microspheres as drug delivery system


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MICROSPHERES AS DRUG DELIVERY SYSTEM Dr. Issra H. Al-Ani Al-Ahliyya Amman University Jordan


DEFINITION Microspheres can be defined as solid, approximately spherical particles ranging in size from 1 to 1000 µm. They are made from polymeric, waxy, or other protective materials such as starches, gums, proteins, fats and waxes and used as drug carrier matrices for drug delivery. Natural polymers as albumin and gelatin are also used in preparation of microspheres.

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In addition, some related terms are used as well. For example, “microbeads” and “beads” are used alternatively. Sphere and spherical particles are also employed for a large size and rigid morphology

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Biodegradable microspheres have the advantage over large polymer implants in that they do not require surgical procedures for implantation and removal. They are degraded in the body to biocompatible materials.

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Biodegradable microspheres are used to: *Control drug release rates. *Conserve the stability of some drugs as proteins and peptides. *Also to target drugs to specific sites in the body, thereby optimizing their therapeutic response, decreasing toxic side effects, and eliminating the inconvenience of repeated injections. *They are also used in gene delivery and in diagnostic materials.

Examples on polymers used in microspheres CDDS : 

Examples on polymers used in microspheres CDDS 1- Chitosan MS. 2-Gelatine MS. 3-Polyadipic anhydride MS 4-Gellan- gum MS. 5-Polypeptide MS. 6-Albumin MS. 7-Poly lactic acid (PLA) MS. 8-Poly lactic - co- glycolic acid (PLGA) MS.


ADVANTAGES OF MICROSPHERES IN DRUG DELIVERY 1. Controlled release delivery Biodegradable microspheres are used to control drug release rates thereby decreasing toxic side effects, and eliminating the inconvenience of repeated injections. Biodegradable microspheres have the advantage over large polymer implants in that they do not require surgical procedures for implantation and removal. PLGA copolymer is one of the synthetic biodegradable and biocompatible polymers that has reproducible and slow-release characteristics in vivo .

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Products in the market for control drug delivery: Luproline (Lupron Depot) (depote susp.7.5 mg, 4 months, prostate cancer) Goseriline acetate (Zoladex) in the United States (prostate cancer and breast CA) leuproline acetate (Enantone Depot), Bromocriptine (Pariodel LA) in Europe.

2.Protein/Peptide Stability : 

2.Protein/Peptide Stability The key to the success of proteins to be prepared as pharmaceutical products is to have in place an efficient drug delivery system that allows the protein drugs to gain access to their target sites at the right time and for the proper duration. Four factors must be considered to fulfill this goal: route of administration, pattern of drug release, method of delivery, and fabrication of formulation. Microspheres help to protect proteins because they are not allowed to react with anything until the polymer is degraded, thus minimizing the contact with solutions that could cause the proteins to react.

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Examples: 1- Albumine (prototype). 2- Vaccines (HI), diphtheria toxoid (DT), tetanus toxoid (TT), and pertussis toxin (PT) in poly (lactic acid) and PLGA microspheres were prepared by spray drying, all antigens were found to maintain their immunogenicity. 3- lyzozymes.

3.Drug targeting : 

3.Drug targeting Drug targeting could be the greatest advantage of microspheres. Most drugs are targeted in the body to give desired results either in specific tissues or organs. A good example of how microsphere technology could be implemented is targeting cancer cells in chemotherapy, as drugs and chemical agents attack cancer cells but have a toxic effect on healthy ones which could very easily cause the cells to die.

A-Passive Targeting: : 

A-Passive Targeting: Passive targeting depends on the size of microspheres. The lung’s capillaries will let the passage of particles less than seven microns (micrometers) through. If one wants the drug to be released into the lungs then the correct size would be around ten microns since they would then be captured in the capillaries . Eg. Carboplatine microspheres .

B- Active targeting: : 

B- Active targeting: Intigrin, Lectin, immunoglobulins, lipoproteins, monoclonal antibodies, specific peptides and receptor antagonists were all used as ligands conjugated with microsperes as leading molecules for precise targeting

4. Gene delivery: : 

4. Gene delivery: Encapsulation of therapeutic agents such as DNA in microspheres protects the agent from enzymatic degradation, enhances tissue specificity due to localized delivery, eliminates the need for multiple administration, and allows for controlled and sustained delivery.

5. Microspheres in diagnostic materials : 

5. Microspheres in diagnostic materials Gamma emitters such as 99Tc and 131I have been incorporated with microspheres for diagnostic purposes. Radio labeling of microspheres is usually achieved either during or after their preparations. Although the former method is still more commonly used in medicine, the latter is preferred, especially for shorter-lived radioisotopes, because stability and logistical problems are in this way minimized.


METHODS OF PREPARATION OF MICROSPHERES Microspheres have been prepared by three basic methods as well as other modified methods: 1- Solvent extraction / evaporation method (single and double emulsification) 2- Coacervation or phase separation. 3-Spray drying. 4- Modified methods.

1- Solvent extraction/evaporation method: : 

1- Solvent extraction/evaporation method: Oil phase (polymer + solvent) is injected into the aqueous phase (water + surfactant), the solvent dissolves into the aqueous phase and evaporates at the air-liquid interface. This method was successfully used for numerous of water insoluble and slightly soluble drugs encapsulated in microspheres such as lidocaine,naletrxone , bupivacaine, 5-aminosalicylis acid, flurbiprofen, all-trans retinoic acid and testosterone.

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This method was successfully used for numerous of water insoluble and slightly soluble drugs encapsulated in microspheres such as lidocaine, naletrxone , bupivacaine, 5-aminosalicylis acid, flurbiprofen, all-trans retinoic acid, testosterone This method is suitable for such kind of drugs where the water soluble drugs may infiltrate to the aqueous phase and decrease its entrapment efficiency.

2- coacervation phase separation: : 

2- coacervation phase separation: This method is based on dispersion of drug as solid or organic solution in organic polymeric solution, then addition of the second solvent in which the polymer is insoluble where phase separation occurs and polymer loaded with drug precipitate as microspheres. BSA is an example prototype for this method.

3-Spray drying: : 

3-Spray drying: In this technique the drug and polymer are mixed in a solvent system, then the solvent is evaporated by spraying the solution leaving the polymeric particles loaded with the drug. This method generates heat so it is not suitable for heat sensitive drugs[116]. Fluconazole and tetracycline hydrochloride are examples on drugs prepared by this method.


RELEASE OF DRUG FROM MICROSPHERES Microspheres belong to the monolithic system which refers to a rate controlling polymer matrix through which the drug is dissolved or dispersed. In contrast, a reservoir device consists of shell like dosage form with the drug contained within a rate controlling membrane. In non biodegradable polymer: the drug is released by dissolution into the polymer and then diffusion through the polymer wall . Eg: levonorgestrel (Norplant®) 5‑year contra­ceptive delivery system

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Biodegradable polymers: The in vivo elimination time is determined by, the nature of the polymer chemical linkage, the solubility of the degradation products, the size, shape and density of the device, the drug and additive content, the molecular weight of the polymer, and the implantation site.

Approaches to modify drug release from MS : 

Approaches to modify drug release from MS 1- Naltroxone (Vivitrol TM ) microspheres(PLA-PLGA) is the first approved alcohol dependence medication in USA. Mechanism: the release pattern of naletroxone as a result of: absorbing water and swelling immediately after injection where the near-surface drug is released first. - As water absorption continues, hydrolysis starts and after several days physical erosion begins . - further drug diffused to the surrounding resulting in sustained release of medication with the elimination of water and carbon dioxide as degradation products of the polymer matrix.

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2- DURIN TM It has successfully achieved controlled, zero-order drug release for up to 6 months in vivo. Because of the broad range of physical properties and degradation times that can be designed into biodegradable polyesters, DURIN implants can deliver a wide variety of drugs including both hydrophobic and hydrophilic compounds as well as small and large molecules.

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3- Different patterns of release could be achieved through other modifications as: coating of microspheres with other polymer for further prolongation of release time. Eg:algenate-polyethylenimine coated alginate microspheres loaded with furosemide. The membrane acted as a physical barrier to drug release from the beads. Alginate coating of algenate-polyethylenimine beads further prolonged the release of the drug by increasing membrane thickness and reducing swelling of the beads possibly by blocking the surface pores.

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4- Another approach of modifying the release time of drug from microspheres is by using blend of polymers with different properties like the use of blend of PLGA and polyoxyethylene . Also, PLGA microspheres made of different molecular weights of the polymer have been prepared. Three molecular weights (6,000, 30,000 and 41,000) were blended to achieve long term release where the higher molecular weights degrade more slowly. Zero order release pattern with very low or no burst effect was achieved

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Caractarization of ms

Characterization of microspheres : 

Characterization of microspheres 1- Yield values and loading efficiency: The obtained Wt. of microspheres Yield value = -------------------------------------------- x 100 Theoretical Wt. to be prepared Actual amount of drug obtained by extraction Loading Efficiency = --------------------------------------------------------------------- x 100 Theoretical amount of drug added in preparation

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2- Microspheres morphology: The morphology the prepared loaded microspheres is analyzed by scanning electronic microscope (SEM) after palladium/ gold coating of the samples on an aluminum stub.

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3- Microspheres size distribution: The mean sizes of microspheres is determined using several methods like laser diffractometry method.

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4- Bulk density measurement: Bulk density prepared microspheres was measured using different methods like dipping method.

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Glass transition temperature (Tg) is measured by DSC for the blank (unloaded) and the prepared loaded microspheres . 5- Measurement of glass transition temperatures (Tg) by differential scanning calorimetry (DSC):

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6- degree of hydration: is measured to evaluate water uptake by the system as a first step in biodegradation.

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SEM Photos after certain time of in vitro degradation.

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