Formulation Development of Protein Dosage Forms

Akers, Michael J.; Vasudevan, Vasu; Stickelmeyer, Mary P.

doi:10.1007/978-1-4615-0549-5_2

Cited by 50 publications

(36 citation statements)

References 130 publications

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“…contain various excipients such as sugars, polymers, buffer salts, and surfactants. [1][2][3][4] The effect of borax on the thermal properties of a multi-component frozen solution was studied (Fig. 4).…”

Section: Fig 1 Derivative Thermograms Of Frozen Aqueous Solutions Cmentioning

confidence: 99%

“…Protecting the native protein conformation from various stresses and obtaining good structure cake are particularly important in freeze-drying of protein solutions. [1][2][3] Increase in the component molecular mobility above the T g Ј often induces cake collapse during the freeze-drying process. The higher collapse temperature and consequently acceptable product temperature for the primary drying process, afforded by the complex formation, should significantly reduce the time and energy requirements for freeze-drying.…”

Section: Fig 1 Derivative Thermograms Of Frozen Aqueous Solutions Cmentioning

confidence: 99%

“…3,7) Controlling the physical properties of the freeze-concentrates and subsequently freeze-dried solids should provide the key to production of stable protein and other biopolymer formulations. 1,2,7) Thermal analysis of frozen aqueous carbohydrate solutions often shows several transitions of the amorphous supercooled phase including the "real" glass transition (T g ) and the glass transition of maximally freeze-concentrated solutes (T g Ј) at temperatures depending on the solute compositions. 9,10) The terming and implications of these thermal transitions are still under some debate, whereas it has been established that the changes in the solute and surrounding water mobility at the transition temperatures have significant impact on the physical and chemical stability of the components.…”

mentioning

confidence: 99%

“…1,2) The "real" glass transition of the frozen solution (T g ) occurs without ice melting, and is often less apparent in thermal analysis.…”

mentioning

confidence: 99%

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Effect of Sodium Tetraborate (Borax) on the Thermal Properties of Frozen Aqueous Sugar and Polyol Solutions

Izutsu

Rimando²,

Aoyagi

et al. 2003

CHEMICAL & PHARMACEUTICAL BULLETIN

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Recent advances in biotechnology have focused attention on the stable storage of the biological polymers (e.g., proteins) and biological systems (e.g., cells) for medical use. Freezing and freeze-drying are popular methods to archive their long-term stability.1-4) Various co-solutes such as sugars (e.g., sucrose, trehalose) and other polyols protect proteins and cells through different mechanisms against stresses in aqueous solutions, frozen solutions, and freeze-dried solids. 5,6) Freezing an aqueous solution concentrates the solutes into a supercooled solution surrounded by ice crystals. 7,8) The sugars and polyols protect the proteins and cell membranes against dehydration-induced structural perturbation by substituting water molecules through direct molecular interactions (e.g., hydrogen bonding). Decreased molecular mobility in the polyol-based glass-state amorphous phase reduces chemical changes of the components.3,7) Controlling the physical properties of the freeze-concentrates and subsequently freeze-dried solids should provide the key to production of stable protein and other biopolymer formulations. 1,2,7) Thermal analysis of frozen aqueous carbohydrate solutions often shows several transitions of the amorphous supercooled phase including the "real" glass transition (T g ) and the glass transition of maximally freeze-concentrated solutes (T g Ј) at temperatures depending on the solute compositions. 9,10) The terming and implications of these thermal transitions are still under some debate, whereas it has been established that the changes in the solute and surrounding water mobility at the transition temperatures have significant impact on the physical and chemical stability of the components.11) The T g Ј transition, which involves ice melting around the solute molecule, is often the most apparent, and is the most important in the development of freeze-dried formulations because the increased solute mobility above the T g Ј typically induces cake collapse during the freeze-drying process.1,2) The "real" glass transition of the frozen solution (T g ) occurs without ice melting, and is often less apparent in thermal analysis.It is well known that borate forms chemical complexes with polyhydroxy compounds. [12][13][14] Addition of sodium tetraborate decahydrate (borax), which hydrolyzes to boric acid and sodium borate (Na 2 B 4 O 7 ϩ7H 2 O®2B(OH) 3 ϩ 2B(OH) 4 Na), to aqueous sugar and/or other polyol solutions results in various complexes between the borate ion and the polyols. Increase in the "effective" molecular size and changes in the molecular interactions by the complex formation (e.g., borate-trehalose) leads to reduced component mobility in the amorphous freeze-dried solids and hydrated mixtures. [15][16][17] Co-lyophilization with the borate-sugar combinations improves the protein stability at higher temperatures. 15)The large dependence of the frozen saccharide solution T g Јs on their molecular weights has suggested alternation of the T g Ј through the borate-polyol complex formation. 18,19) ...

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Section: Fig 1 Derivative Thermograms Of Frozen Aqueous Solutions Cmentioning

confidence: 99%

Section: Fig 1 Derivative Thermograms Of Frozen Aqueous Solutions Cmentioning

confidence: 99%

mentioning

confidence: 99%

“…1,2) The "real" glass transition of the frozen solution (T g ) occurs without ice melting, and is often less apparent in thermal analysis.…”

mentioning

confidence: 99%

See 2 more Smart Citations

Effect of Sodium Tetraborate (Borax) on the Thermal Properties of Frozen Aqueous Sugar and Polyol Solutions

Izutsu

Rimando²,

Aoyagi

et al. 2003

CHEMICAL & PHARMACEUTICAL BULLETIN

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show abstract

“…6) Some buffer components also favorably or adversely affect the protein stability through direct interactions and/or through changing the local environments in the dried state. For example, freezing of certain buffer systems (e.g., sodium phosphate) often induces crystallization of a component salt and resulting shift of the local pH surrounding the proteins.…”

mentioning

confidence: 99%

Stabilization of Protein Structure in Freeze-Dried Amorphous Organic Acid Buffer Salts

Izutsu¹,

Kadoya

Yomota³

et al. 2009

Chem. Pharm. Bull.

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The development of protein pharmaceuticals requires rational formulation design to ensure appropriate storage stability, because the degradation of such pharmaceuticals through various chemical and physical pathways not only reduces their therapeutic effects but also increases the risk of product immunogenicity. [1][2][3][4][5] Freeze-drying is a popular method of conferring long-term stability of therapeutic proteins that is not achievable in aqueous solutions. Removal of the surrounding water molecules during the freeze-drying process, however, often perturbs the protein structure, leading to irreversible aggregation in the reconstituted solutions. The structurally altered protein molecules are also prone to chemical degradation during storage.1) Maintaining the protein conformation by process and ingredient (e.g., stabilizer, pH buffer, isotonic agents) optimization thus improves both the physical and chemical stability of protein formulations.Choosing the solution pH and buffer system appropriate to a particular protein is a simple but significant element in the formulation design because the chemical and physical integrity of proteins in the aqueous solutions and freeze-dried solids depend largely on the pH. 6) Some buffer components also favorably or adversely affect the protein stability through direct interactions and/or through changing the local environments in the dried state. For example, freezing of certain buffer systems (e.g., sodium phosphate) often induces crystallization of a component salt and resulting shift of the local pH surrounding the proteins.7-11) Freeze-drying from some buffer systems (e.g., L-histidine, citrate, or Tris) often leads to higher activity retention of proteins (e.g., coagulation factor VIII, recombinant human interleukin-1 receptor antagonist) relative to those from other buffers.12-15) Conformation of the proteins lyophilized in these buffer systems is of particular interest.Reported properties of some carboxylic acid salts, including stabilization of native protein conformation in aqueous solutions (e.g., antithrombin III) 16,17) and their propensity to form glass-state amorphous solids upon lyophilization, 18) suggest their ability to protect protein conformation against dehydration stress through mechanisms similar to disaccharides. Non-reducing disaccharides (e.g., sucrose, trehalose) are popular stabilizers in solution and freeze-dried protein formulations. Various saccharides and polyols thermodynamically favor native protein structures over denatured states in aqueous solutions by a "preferential exclusion" mechanism. 19) Sucrose and trehalose protect proteins by substituting surrounding water molecules through hydrogen bonds during the freeze-drying process. 4,[20][21][22] Limited molecular mobility in glass-state lyophilized disaccharide solids also protects embedded proteins from chemical degradation (e.g., deamidation) during storage. 23)The present study assesses the physical properties and protein-stabilizing effects of carboxylic acid buffer systems (e.g.,...

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Freeze‐Drying, Pharmaceuticals

Liu

2010

Encyclopedia of Industrial Biotechnology

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This article provides an overview of the fundamental aspects for pharmaceutical freeze‐drying, including the rationale for freeze‐drying process design and control, the basics of formulation development for freeze‐drying, the importance of the container‐closure system, and a general description of pharmaceutical freeze‐dryers. In the second part of this article, the challenges in freeze‐drying scale‐up and transfer, freezing control, use of cosolvent, freeze‐drying in syringes, process analytical technology, and quality‐by‐design in freeze‐drying have been discussed, and some new advancements related to these aspects are also highlighted.

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Formulation Development of Protein Dosage Forms

Cited by 50 publications

References 130 publications

Effect of Sodium Tetraborate (Borax) on the Thermal Properties of Frozen Aqueous Sugar and Polyol Solutions

Effect of Sodium Tetraborate (Borax) on the Thermal Properties of Frozen Aqueous Sugar and Polyol Solutions

Stabilization of Protein Structure in Freeze-Dried Amorphous Organic Acid Buffer Salts

Freeze‐Drying, Pharmaceuticals

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