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Manufacturing Challenges

Inhaled liposomal products are not as straightforward to develop as some other inhaled dosage forms, like nebulizer solutions, and may have more complex and expensive manufacturing processes, so would only be exploited when the simpler formulation alternatives are either unsafe, less effective, or not viable [24,32]. Prior to entering the clinic with the liposomal formulation, the manufacturing conditions and choice of lipids should be identified that produce liposomes of the appropriate size, that are safe for inhalation, and that contain the appropriate amount of drug so it is released at the proper time and at a rate that is both safe and therapeutic. Furthermore, the manufacturing processes should be well characterized so that each batch of the liposomal product is comparable and possesses an adequate shelf life.

While it is true that pharmaceutical preparations of liposomes require a sophisticated manufacturing process, and not all CMOs have the expertise or the equipment in house, these processes are now becoming increasingly well accepted given that liposome products have been on the market for more than 20 years. There are many ways to prepare liposomes [76-78]: they form spontaneously when lipid mixtures are hydrated in excess water yielding a heterogeneous size distribution. The micronsized multilamellar liposomes that are generated can subsequently be processed to reduce their size distribution by a variety of means including sonication, homogenization, microfluidization, or extrusion through filters or via a combination of these processes. Many drug products can be terminally sterilized after manufacture to assure sterility, but that is not generally the case for liposomes [79-81]. Instead, two options are available to provide assurance of sterility. For larger liposomes that cannot be sterile filtered, every step of the manufacturing process must be conducted in an aseptic environment, which requires specialized manufacturing facilities and may be labor intensive. In contrast, unilamellar liposomes can often be sterile filtered and only the subsequent vial or ampule filling step of the process needs to be conducted under aseptic conditions, which reduces the manufacturing burden.

The purity of the lipid and sterol excipients is critical to the ability to manufacture liposomes that possess acceptable long-term stability. Fortunately, there are now multiple suppliers of high-quality lipid and sterol excipients. More than 75 registered Drug Master Files (DMFs) for pharmaceutical grade lipids exist in the United States [32] and an abbreviated list of some of the more commonly used excipients is shown in Table 8.1.

Selected Pharmaceutical Grade Lipids with the U.S. Drug Master Files

TABLE 8.1

Product Name/#

Supplier

U.S. DMF #

Typea

Date

Cholesterol

770,000 (ovine wool)

Avanti

9,285

II

8/12/1991

Cholesterol HP

Dishman

14,346

II

8/3/1999

770,100 (plant)

Avanti

23,761

II

4/28/2010

DMPG: dimyristoyl phosphatidylglycerol

770,445

Avanti

7,369

IV

3/7/1988

Lipoid PG 14:0/14:0

Lipoid

8,463

IV

3/5/1990

Coatsome MG-4040LS

Nippon Oil & Fats Co.

9,578

IV

2/21/1992

Coatsome MG-4040LS

Nippon Oil & Fats Co.

17,807

II

11/2/2004

DPPC: dipalmitoyl phosphatidylcholine

770,355

Avanti

7,187

II

7/18/1987

Coatsome MC-6060

Nippon Oil & Fats Co.

8,403

IV

1/27/1990

Coatsome MC-6060

Nippon Oil & Fats Co.

9,263

II

7/30/1991

LP-04-057

Genzyme

12,555

II

6/23/1997

Lipoid PC 16:0/16:0

Lipoid

13,000

IV

5/19/1998

Lipoid PC 16:0/16:0

Lipoid

13,001

II

5/19/1998

Coatsome MC-6060EX

Nippon Oil & Fats Co.

20,876

II

9/24/2007

DPPG: dipalmitoyl phosphatidylglycerol

770,455

Avanti

9,727

II

6/9/1992

LP-04-016

Genzyme

14,837

II

4/17/2000

Coatsome MG-6060LS

Nippon Oil & Fats Co.

22,318

II

12/17/2008

EPC: egg phosphatidylcholine

Lipoid E PC

Lipoid

8,657

II

7/16/1990

770,051

Avanti

12,760

II

11/25/1997

Coatsome NC-50

Nippon Oil & Fats Co.

17,404

IV

5/17/2004

Coatsome PC-98SR

Nippon Oil & Fats Co.

22,208

IV

11/19/2008

ESM: egg sphingomyelin

Lipoid E SM

Lipoid

14,414

IV

9/24/1999

Coatsome NM-10

Nippon Oil & Fats Co.

17,234

II

3/8/2004

HSPC: hydrogenated soy phosphatidylcholine

Lipoid S PC-3

Lipoid

8,907

IV

12/27/1990

Coatsome NC-21E

Nippon Oil & Fats Co.

20,764

II

8/8/2007

Source: Cipolla, D. et al., Liposomes, niosomes and proniosomes—A critical update of their (commercial) development as inhaled products, in Respiratory Drug Delivery Europe 2011, Davis Healthcare Int’l Publishing, River Grove, IL, 2011. With permission. a Type II DMF refers to drug substance, drug substance intermediate, and the material used in their preparation or drug product; Type IV DMF refers to excipient, colorant, flavor, essence, or material used in their preparation.

 
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