An Overview on Advanced Parenteral Drug Delivery System in Clinical Disease Management

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Kapoor Shweta

Kapoor Shweta

Therapeutic effect of drug depends on method by which it is delivered. Number of drug delivery system (DDS) has been developed from time immortal. One of the DDS is parenteral drug delivery system, which is firstly reported in the mid 19

th

century by Alexander wood.

Since then a number of technological advances have been made in the area of parenteral drug delivery leading to the development of sophisticated systems that allow drug targeting and the sustained or controlled release of parenteral medicines. The purpose of this review is to discuss and summarize some of the interesting technologies of parenteral drug delivery system that can be helpful in the management of clinical diseases. The article highlights important applications in the design of various novel delivery systems like liposomes, niosomes, nanoparticle and microparticles, cyclodextrins, emulsions, prodrug and polymeric micelles

Introduction

The method by which a drug is delivered can have a significant effect on its efficacy. Some drugs have an optimum concentration range within which maximum benefit is derived and concentrations above or below this range can be toxic or produce no therapeutic benefit at all. On the other hand, the very slow progress in the efficacy of the treatment of severe diseases, has suggested a growing need for a multidisciplinary approach to the delivery of drug to targets tissues. From this, new ideas on controlling the pharmacokinetics, pharmacodynamics, non-specific toxicity, immunogenicity, biorecognition and efficacy of drugs were generated. These new strategies, emerges the need of called drug delivery systems (DDS), which are based on interdisciplinary approaches that combine polymer science, pharmaceutics, bioconjugate chemistry and molecular biology. To minimize drug degradation, to prevent harmful side-effects, to increase drug bioavailability & the fraction of the drug accumulated in the required zone, various drug delivery and drug targeting systems are in continuous research. These paper emphasis on the study of advanced parenteral drug delivery system with its application (Table 1) in reference of detail discussion of liposomes, niosomes, nanoparticles & microparticles, cyclodextrins, emulsions, prodrug (ADEPT, Polymer drug conjugates) and polymeric micelles.


1) Liposomes

Liposomes were discovered in the mid 1960s

1

and originally studied as cell membrane models, since then they have been gained recognition in the field of drug delivery. Liposomes are formed by the self-assembly of phospholipid molecules in an aqueous environment, shown schematically in Figure 1, the amphiphilic phospholipid molecules form a closed bilayer sphere in an attempt to shield their hydrophobic groups from the aqueous environment while still maintaining contact with the aqueous phase via the hydrophilic head group. The resulting closed sphere may encapsulate aqueous soluble drugs within the central aqueous compartment (Figure 1a) or lipid soluble drugs within the bilayer membrane (Figure 1b). Alternatively, lipid soluble drugs may be complexed with cyclodextrins and subsequently encapsulated within the liposome aqueous compartment

2

.


The encapsulation of drugs with liposomes alters drug pharmacokinetics and this may be exploited to achieve targeted therapies. Alteration of the liposome surface is necessary in order to optimize liposomal drug targeting and to achieve prolonged circulation times


liposome size between 70-200nm is necessary

3-11

. Liposomes are the most widely studied modern drug delivery system because of its amazing application for the management of following diseases.


i) Liposomal anticancer agent -

The use of liposomes as anticancer drug delivery systems was originally hampered by the realization that liposomes are rapidly cleared from the circulation and largely taken up by the liver macrophage

12

. It was observed that doxorubicin loaded stealth liposomes circulate for prolonged periods

13

, accumulate

14

and extravagate within tumours & also improve tumoricidal activity

15

in mice. In one study it has been reported that in patients, liposomal doxorubicin accumulates within Kaposi’s sarcoma lesions

16

and produces a good therapeutic response

17-18

. Liposomal doxorubicin is now licensed as Caelyx

19

, for the treatment of Kaposi’s sarcoma. This formulation is currently in clinical trials for ovarian cancer and could be approved shortly for use in ovarian cancer patients who have failed to respond to paclitaxel and cisplatin

20

.

ii) Liposomes as vaccine adjuvants -

Liposomal vaccines can be made by associating microbes, soluble antigens, cytokines

21

or deoxyribonucleic acid (DNA)

22

with liposomes, the latter stimulating an immune response on expression of the antigenic protein

23

. Liposomes encapsulating antigens, which are subsequently encapsulated within alginate lysine microcapsules

24

to control the antigen release and to improve the antibody response. Liposomal vaccines may also be stored dried at refrigeration temperatures for up to 12 months and still retain their adjuvanticity

25

.

iii) Liposomal anti-infective agents -

Liposomal amphotericin B (Ambisome)

26

, used for the treatment of systemic fungal infection. This is the first licensed liposomal preparation

27

. It was observed in one study that liposomal amphotericin B, by passively targeting the liver and spleen, reduces the renal

28

and general toxicity of the drug at normal doses.


2) Niosomes

Niosomes are unilamellar or multilamellar vesicles, where in an aqueous solution is enclosed in highly ordered bilayer made up of nonionic surfactants with or without cholesterol (chol) and dicetyl phosphate and exhibit a behavior similar to liposomes

in-vivo


29

. They can be used in the treatment of cancer and also used as vaccine adjuvant. Some of its applications are discussed here.

i) Anticancer niosomes
-

Anticancer niosomes, if suitably designed will be expected to accumulate within tumours. For example niosomal encapsulation of methotrexate

30

and doxorubicin increases drug delivery to the tumour and tumoricidal activity. It was reported that doxorubicin niosomes having size 200nm with a polyoxyethylene (molecular weight 1,000) surface are rapidly taken up by the liver

31

and accumulate to a lesser extent in tumour, this technology may prove advantageous for the treatment of hepaticneoplasms. It was also observed that the activity of other anticancer drugs, such as vincristine

32

, bleomycin

33

, plumbagin and a plant derived anticancer agent

34

are improved on niosomal encapsulation.

ii) Niosomes at targeted site

-

Uptake by the liver and spleen make niosomes ideal for targeting diseases manifesting in these organs. One such condition is leishmaniasis and a number of other studies

35-36

has shown that niosomal formulations of sodium stibogluconate improve parasite suppression in the liver

37

spleen and bone marrow

38

. Niosomes may also be used as depot systems for short acting peptide drugs on intramuscular administration

39

.

iii) Niosomes as vaccine adjuvants

It was studied that niosomal antigens are potent stimulators of the cellular and humoral immune response

40-41

. The formulation of antigens as a niosome in water-in-oil emulsion further increases the activity of antigens

42

and hence enhanced the immunological response.


3) Nanoparticles and Microparticles

Nanoparticles and microparticles are usually prepared by the controlled precipitation of polymers solubilised in one of the phases of an emulsion

43-45

. Precipitation of the polymer out of the solvent takes place on solvent evaporation, leaving particles of the polymer suspended in the residual solvent. For particulate dispersions, the required particle size of nanoparticles lies between the range of 30-500nm while for microparticles in excess of 0.5micron. Their applications in management of diseases are discussed below.

i) Tumor targeting nanoparticles and microparticles

-

The accumulation of non-stealth doxorubicin nanoparticles within the Kupffer cells of the liver may be used to target hepatic neoplasms indirectly

46

, this is achieved by providing a depot of drug for killing nearby neoplastic tissue. Microparticles


may also be injected directly into tumours. It was observed that the direct injection of microparticles into solid tumours increases the tumoricidal activity of the drugs 5-fluorouracil

47

and doxorubicin

48

.

ii) Vaccine adjuvants
-

Nanoparticles have also been used as vaccine adjuvants. It was reported that antigens, which adsorbed onto the surface or entrapped in the matrix of polymethylmethacrylate nanoparticles induces an enhanced immunological response

49

. For example polymethylmethacrylate nanoparticles containing the influenza antigen may protect people against disease to a greater extent than the antigen alone.

iii) Other applications

-

Restenosis, defined as the re-obstruction of an artery following procedures such as angioplasty or artherectomy may be treated by the local application of dexamethasone-loaded polylactic acid co-glycolic acid nanoparticles

50

. Cyclosporin A, an immunosuppressant drug used to prevent graft rejection after transplantation by the inhibition of T-lymphocytes, may be targeted to regional lymph nodes by the intramuscular administration of cyclosporin A polylactic acid nanoparticles

51

.

In short it can be said that, by virtue of their small size solid nanoparticles provide opportunities for targeted parenteral therapies and may also be used as immunoadjuvants.


4) Cyclodextrins

Cyclodextrins (CDs), with lipophilic inner cavities and hydrophilic outer surfaces, are capable of interacting with a large variety of guest molecules to form noncovalent inclusion complexes. Only the modified cyclodextrins

52

, such as hydroxypropyl b-cyclodextrin (HP-β-CD)

53-54

and sulphobutyl b-cyclodextrin (SBE-β-CD

55

, are regarded as safe for parenteral use. Applications of CDs in parenteral delivery are solubilization of drugs, reduction of drug irritation at the site of administration, and stabilization of drugs unstable in the aqueous environment.

i) As a solubility enhancer
-

Singla et al discussed the use of CDs to enhance the solubility and stability of paclitaxel in formulations and mentioned that the approach needs further research to overcome the serious limitations of CD-based formulations

56

. It was studied that the solubilizing potentials of both SBE-β- and HP-β-CDs for the drugs melphalan and carmustine were qualitatively similar but the intrinsic reactivities were significantly less with SBE-β-CD

57

. Formation of a stable, water-soluble dexamethasone complex with sugar branched β-CDs suggested the potential of these CDs as excellent carriers in steroidal injectable formulations

58

. It was observed in one study that an aqueous phenytoin parenteral formulations containing HP-β-CD exhibited reduced drug tissue irritation and precipitating tendency because their pH values were significantly closer to the physiological value (7.4)

59

. SBE-β-CD was found to be useful in the preparation of parenteral solutions of poorly water-soluble drugs

60

.


5) Emulsions

Emulsions are usually used as a means of administering aqueous insoluble drugs by dissolution of the drugs within the oil phase

61-64

or to prevent drug hydrolysis or drug uptake by infusion sets

65

.


It is recommended that emulsions destined for the intravenous (IV) route have a submicron droplet size

66

, although emulsions with a droplet size of 10mm have been used parenterally. Emulsions are useful to deliver drug at particular site and helpful to reduce drug toxicity.

i)

As drug targeting systems


It was observed that emulsion formulations, with a droplet size of 100 to 200nm, usually result in high drug liver uptake on IV injection 67-68 . Emulsions are helpful to deliver drug at particular site, active targeting may be achieved by conjugating antibodies to the distal ends of the polyoxyethylene chain emulsifiers, provided the emulsion droplets have a submicron droplet size 69 , as shown schematically in Figure 2.

ii) Reduces drug toxicity

-

Emulsions may also be used to reduce drug toxicity. For example use of a water in oil emulsion of amphotericin deoxycholate, as opposed to a solution, reduces the incidence and severity of renal impairment and chills in patients while still maintaining the antifungal efficacy of the drug

70

.

6) Prodrugs

A prodrug is a pharmacological substance, which is administered in an inactive form. Once administered, it is metabolized in the body

in vivo

into the active compound. The use of prodrugs in cancer chemotherapy as a means of targeting relatively toxic compounds to specific areas of pathology is enjoying renewed activity. Two of the technologies being evaluated at present are antibody directed enzyme prodrug therapy (ADEPT) and the use of polymeric prodrugs.

i)

ADEPT


-

The principle behind the ADEPT approach is shown schematically in Figure 3. Basically, an antibody-enzyme conjugate is administered intravenously, localizes in tumour tissue and subsequently activates an administered prodrug predominantly within such tumours

71

.
Prodrug activating enzyme is carboxypeptidase G2. In short is I is worthy to say that proof of principle studies of the ADEPT approach have already been conducted in the clinic, although problems such as the immunogenicity of the non-human enzyme and the long half life of the active drug leading to toxic sequelae still remain to be addressed.

ii) Polymeric prodrugs -

Drug delivery with polymeric prodrugs, first envisioned 25 years ago

72

, involves the use of an active substance and possibly a targeting moiety, both linked via spacers to a water-soluble polymeric backbone. From this basic blueprint a number of polymer drug conjugates used for cancer chemotherapy and have been synthesized with cleavable drug polymer linkers. These include soluble polymeric prodrugs of daunorubicin

73

, doxorubicin

74

, cisplatin and 5-fluorouracil

75

. Passive tumour targeting with polymer drug conjugates improves the tumoricidal activity of anticancer agents

76

. Distribution to potential sites of toxicity, such as the distribution of doxorubicin to heart tissue

77

, is also decreased with polymer drug conjugates. In short, polymer drug conjugates have progressed from an elegant scientific concept to the clinic and may result in a new form of therapeutics for routine use.

7) Polymeric micelles

Amphiphilic block copolymers such as the Pluronics (polyoxyethylene polyoxypropylene block copolymers) self-assemble into polymeric micelles. For drug delivery purposes, hydrophobic drugs may be solubilised within the core of the micelle

78-79

or alternatively conjugated to the micelle-forming polymer

80

. They thus circulate for prolonged periods

81

and deliver more of the drug to tumour tissue when compared with administration of the drug in solution

82

. This property makes them a choice for the treatment of various diseases.

i) As tumoricidal and targeted agent

It was noted in one study that Pluronic micelles solubilizing epirubicin and doxorubicin increase the tumoricidal activity of these anticancer drugs

83

. Polymeric micelles bearing targeting ligands may also be used as drug targeting agents. For example haloperidol pluronic micelles targeted to the brain by conjugation with brain specific antibodies

84

.

Conclusion

The past 10 years have witnessed a real explosion in the number of technologies available to control drug biodistribution. These have been exploited to produce particulate, soluble, implantable drug delivery systems, which accumulates drug in the desired area (in-situ) of the anatomy or pathology. Drug delivery technologies such as those discussed above may be used to control drug delivery on parenteral administration. Some of the newer systems, such as liposomal doxorubicin, may soon be licensed for new indications. Additionally, the beginning of the next century may see some new formulation or drug delivery initiatives, such as the polymer drug conjugates and possibly the ADEPT systems, transformed into commercial products. Liposomes may also one day open the door to routine gene therapy in the clinic. Parenteral drug delivery systems have grown to become important technology platforms used by companies in the pharmaceutical in recent years. Parenteral in-situ drug delivery system is good study object. So it is important to study parenteral drug delivery system as it is provides rapid treatment objective to save unvaluable life of human being.

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Table 1: Main applications of Parenteral drug delivery system

S.no
Drug delivery technology  Main applications
1 Liposome Passive tumour targeting

Vaccine adjuvants

Passive targeting to lung
endothelium in gene delivery

Targeting to regional lymph
nodes

Targeting to cell surface
ligands in various organs/areas

Sustained release
depot at point of injection

2 Niosome Passive tumour targeting

Vaccine
adjuvants
Sustained release depot at point of injection

3 Nanoparticle Passive
tumour targeting
Vaccine adjuvants
4 Microparticle Sustained release depot at
point of injection

Vaccine adjuvants

5 Cyclodextrin Lipophilic drug solubilisation for
Parenteral use
6 Emulsion Lipophilic drug
administration vehicles

Targeting to cell surface antigens

7 Prodrug

i) ADEPT

ii) Polymer drug
conjugates

 


 

Active tumour
targeting

Polymer drug
conjugates

8 Polymeric micelles Active tumour targeting

Liposomes 1a) = aqueous soluble drug encapsulated in aqueous compartment 1b) = a hydrophobic drug in the liposome bilayer.

Figure 1: Liposomes 1a) = aqueous soluble drug encapsulated in aqueous compartment; 1b) = a hydrophobic drug in the liposome bilayer.

Targeted emulsion droplet bearing covalently linked antibodies

Figure 2: Targeted emulsion droplet bearing covalently linked antibodies

Image Image

Figure 3: Principle behind ADEPT approach to drug targeting. Step 1 — injection of

antibody enzyme conjugate; step 2 — activation of the prodrug

About Authors:

Kapoor Shweta* , Ramoliya Rajesh, Shrivatava Satyaendra, Dubey Darshan, Jain Sanjay

Kapoor Shweta

Kapoor Shweta

* For correspondence 

Smriti College of Pharmaceutical Education, 4/1 Piplia Kumar Kakad, Mayakhedi road,

Indore (MP) 452010 Tel: +91-731-2802262 Fax: +91-731-2802467

E-mail- kapoorscope@gmail.com, Kapoor.sk@rediffmail.com

Image

Shrivatava Satyaendra

Dubey Darshan

Dubey Darshan

Volumes and Issues: 
Reviews: 

Comments

P.Praveen Kumar's picture

Pharmacists as valuable members of the multi -professional health care team are one of the first sought by patients, and the last one with whom they interact if a prescription is received. On this World, pharmacists throughout the Commonwealth are urged to ‘keep the promise’ to their patients by strengthening the patient-pharmacist relationship. This is achieved through listening to patients, providing advice on medicines, participating in the fight against stigma and discrimination associated with the disease AIDS and encouraging patient concordance with prescribed treatment regimes Pharmacy associations must ‘keep the promise’ by ensuring their representation on national decision-making bodies and should collaborate with academic institutions, NGOs and the pharmaceutical industry to kept a breast of information on the most recent medicines approved for the treatment of the disease. The active part played by some non-Governmental organizations in bringing out public interest litigations against such cases of discrimination and the judicial pronouncements by courts in support of the rights of such people has partly helped in alleviating the misery of the affected persons. People Living with HIV/AIDS have provided the best response to the stigma and the denial that shroud the epidemic. Every pharmacist may be involved in some aspect of the campaign. Community pharmacists in particular are ideally situated to play an important role in prevention of HIV infection. Traditionally, condoms have always been sold in pharmacies, but the role of the pharmacist goes beyond supply of condoms. Pharmacists educate consumers and supply information. This is important in the promotion of safe and healthy sexual behaviour.