Need For Liposomal Drug Formulation Biology Essay

Nanoparticles are the solid atoms which are colloidal in nature and their size ranges from 10 to 400nm. They are made up of macromolecular stuffs where the active ingredient ( drug ) is entrapped, encapsulated or incorporated or onto which it is adsorbed or attached. For drugs, big and wide antigenic sequences and immunomodulatory factors liposomes can be used for encapsulation and these serve as powerful bringing vehicles. Liposomes are used to aim the drugs to tumours and therefore stand foring an attractive curative scheme. Thus liposomal drug bringing system is a better manner to administrate drugs so as to avoid any complications and side effects and besides to supply better handiness of the drug.

One of import feature of liposomal preparation is that it can avoid reticuloendothelial system ( RES ) consumption. The decrease in RES uptake leads to increased pharmacokinetic and biological benefits to the chemotherapy under procedure. It imparts better specificity and selectivity and plasma half life is increased with lessening in toxic effects.

Liposomal drugs fluxing in the blood can non exude/extravasate from the blood vass that are integral, alternatively these drug molecules accumulate in the countries where there are discontinuous capillaries like those in tumour tissues. It is known that Kaposi ‘s Sarcoma is a extremely vascularised tumor with capillary escape therefore the belongings of liposomal drug discussed here proves to be helpful in this instance. Liposomes nevertheless besides target the RES and while go arounding in the blood these liposomes bind to the Igs and plasma proteins which leads to RES uptake which is can be utile in instance of immunomodulatory therapy but in most anti-cancer therapies this is non desirable.

History and Development of DaunoXome:

Daunoxome ( liposomal daunorubicin ) is a merchandise originally developed by NeXstar pharmaceuticals and launched in the twelvemonth 1996. The company was so owned by Gilead Sciences in March 1999. DaunoXome was so acquired from Gilead Sciences by ‘Galen ‘ which is a Northern Ireland Pharmaceutical company. DaunoXome is used for the intervention of Kaposi ‘s Sarcoma. Kaposi ‘s Sarcoma was identified in the twelvemonth 1872 by Moritz Kaposi, a Magyar skin doctor. Kaposi ‘s Sarcoma is characterized by mesenchymal tumour which involves blood and lymph vass. There are many discrepancies of this disease. Kaposi ‘s Sarcoma is normally seen in patients with HIV infection. It is going one of the fast growth malignant neoplastic disease among AIDS patients worldwide. DaunoXome demonstrated higher degrees of in vivo stableness and specificity due to which the patients enduring from Kaposi ‘s Sarcoma could profit at higher doses without any important cardiotoxicity. Daunorubicin is an anthracycline antibiotic which induces programmed programmed cell death in cells and it is cell specific.

Preclinical Trials/Studies:

Phase IV Preclinical surveies were performed utilizing DaunoXome ( liposomal daunorubicin ) which is used for handling the patients with AIDS related Kaposi ‘s sarcoma. The topics which were chosen for this survey were eligible if they were HIV positive, had Kaposi sarcoma and were subjected to at least one daunorubicin intervention. From 13 university infirmaries 94 capable files were studied out of which 80 % received cytostatic intervention prior to the first daunorubicin intervention rhythm. The average CD4 lymph cell count was found to be 114/µl and to the 70 % of patients the drug daunorubicin was given as individual chemotherapy. The partial response rate and the complete response rate was found to be 26.5 % and 11.5 % severally in conformity with ACTG ( Aids Clinical Trials Group Oncology Committee ) . In 29 % of the intervention cycles the haematopoietic growing factor was prescribed and after the concluding rating 71 % out of the entire figure of topics were alive and even after administrating high doses of the drug there was no cardiotoxicity observed. Following table illustrates the chief features of the 94 topics with AIDS related Kaposi ‘s Sarcoma prior to the first daunorubicin intervention rhythm:

A stage II survey was conducted on 18 topics and out of these 18, 8 were subjected to higher doses of DaunoXome and 10 were subjected to low doses of the same drug and it was seen that the drug could resistant and relapsed lymphoma without demoing any cardiotoxicity.


56 ( 60 % ) of the topics were enduring from at least one timeserving disease prior to the first daunorubicin intervention rhythm and at baseline the average HIV plasma tonss ( in 54 [ 57 % ] of topics ) and the average CD4 count was found to be 5.38 ± 5.58 and 5.16 ± 5.09 and 114± 20 /µl severally.

80 % of the topics received cytostatic intervention prior to daunorubicin administraion along with disposal of doxorubicin in 27 % ( 26 ) of topics. The average period was of 1 twelvemonth counted from get downing of diagnosing of Kaposi ‘s Sarcoma to the first intervention rhythm of daunorubicin.

Daunorubicin Administration:

In 66 out of the sum ( 94 ) topics Daunorubicin was administered as a individual therapy. In 28 topics daunorubicin was given ab initio to 3/28 chiefly and to 25/28 secondarily with other cytostatic intervention. The average daunorubicin dosage strength was 77 % . Due to the patterned advance Kaposi Sarcoma the dosage in 14 topics was increased from 40 to 60 mg/m? and in 6 of the topics the dosage was decreased due to intolerance or toxicity. The average cumulative dosage and the average intervention continuance for daunorubicin were 674 mg/m? and 258 ± 25 yearss severally.

Concluding Evaluation and Analysis:

The CD4 count was done and it was found that the average CD4 cells were higher than those found at the baseline. In 33 out of the entire figure of topics the plasma viral burden was evaluated and the average values were non different from the baseline. 67 topics were found to be alive during the concluding rating.

Clinical Trials/Studies:

A randomised, open-label clinical survey was conducted at 13 Centres. The survey took topographic point in Canada and USA and was performed on topics holding advanced HIV-related Kaposi ‘s sarcoma which is characterized by the presence of 25 or more mucocutaneous lesions, 10 or more within a month etc. For this intent a regimen doing usage of two drugs was applied as first line cytotoxic therapy. The drugs DaunXome 40mg/m2 and ABV ( doxorubicin [ adriamycin ] 10mg/m2, bleomycin 15U and vincristine 1mg ) were administered every 2 hebdomads intravenously. Adriamycin is a registered hallmark of Pharmacia and Upjohn Co. For the responses to be recorded and assessed the ACTG ( Aids Clinical Trials Group Oncology Committee ) standard was used. The efficaciousness consequences were summarized as follows:

figure 1

Out of 33 ABV, 20 respondents responded by shrinking and/or lessening in figure of lesions which is a more rigorous standards than flattening of lesions.

Out of 27 DaunoXome, 11 respondents did non react by the standards of flattening of the lesions but by different standards. The tumour response to both, Daunoxome and ABV was easy compared with regard to the anatomical sites such as pess, unwritten pit, face, bole, legs etc. utilizing photographic grounds.

Market Blessing:

In the twelvemonth 1996 NeXstar Pharmaceuticals Inc. announced that the concluding selling mandate for DaunoXome which is a drug used for intervention of Aids related Kaposi ‘s Sarcoma will be issued by the 10 member provinces of the EUROPEAN COMMUNITY which include: Germany, Denmark, Greece, Ireland, Sweden, Portugal, Luxembourg, Belgium, Austria, Netherland. The company acquired the blessing from the United States FOOD AND DRUG ( FDA ) to sell the drug in April 1996 and therefore they launched the drug DaunoXome on May 1st 1996. DaunoXome has been approved in CANADA as a deliverance therapy for the intervention of Kaposi ‘s Sarcoma. To broaden or spread out the clinical usage of DaunoXome, Nexstar pharmaceuticals decided to carry on stage II tests on DaunoXome in U.S and Europe for intervention of several other oncological conditions such as lung malignant neoplastic disease, chest malignant neoplastic disease, leukemia, lymphoma etc.

In carnal theoretical accounts it was found that liposomal drug DaunoXome was more effectual than when administered as a free drug intravenously. A stage II test was performed on 11 adult females with anterior untreated metastatic chest malignant neoplastic disease and it was found that DaunoXome is significantly tolerated and has shown anti-tumor activity for handling advanced chest malignant neoplastic disease.

In few states nevertheless, the drug DaunoXome can be prescribed by certain doctors who demand the merchandise even if there is no regulative blessing for that merchandise in that state. However, all the proficient support, aid and counsel is provided by the selling professionals belonging to the company. NeXstar pharmaceuticals priced DaunoXome in few of its market in a currency with regard to that state where such pharmaceuticals are sold but the grosss were affected due to fluctuations in the currency.


In 4 topics under test during the initial phases the systolic blood force per unit area decreased by 20-30mm which gave rise to chest hurting similar to angina pectoris. In 3 of 4 topics under test the symptoms decreased after halting the drug extract and the symptoms did n’t happen once more as the patient was given 100mg cortisol prior the 2nd rhythm. In 1 of the 4 topics the intervention had to be aborted due to the terrible hypotension observed during the start of the 2nd rhythm. However, 1 hr before the intervention with DaunoXome all the topics were given 100mg cortisol so as to avoid any possibility of hypotension. Rate 4 was n’t seen in 15 topics under survey and in 5 topics Grade 3 leucopoenia was seen and grade 1 thrombopenia was observed in non more than 1 capable. Toxic effects like sickness and emesis were observed in 4 topics for 2-3 yearss after the disposal of DaunoXome. One of the topic developed mild alopecia.


In urothelial Transitional Cell Carcinoma ( TCC ) DaunoXome showed no important activity and this consequence was due to the fact that this drug could non handle tumor in this sort of malignance. However in the instance of advanced vesica malignant neoplastic disease 100mg/m? dosage of DaunoXome every 3rd hebdomad is non found to be active. The liposomal DaunoXome is made up of three major constituents and these are: primary compound daunorubicin, cholesterin and distearoylphosphatidylcholine ( DPC ) . Daunorubicin is prepared/formulated as a citrate salt so as to help in drug encapsulation. The consumption in the reticuloendothelial system ( RES ) is minimum because of the smaller atom size and the impersonal nature of DaunoXome which finally consequences in drawn-out drug circulation. Efficiency of DaunoXome ( liposomal daunorubicin ) compared to the conventional daunorubicin was studied utilizing mice with lymphosarcoma and it was found that daunorubicin degrees in plasma were higher in mice treated with DaunoXome than those treated with conventional daunorubicin. The free daunorubicin was quickly excreted than liposomal daunorubicin. However, the tumour drug accretion rate was significantly higher in mice treated with conventional drug than in those treated with Daunoxome ; country under curve values were higher in the DaunoXome intervention than in free daunorubicin intervention.

After the clinical trial/studies were performed it was observed that the more outstanding side effect/toxic consequence caused by DaunoXome is leucopoenia which was seen in 11 % – 17 % of the intervention rhythms. 85 % of the topics that were administered DaunoXome showed marks of class 3/4 neutropenia. Statisticss besides showed that leucopoenia was observed more in DaunoXome treated topics than in combination therapy which includes doxorubicin, bleomycin and Oncovin ( ABV ) . Although non much differences were found in the topics treated with DaunoXome and other conventional drugs used for similar intent, Daunoxome resulted in less alopecia and neuropathy than that caused by conventional chemotherapy.

The clinical tests performed till now included male HIV positive topics. The efficaciousness of DaunoXome was therefore observed with regard to male participants ( topics ) . It is necessary to analyze the consequence of DaunoXome ( liposomal daunorobucin ) on female topics every bit good since small or no information is available on female HIV positive related Kaposi ‘s Sarcoma. Besides really small information is available about the consequence of DaunoXome on HIV negative topics.

Merchandise License:

In the twelvemonth 1995 the merchandise DaunoXome was licensed foremost in the United Kingdom and so it was approved by the FDA.


DaunoXome is utile in intervention of Kaposi ‘s Sarcoma. However, it has several side effects. Daunoxome causes mild alopecia and sickness in patients enduring from Kaposi ‘s Sarcoma. Since these toxic effects are non much important, DaunoXome is still considered as a intervention for Kaposi ‘s Sarcoma caused chiefly due to HIV infection.