volume 2, No. 1

Singh et al.

A mucoadhesive polymer is composed of a synthetic or natural polymer which binds to mucosal membranes acting as biological substrate [27]. Such mucoadhesive polymers called as biological ‘glues’ get incorporated with drugs to enable these drug moieties to bind to their target tissues [28]. Mucoadhesive polymers that adhere to the mucosalepithelial surface are broadly divided into three distinguished classes [29, 30]:

Fig. (3). A representation of the interfacial forces involved in wetting theory.

Fracture theory: This theory is based on the difficulty of separation of two surfaces after mucoadhesion. It focuses on the ratio of force required for polymer detachment from the mucus to the strength of their adhesive bond [25]. This theory aims for the determination of fracture strength (G) following the separation of two surfaces via its relationship to Young’s modulus of elasticity (E), the fracture energy () and the critical crack length (L). It is equivalent to adhesive strength denoted by eqn. (4) [13, 26]. G = (E/L)1/2

(4)

where, E= Young’s modulus of elasticity = Fracture energy L = Critical crack length when two surfaces are separated

Fig. (4). Classification and examples of mucoadhesive polymers [34].

1.

Polymers that owe their mucoadhesion as a result of stickiness since they becomes sticky in nature when kept in water [31].

2.

Polymers that owe their mucoadhesion as a result of nonspecific, noncovalent interactions that are primarily electrostatic in nature (although hydrogen and hydrophobic bonding may be significant) [32].

3.

Polymers that owe their mucoadhesion as a result of binding to specific receptor site on tile self surface [33].

All three polymer types can be used for drug delivery [34]. Further the mucoadhesive polymers can also be categorized into two broad categories based on the rheological aspects, materials which undergo matrix formation or hydrogel formation by either a water swellable material (hydogels) or a water soluble material (hydrophilic polymers) as shown in Fig. (4). Hydrophillic polymers: These polymers possess carboxylic group and excellent mucoadhesive properties.


Table 1.


Description of different release behavior of formulations.

Release Form

Description

Delayed release

The drug release occurs at a later time following administration, e.g. enteric coated tablets, pulsatile-release capsules.

Prolonged release

The drug onset is delayed as a result of overall slow release rate from the dosage form which shows absorption over a longer period of time.

Sustained release

An immediate drug release sufficient to provide a therapeutic dose soon after administration, followed by a gradual release over an extended period.

Extended release (ER)

A slow drug release occurs that maintains the plasma concentrations at a therapeutic level for a prolonged period of time (usually between 8 and 12 hours).

Controlled release (CR)

A constant rate of drug release that maintains plasma concentrations invariant with time.

Hydrogels: These polymers swell on contact with water and adhere to the mucus membrane. Sustained release dosage form provides the principal advantage of creating a steady drug release profile making the drug substance available over an extended period of time following ingestion. Sustained release dosage forms are designed to bring the plasma drug level immediately to therapeutic concentration by means of an initial dose delivery and then sustaining this level for a certain predetermined time with the next maintenance dose [35, 36]. Table 1 shows the difference between different dosage forms that determines the release behavior of individual type of formulation [37]. Other advantages gained formulations include [38]:

by

sustained

release

(i)

Uniformity in plasma drug profile with fewer chances of gaining super- or subtherapeutic concentrations of drug, or its active metabolite(s); and

(ii)

Extended period of therapeutic response after the dose ingestion thus reducing the frequency of administration

(iii)

Reduced adverse side effects

(iv)

Better patient compliance

MICROSPHERE TECHNOLOGY Mucoadhesive microspheres: Microspheres may be defined as solid, spherical particles that range in size 1-1000 μm and made of polymeric, waxy or other protective materials such as biodegradable synthetic polymers and modified natural products such as polysaccharides, gums, proteins, fats and waxes. For example, natural polymers include albumin and gelatin. Similarly the synthetic polymers include polylactic acid and polyglycolic acid [39]. Microspheres are small in size and possess large surface to volume ratio. The lower sized microspheres have colloidal properties. The interfacial properties of microspheres are extremely important, often dictating their activity.

Mucoadhesive microspheres are the microparticles and/or microcapsules ranging in size from 1-1000μm and consist either entirely of a mucoadhesive polymer or having its outer coating, respectively and an inner core of drug. Mucoadhesive microspheres have the potential of being used for target specific and controlled drug delivery which encouples the mucoadhesion properties of attached polymers. These mucoadhesive and biodegradable polymers undergo selective uptake by the M cells of payer patches in gastrointestinal (GI) mucosa and this uptake mechanism has been used for the delivery of high molecular weight drugs (proteins and peptides), antigens. Advantages of microspheres: Microspheres form one of the most widely used drug delivery system and hence possesses several advantages [42, 43]. •

Reliable means of site specific drug targeting by maintaining the desired concentration at the site of interest without any untoward effect.

•

Biodegradable microspheres provide sustained release of drug throughout the particle matrix.

•

Target drug to various diseased sites such as targeting of anticancer drugs to the tumour cells.

•

The size, surface charge and surface hydrophobicity of microspheres have been found to be an important factor in determining the fate of particles in vivo.

•

Beneficial in blood flow determination. For example, microspheres are injected into the left atrium or left ventricle. On mixing with blood, these microspheres are ejected into the bloodstream and distributed as per cardiac output in the circulation. Thereafter a reference blood sample is collected from the femoral artery at a speed Fref. The cardiac output (CO) in ml/min is the calculated as shown in eqn. (5). CO = Fref (Atot/Abl) (5) where Atot represents the counts of total injected activity and Abl represents the activity measured in the withdrawn blood. Similarly, renal blood flow (RBF) is calculated as shown in eqn. (6)

Microparticles are classified in two types [40, 41]: 1.

Microcapsules: The entrapped substance completely surrounded by a distinct capsule wall.

is

2.

Microspheres: The entrapped substance is dispersed throughout the microsphere matrix.

RBF = Fref (Ak/Abl) (6) where Ak represents the counts of activity in the kidney [44].


Singh et al.

•

Provide protection to unstable drugs both before and after administration, prior to their availability at the site of action.

•

Help in manipulating the in vivo action of drug, pharmacokinetic profile, tissue distribution and cellular interaction of the drug.

Application of microspheres in drug delivery: There are several applications of microspheres some of which are stated as follows [45]:

administration. Particles greater than 7 μm get entrapped in the capillary. Particles coated with a polymer (poloxamer) and of size 60-150 nm are taker up to a considerable extent by the bone marrow. Similarly, particles of size larger than 250 nm can be used for spleen targeting. •

The release profile of the drug should be reproducible without significant initial burst.

•

The technique employed for microspheres production should produce free-flowing microparticles effective for uniform suspension of the microparticle.

•

The process should not adversely affect the stability of the drug.

•

No toxic reaction or product should be produced with the final product.

Targeting of Active Agents [46] •

Inactive: Here the term inactive means that the microsphere surface is not modified in any means. These unmodified microspheres gather in specific tissue reticuloendothelial system

•

Active: The term active indicates to alter microsphere surface with ligand (antibodies, enzymes, protein A, polysaccharides)

•

Physical: Temperature or pH sensitive microspheres

•

Directly to diseased site

Increasing Efficacy and Decreasing Toxicity [47] •

Changes the absorbance and biodistribution

•

Delivers drug in desired form

•

In case of multidrug resistance helps to prevent drug interactions

Protection of Active Agent [48] •

Decreases harmful side effects

•

Protects drug that undergoes gastrointestinal environment

metabolism

in

Providing Desired Release Profile [48] •

Affects the time in which the drug is released

•

Prolong time -increases duration of action and decreases frequency of administration

•

Dependent on drug and polymer properties

Methods of microsphere preparation: There are several techniques of microspheres preparation, but the choice of these techniques mainly depends on several factors such as the nature of the polymer used, the drug, the intended use, and the duration of therapy as shown in Table 2. These techniques of microsphere preparation and its choice are determined by various formulation and technology related factors as mentioned below [45]: The physical, chemical and biological activity of the incorporated drugs should be maintained during the microencapsulation method [45]. •

The microspheres should have high encapsulation efficiency and yield enough for mass production.

•

The microspheres should possess the reasonable size range for the oral and parenteral administration. It should not be longer than 180 μm for parenteral

Spray Drying (An anhydrous technique): Spray drying is another method for preparation of microspheres. It involves the use of volatile organic solvents such as dichloromethane, acetone, etc in which polymer is first dissolved [49] as shown in Fig. (5). Then the solid drug is slowly dispersed in this polymer solution along with continuous stirring at high speed homogenization. After a homogenous mixture is obtained, this dispersion is atomized in a stream of hot air and the process is known as atomization [50]. Small droplets or the fine mist of drug polymer solutions form after evaporation of volatile solvent instantaneously that leads to the formation of the microspheres in a size range 1-1000 μm. These micro particles are then separated by means of the cyclone separator from the hot air and the traces of the left over solvent is removed by vacuum drying [51]. Spray drying method has the major advantage of being rapid, feasible under aseptic conditions and leads to the formation of porous micro particles. The spray drying obtained microspheres can be improved in quality by the addition of plasticizers such as citric acid, which promote polymer coalescence on the drug particles and hence help in the formation of spherical and smooth surfaced microspheres [52]. Further, the rate of spraying, the feed rate of polymer drug solution, nozzle size, and the drying temperature affects the size of microspheres. This method of microencapsulation is however simple, reproducible, easy to scale up and independent of the solubility characteristics of the drug and polymer [53]. Solvent Evaporation: Solvent evaporation method is again similar to spray drying involving the use of volatile organic solvent. This process is the most extensively used for microencapsulation and carried out in a liquid manufacturing vehicle [54]. Here the process consists of two phases: first is the buffered or plain aqueous solution phase of the drug with or without a viscosity building or stabilizing agent and second is the organic phase consisting of polymer solution in volatile solvents like dichloromethane (or ethyl acetate or chloroform). This polymer solution dispersed in a volatile solvent is immiscible with the liquid manufacturing vehicle phase. The core material that needs to be microencapsulated is first dispersed in the liquid manufacturing vehicle phase with vigorous stirring to form the primary water in oil emulsion. The emulsion mixture is then either added to a large volume of water containing an emulsifier like PVA (polyvinyl alcohol) or PVP (poly vinyl pyrrolidone) to form



Fig. (5). Diagrammatic representation of spray drying method.

the multiple emulsions (w/o/w) [55]. The double emulsion mixture is heated if necessary to evaporate the volatile solvent under continuous stirring. The polymer shrinks around the core material that may be either water soluble or water insoluble materials [56]. After a particular time when whole of the solvent evaporates the core materials get encapsulated by the polymer solution leaving solid microspheres. These microspheres can then be washed, centrifuged and lyophilized to obtain the free flowing and dried microspheres of appropriate size [57]. Hot Melt Microencapsulation: In this the polymer is first melted and then mixed with drug molecules that already have been sieved to a particular size. Then this mixture is suspended in a non-miscible solvent like silicone oil with continuous stirring, and heating at 5°C above the melting point of the polymer [58]. After the emulsion gets stabilized, it is cooled to solidify polymer particles. The resulting microspheres obtained range in diameter from 1-1000 m, are then washed by decantation with petroleum ether as represented in Fig. (6). This method is suitable for microencapsulation of water labile polymers, e.g.

polyanhydrides. The only disadvantage of this method is moderate temperature to which the drug is exposed [59]. Single emulsion technique: In this method a dispersion or solution of natural polymers is prepared in aqueous medium. This mixture is then dispersed in the non-aqueous medium such as oil followed by cross linking of dispersed globules either by means of heat or chemical cross linking agents as shown in Fig. (7) [60]. Based on the type of cross linking the method is classified as: Thermal cross-linking method: In this method cross linking is done by adding dispersion to previously heated oil under continuous stirring to obtain microspheres of specific size range. However this method is suitable for thermolabile drugs as heat denaturation of drug occurs [61]. Cross linking agent method: This method involves the use of certain cross linkers such as glutaraldehyde, formaldehyde, di-acid chloride, etc. for microsphere preparation. This technique suffers from excessive exposure of active ingredients to chemicals if added at the preparation time. First, a specific concentration solution of polymer in

Fig. (6). Diagrammatic representation of hot melt microencapsulation method.


Singh et al.

Fig. (7). Diagrammatic representation of single emulsion method.

aqueous medium is prepared which is then added under continuous stirring to the continuous phase consisting of oil and surfactant to form water in oil (w/o) emulsion. Then a drop-by-drop solution of a measured quantity of aqueous cross linkers is added at specific time intervals to allow uniform mixing. Stirring was continued for a particular time until microspheres of specific size range are obtained which are then separated using a washing organic solvent [62].

•

Double emulsion method (A hydrous technique): This method involves the formation of multiple emulsions or double emulsion of type water in oil in water (w/o/w) and is best suited for water soluble drugs. It involves both natural as well as synthetic polymers in formulation. First an aqueous drug polymer solution is dispersed in a lipophilic organic continuous phase under vigorous stirring to form a homogeneous mixture [63]. The continuous phase consists of polymer solution that eventually encapsulates the drug present in dispersed aqueous phase as shown in Fig. (8). This primary emulsion is then subjected to sonication before addition to aqueous solution of polyvinyl alcohol (PVA) that results in the formation of double emulsion [64]. The later double emulsion formed is subjected to solvent evaporation or solvent extraction process by maintaining emulsion at reduced pressure or stirring so that volatile organic phase evaporates out. The emulsion is added to the large amount of water (with or without surfactant) into organic phase diffuse out and the solid microspheres are separated out by filtration and washing [65].

Suspension polymerization: Also known as bead or pearl polymerization, this method involves the heating of monomer or mixture of monomers along with drugs as droplets dispersion in a continuous aqueous phase containing an initiator and other additives. This method can be carried out at low temperature since continuous external phase is normally water through which heat can easily dissipate [67]. Suspension polymerization leads to the formation of high molecular weight polymer at relatively faster rate. However it leads to the association of polymer with unreacted monomer and other additives thus creating a major disadvantage [68].

•

Emulsion polymerization: This method is similar to suspension polymerization but differs in one step. In this method, the initiator present in the aqueous phase later on diffuse to the surface of the micelles or emulsion globules [69].

Polymerization techniques: This technique is further classified into two types: •

Normal polymerization method

•

Interfacial polymerization method

Normal polymerization method: This method uses different techniques such as bulk, suspension precipitation, emulsion and miceller polymerization process. •

Bulk polymerization: A monomer or a mixture of monomer containing an initiator is first heated to initiate the polymerization reaction and carry out the process. The initiator or catalyst facilitates or accelerates the rate of reaction. The polymer thus obtained is molded or fragmented as microspheres. Drug must be either adsorbed or added during the process of polymerization for better encapsulation efficiency. This method leads to the formation of pure

polymer but suffers a difficulty in dissipating heat of reaction which adversely affects the thermolabile active ingredients [66].

Interfacial polymerization method: As the term denotes, it involves reaction of monomers at the interface between the two immiscible liquid phases to form a polymer film enveloping the dispersed phase. Two reaction monomers employed involve one which is soluble in continuous phase and the other being dispersed in continuous phase. The continuous phase is generally aqueous in nature throughout which the second monomer is emulsified. Monomers in either phase diffuse and polymerize rapidly at the interface [70]. Coacervation method: This technique is simple and broadly applicable. The aqueous solution of drugs to be encapsulated is dispersed in a water immiscible solvent containing the dissolved polymer. The polymer layer gets deposited on the surface of the aqueous droplets on subsequent evaporation of the volatile solvent [71]. Solvent Removal: Also known as non-aqueous method of microencapsulation, it is particularly suitable for water labile polymers such as the polyanhydrides. In this method, a dispersion or solution of drug is made in a selected polymer in a volatile organic solvent like methylene chloride. This mixture is then suspended in oil phase containing surfactant and volatile organic solvent. Once the polymer solution is



Fig. (8). Diagrammatic representation of double emulsion method.

poured into oil phase, petroleum ether is added and stirred until solvent is extracted into the oil solution. This results in the formation of microparticles which are then dried in vacuum [72].

Table 2.

Phase Inversion Microencapsulation: This is another method of preparation of microspheres which involves the addition of drug to a diluted polymeric solution (usually 15% w/v in methylene chloride) [73]. This mixture is then

Various techniques for microspheres preparation [76-81].

Process

Coating polymers/ Materials

Suspending Medium

Advantages

Disadvantages

Spray-drying

Hydrophilic or hydrophobic polymers

Air, nitrogen

Rapid, reproducible and easy to scale up, feasibility of process under aseptic conditions, suitable for both batch and bulk manufacturing

Chances of crystallinity lose by polymers on fast drying, temperature-sensitive compounds are degraded and control of the particle size is difficult

Solvent evaporation


Suitable for thermolabile and hydrophobic compounds.

Not suitable for high hydrophilic drugs since the drug may not be dissolved in the organic solvent and/or may diffuse into the continuous phase during emulsification, leading to a great loss of drug.

Hot melt microencapsulation


Organic/ aqueous

Reproducible with respect to yield and size distribution, also Aqueous/ organic

suitable for the water labile polymers, e.g. poly

Not suitable for thermolabile substances.

anhydrides. Single emulsion technique


Double emulsion technique


Aqueous/ organic

Polymerization technique

Hydrophilic or hydrophobic monomers

Aqueous/ organic

Highly spherical polymer microspheres can be obtained with monodispersity in size and high drug encapsulation efficiency

Coacervation method

Hydrophobic polymers or hydrophilic polyelectrolytes

Organic/ aqueous

Simple and utilizes aqueous system for the preparation

Solvent removal method


Organic

Suitable for temperature sensitive compounds as there is no use of elevated temperature

Phase inversion method/wet inversion method


Aqueous/ organic

Aqueous/ organic

Simple and easy

Excessive exposure of active ingredient to chemicals which degrades them.

Suitable for aqueous soluble drugs, peptides, proteins and the vaccines. This method can be used with both the natural and synthetic polymers.

Simple and fast process, involves relatively little loss of polymer and drug

The particle formation process is quite complicated and influenced by a host of process parameters.

Organic


Table 3.

S. No.

1.

2.

List of recent patents on microspheric formulation.

Patent No.

United States Patent 6238705


Active Ingredients

Protein

Protein

3.


4.

Therapeutic agents such as steroids (estradiol, testosterone, prednisolone, United States Patent 6458387 dexamethasone, hydrocortisone, lidocaine base, procaine base)

5.

6.

7.

Singh et al.

United S tates Patent 5462866



Protein factors

Living cells such as islets of Langerhans

-

Living cells

Method (s) for Preparation

Work Done

Release Pattern

Reference

Ionic gelation

In the present invention the authors prepared a formulation for the sequestration and sustained delivery of an active ingredient in the form of porous particles. The formulation comprises of the product of the controlled dehydration of particles formed by the reaction of a polymeric anionic material with a polyvalent cation. This composition was then loaded with an active ingredient by soaking the prepared particles in a solution of the active ingredient which were then dehydrated. Then again these loaded particles must be soaked in a solution of a polymeric cationic material, to form particles providing the controlled release of the active ingredient.

Sustained release

[82]

Ionic gelation

The present invention deals with the use of unmodified alginate (a class of anionic polysaccharides) hydrogels for the preparation of sustained release protein loaded beads. These protein containing unmodified biodegradable and biocompatible alginate hydrogels are formed in a timedelayed manner whereby the materials gels and release the loaded therapeutic protein for an extended period of time.

Mucoadhesive sustained release

[83]

Ionic gelation

The present invention deals with the unique formulation method for the preparation of a convenient multicomponent water soluble polymeric film or microparticulate vehicle for the delivery of protein factors for appropriate therapeutic effects, i.e. angiogenesis for sustained period of time, depending upon the release characteristics of the polymeric matrix.

Sustained release

[84]

Complexation process

In this invention various methods of formation of sustained release microspheres of therapeutic and/ or diagnostic agents was provided. The microspheres produced had a smooth surface with a plurality of channel openings having a diameter of less than 1000 angstroms. The microspheres were prepared by either chemical crosslinking or thermal crosslinking method using macromolecule (a protein or nucleic acid) and at least one water soluble polymer which was a carbohydrate based polymer.

Sustained release

[85]

Polymerization method

This invention details about the method and apparatus for producing uniform microspheres from polyanion and polycation monomers which may range from 200 to about 500 or larger spheres. The method involves the mixing the droplets of a polyanion solution and the stream of polycation solution under polymerization conditions at minimal impact velocities to form uniform polymeric semipermeable microspheres containing biological material such as islets of Langerhans.

Sustained release

[86]

Chemical cross linked method

The present invention facilitates production of small, uniformly sized polymeric microspheres in a manner not limited, in terms of obtainable size range, by the viscosity or density of the structural polymer. This process involves the generation of spherical beads or particles of a suitable template polymer such as polyvinyl alcohol, and crosslinking them having desired or predetermined size. This “template” polymer refers to a soluble polymer that is used to create temporary particle forms (porous or nonporous). Another polymer called “structural” polymer invades or surrounds the temporary polymer and creates the permanent structure of the particle following cross linking via covalent bonds.

Sustained release

[87]

Ionic gelation

This invention generates porous structures, different methods for making the porous structures, and methods for using the porous structures as substrates to grow living Mucoadhesive sustained cells. The porous structure comprises of chitosan, alginate release and divalent metal cations, wherein: (a) the chitosan is ionically linked to the alginate; and (b) the structure is porous.

[88]



(Table 3) contd…..

S. No.

8.

9.

10.

11.

Patent No.

United States Patent Application 20040071780


United States Patent Application 20100160246


13.

WIPO Patent Application WO/2010/0236 89

15.


Viable cells such as neurosecretory cell United States lines, -cell-derived cell Patent 5871985 lines, fibroblasts, myocytes, and glial cells.

12.

14.

Active Ingredients



Recombinant protein

Antitumor substances

Polymer dispersion technique


Chemotherapeutic agent

-


Tretinoin

Dyes, perfumes etc.

Radio imaging agents, agro chemicals, etc.


Work Done

Release Pattern

Reference

This invention involves the formation of non cross linked chitosan core matrix device containing viable cells encapsulated in vehicles intended for implantation into an individual. The device is used for maintenance, growth, proliferation, and differentiation of viable cells entrapped between chitosan particles of core matrix.

Mucoadhesive sustained release

[89]

The present invention involves the preparation of polycaprolactone and chitosan coated epichlorohydrincrosslinked alginate (PACE-A) microspheres using reproducible polymer dispersion technique. The coating Mucoadhesive of chitosan and polycaprolactone increases the mechanical sustained release strength and stability and modify the time of antigen release. The microspheres are used as a carrier system for the systemic and mucosal delivery of both macromolecules and small molecules.

[90]

The invention involves the preparation of drug loaded pH sensitive microspheres and various novel methods used for the same. The microspheres prepared are used for the treatment of hepatic tumors. These microspheres are capable of releasing the loaded substance at a predetermined pH in an effective manner and reduce the damage to surrounding healthy tissue.

[91]

Sustained release

This invention refers to the use of chemotherapeutic agent Mucoadhesive loaded microspheres consisting of a water-insoluble, sustained water-swellable polymer anionically charged at pH 7, and release is used in the treatment of a brain tumor.

[92]

The invention involves preparation and use of thermally expandable thermoplastic microspheres consisting of a polymer shell. The polymer shell is made from ethylenically unsaturated monomers (40-70 wt % of acrylonitrile, 5-40 wt % of methacrylonitrile, 10-50 wt % of monomers selected from the group consisting of esters of acrylic acid, esters of methacrylic acid and mixtures thereof) encapsulating a propellant (at least one of methane, ethane, propane, isobutane, n-butane and neopentane).

Sustained release

[93]

In this invention, a substantially porous, micro-particle is formed comprising of therapeutically effective amounts of tretinoin and ethyl cellulose. It provides different methods of preparation of microparticles comprising of a polymer of natural or semisynthetic origin with a pore size that ensures a desired sustained or controlled release of tretinoic acid upon topical application.

Sustained release

[94]

The present invention relates to the generation of microcapsules with a mean diameters of 0.1-5 mm consisting of a membrane and a matrix containing at least one active principle and obtainable by a series of steps. First step involves a matrix formation from gel formers, Mucoadhesive anionic polymers and active principles and second step sustained involves the introduction of this matrix dropwise into release aqueous chitosan solutions. Here the use of thermo gelling natural heteropolysacharides or proteins together with anionic polymers form membranes in the presence of cationic chitosan that further enables new microcapsules formation.

[95]

The present invention is related to the production of microspheres by a process that includes passing a polymer and solvent containing composition through an orifice into a second composition containing water, microspherestabilizing agent. The whole process takes place under at least one of conditions wherein (a) the first composition flows through a first conduit along a first path and exits the first conduit at the orifice, the second composition flows through a second conduit along a second path in an upstream to downstream direction, the first conduit is connected to the second conduit and terminates at the orifice, the first and second paths being orientated at an

[96]

Sustained release


Singh et al.

(Table 3) contd…..

S. No.

Patent No.

Active Ingredients


Work Done

Release Pattern

Reference

angle relative to each other, wherein 0°