Detailed Analysis of the Scope and Claims of United States Patent 4,537,883
Introduction
United States Patent 4,537,883, titled "Lyophilized Cyclophosphamide," was granted on August 27, 1985, to inventors Robert L. Alexander, Robert J. Bequette, Terry T. Kensler, and Joseph A. Scott, and assigned to Mead Johnson & Company. This patent is significant in the field of pharmaceuticals, particularly for the formulation and stabilization of cyclophosphamide, a widely used antineoplastic drug.
Background of the Invention
Cyclophosphamide, chemically known as 2-[bis(2-chloroethyl)amino]tetrahydro-2H-1,3,2-oxazaphosphorine 2-oxide, is a cyclic phosphoric acid ester amide that was first disclosed and claimed in U.S. Pat. No. 3,018,302 granted on January 23, 1962, to H. Arnold et al.[5].
Scope of the Invention
The patent describes an improved solid pharmaceutical composition of lyophilized cyclophosphamide. The key innovation is the discovery that a lyophilized cyclophosphamide-mannitol solid composition exhibits improved thermal stability and superior solubility characteristics when it contains an amount of water approximately equimolar to the cyclophosphamide content taken as the anhydride[1][5].
Composition
The preferred solid compositions are comprised of:
- About 20 parts by weight of cyclophosphamide (as the anhydrous form)
- About 1.5 parts by weight of water
- From about 10 to 40 parts by weight of excipient, primarily mannitol
The most preferred compositions include about 20 parts by weight of cyclophosphamide, about 1.5 parts by weight of water, and about 15 parts by weight of mannitol[1][5].
Preparation Methods
The compositions can be prepared by two methods:
- Lyophilization and Humidification: This involves preparing a sterile solution for lyophilization, which typically includes about 1 part by weight of excipient (mainly mannitol), about 1.5 parts by weight of cyclophosphamide (as the monohydrate), and about 40 parts water. The solution is then lyophilized and humidified to achieve the desired moisture content[1][5].
- Alternative Method: This method also involves preparing a sterile solution but may vary in the specific steps and conditions to achieve the optimal composition.
Claims
The patent includes 16 claims that cover various aspects of the invention:
Claim 1
The first claim describes a lyophilized pharmaceutical solid composition containing cyclophosphamide, water, and an excipient primarily composed of mannitol, with specific weight ratios and moisture content[5].
Subsequent Claims
Subsequent claims detail the specific proportions of the components, the methods of preparation, and the physical properties of the lyophilized solid composition. These claims emphasize the improved stability, solubility, and appearance of the composition compared to existing dry powder premixes of cyclophosphamide[1][5].
Patent Landscape
The patent landscape surrounding U.S. Pat. No. 4,537,883 includes several related patents and publications:
Related Patents
- U.S. Pat. No. 3,018,302: This earlier patent by H. Arnold et al. discloses the initial discovery of cyclophosphamide and related compounds[5].
- U.S. Pat. No. 5,418,223: This patent by Palepu et al. describes a method for lyophilizing cyclophosphamide that avoids the need to add water back to the lyophilizate for stabilization[2].
- WO1994008592A1: This patent application by Hannu et al. describes a storage-stable lyophilized cyclophosphamide composition using dextran as an excipient[2].
Industry Impact
The invention described in U.S. Pat. No. 4,537,883 has significantly impacted the pharmaceutical industry by providing a more stable and soluble form of cyclophosphamide. This has improved the efficacy and safety of cyclophosphamide formulations, particularly in parenteral use.
Physical Properties and Stability
The "hydrated" cyclophosphamide-mannitol lyophilized solid composition demonstrates superior thermal stability, solubility characteristics, and enhanced appearance compared to other powder premix formulations. These improved properties are crucial for maintaining the drug's potency and ensuring consistent patient outcomes[1][5].
Clinical and Practical Implications
The improved stability and solubility of the lyophilized cyclophosphamide-mannitol composition make it easier to reconstitute and administer, reducing the risk of errors and improving patient compliance. This formulation also ensures that the drug remains effective over a longer period, which is vital for cancer treatment protocols.
Conclusion
U.S. Pat. No. 4,537,883 represents a significant advancement in the formulation of cyclophosphamide, offering improved stability, solubility, and appearance. The patent's claims and scope are well-defined, covering the composition, preparation methods, and physical properties of the lyophilized solid. This invention has contributed substantially to the pharmaceutical industry, enhancing the efficacy and safety of cyclophosphamide treatments.
Key Takeaways
- Improved Stability: The lyophilized cyclophosphamide-mannitol composition exhibits superior thermal stability.
- Enhanced Solubility: The formulation shows better solubility characteristics compared to existing dry powder premixes.
- Optimal Composition: The preferred composition includes specific weight ratios of cyclophosphamide, water, and mannitol.
- Preparation Methods: Two methods are described for preparing the lyophilized solid composition.
- Industry Impact: The invention has improved the efficacy and safety of cyclophosphamide formulations.
Frequently Asked Questions (FAQs)
Q1: What is the primary innovation of U.S. Pat. No. 4,537,883?
A1: The primary innovation is the discovery that a lyophilized cyclophosphamide-mannitol solid composition exhibits improved thermal stability and superior solubility characteristics when it contains an amount of water approximately equimolar to the cyclophosphamide content.
Q2: What are the key components of the lyophilized cyclophosphamide composition?
A2: The composition includes cyclophosphamide, water, and an excipient primarily composed of mannitol, with specific weight ratios.
Q3: How is the lyophilized cyclophosphamide composition prepared?
A3: The composition can be prepared by two methods: lyophilization and humidification, and an alternative method involving different steps and conditions.
Q4: What are the benefits of the lyophilized cyclophosphamide-mannitol composition?
A4: The benefits include improved thermal stability, enhanced solubility characteristics, and better appearance compared to existing dry powder premixes.
Q5: How has this patent impacted the pharmaceutical industry?
A5: The patent has significantly improved the efficacy and safety of cyclophosphamide formulations, particularly in parenteral use, by providing a more stable and soluble form of the drug.
Cited Sources
- US4537883A - Lyophilized cyclophosphamide - Google Patents
- Stable ready to use cyclophosphamide liquid formulations - Justia Patents
- Patent Claims Research Dataset - USPTO
- EP0394045A2 - Cyclophosphamide lyophilizates - Google Patents
- United States Patent 19 - googleapis.com
