United States Patent 5,707,975: Oral itraconazole/saperconazole formulations with hydroxypropyl-β-cyclodextrin and acidic aqueous medium
U.S. Patent 5,707,975 claims an oral formulation for itraconazole or saperconazole that uses a defined hydroxypropyl-β-cyclodextrin (HP-β-CD) with a specified degree of substitution (M.S.) and limited unsubstituted β-cyclodextrin, in an aqueous acidic bulk liquid with a defined alcoholic co-solvent fraction, plus a sweetener/flavor system.
What is the core claim architecture?
The independent claim defines a full recipe with functional and parameter limits. Dependent claims then narrow key variables.
Claim 1 (independent): full formulation scope
Formulation for oral administration comprising:
- Active
- itraconazole or saperconazole
- Solubilizer
- hydroxypropyl-β-cyclodextrin
- M.S. 0.3 to 3
- < 5% unsubstituted β-cyclodextrin
- Bulk carrier
- Alcoholic co-solvent
- 1% (v/v) to 20% (v/v) selected from:
- ethanol, propylene glycol, glycerol
- Sweetening
- one or more intense sweeteners
- one or more bulk sweeteners
- Flavors
- one or more pharmaceutically acceptable flavors
Practical reading: Claim 1 is not limited to one taste system, one exact HP-β-CD grade, or one alcohol. It covers a family defined by the solubilizer chemistry envelope and the co-solvent fraction.
Claim 2 (dependent): tighter HP-β-CD grade
- HP-β-CD:
- M.S. 0.35 to 0.50
- < 1.5% unsubstituted β-cyclodextrin
This is a major narrowing relative to Claim 1.
Claim 3 (dependent): alcohol narrowing
- Alcoholic co-solvent is specifically propylene glycol
Claim 4 (dependent): pH constraint
This is a second major narrowing because acidification can affect cyclodextrin-drug complexation and stability.
Claim 5 (dependent): sweetener specificity
- Intense sweetener is selected from:
- saccharin
- sodium saccharin
- calcium saccharin
- Bulk sweetener is selected from:
- sorbitol, mannitol, fructose, sucrose, maltose, glucose, caramel, honey
Claim 6 and Claim 7 (dependent): worked examples with explicit percentages
These are composition-specific embodiments, not necessarily the only covered compositions.
Claim 6: explicit formulation
Based on total formulation volume basis as stated:
- itraconazole: 4% (w/v)
- HP-β-CD: 60% (w/v)
- propylene glycol: 10% (v/v)
- acid/base to pH 2.0 ± 0.1
- sodium saccharin: 0.08% (w/v)
- flavor(s): up to 1% (w/v)
- water
Claim 7: alternative explicit formulation
- itraconazole or saperconazole: 1% (w/v)
- HP-β-CD: 40% (w/v)
- propylene glycol: 10% (v/v)
- acid/base to pH 2.0 ± 0.1
- sodium saccharin: 0.06% (w/v)
- sorbitol (70%) non-crystallizing solution: 19% (v/v)
- flavor(s): up to 1% (w/v)
- carmel sweetener: 0.02% (w/v)
- water
Where is the legal “boundary” of the claims?
Boundary 1: HP-β-CD specification (M.S. and impurity)
Claim 1’s key distinguishing element is not just “hydroxypropyl-β-cyclodextrin,” but a quantitative envelope:
- M.S. 0.3 to 3
- < 5% unsubstituted β-cyclodextrin
Claim 2 further restricts:
- M.S. 0.35 to 0.50
- < 1.5% unsubstituted β-cyclodextrin
Impact: A competitor using an HP-β-CD grade outside these M.S. or impurity thresholds can fall outside the claim scope even if the overall formulation resembles the example.
Boundary 2: alcoholic co-solvent fraction
Claim 1 requires:
- alcohol co-solvent: 1% to 20% (v/v)
Claim 3 narrows:
- alcohol must be propylene glycol
So a formulation using ethanol or glycerol can still fall within Claim 1 if it is within 1% to 20% and other parameters match. A formulation using no alcohol, or alcohol outside 1% to 20% (for example, higher for solubilization), risks stepping out of Claim 1.
Boundary 3: “aqueous acidic medium” plus a specific pH in dependent claims
Claim 1 states “aqueous acidic medium” (functional/relative wording). The acid strength becomes explicit in Claim 4:
Claim 1 could be argued to cover a range of “acidic” pH conditions, but Claim 4 is clearly a bright-line limitation.
Boundary 4: sweeteners and flavors
Claim 1 uses category language:
- one or more intense sweeteners
- one or more bulk sweeteners
- one or more flavors
Claim 5 supplies specific permitted sweetener lists. That means that if a generic competitor swaps in non-listed intense sweeteners (or non-listed bulk sweeteners), they may avoid Claim 5 but still infringe Claim 1 if Claim 1’s broader category terms are met.
Boundary 5: active selection
Claim 1 is limited to itraconazole or saperconazole. Any other azole antifungal is outside scope.
How broad is claim 1 vs. the dependent chain?
Scope ladder
- Claim 1: broadest coverage
- Active: itraconazole/saperconazole
- HP-β-CD: M.S. 0.3 to 3, impurity <5%
- Acidic aqueous medium (not quantified)
- Alcohol: 1% to 20% v/v from defined list
- Sweeteners and flavors: category level
- Claim 2: narrows HP-β-CD grade
- Claim 3: narrows alcohol identity
- Claim 4: narrows pH to 2.0 ± 0.1
- Claim 5: narrows sweeteners to enumerated candidates
- Claims 6-7: narrow to explicit exemplary compositions
What this means for infringement risk
A near-copy formulation that meets Claim 1’s HP-β-CD envelope and alcohol fraction, while differing in sweetener choice, can still land within Claim 1. To avoid, a competitor typically must change at least one of the bright-line “physics/chemistry” constraints (HP-β-CD M.S./impurity, alcohol fraction/identity, pH if targeting Claim 4).
What is the patent landscape implication for “around” designs?
Without the specification and prosecution history, the safest business framework is to treat the numeric thresholds as the main design levers.
Design-around levers
- HP-β-CD grade substitution
- move M.S. outside 0.3-3 (or outside 0.35-0.50 if targeting Claim 2)
- or raise unsubstituted β-CD impurity above 5% (Claim 1) or above 1.5% (Claim 2)
- Alcohol selection/fraction
- use none, or use outside 1% to 20% v/v
- for Claim 3, replace propylene glycol with ethanol or glycerol and avoid matching Claim 3 if attempting to defeat the dependent claim chain
- Acidification
- keep the formulation “not within pH 2.0 ± 0.1” to avoid Claim 4 (and likely reduce evidence overlap on the intended acidic complexation)
- Sweetener system
- swap intense sweeteners or bulk sweeteners out of Claim 5’s lists to avoid Claim 5 while still potentially risking Claim 1 if category terms are met
Claim coverage mapped to formulation variables (for testing and freedom-to-operate)
Variable matrix
| Variable |
Claim 1 requirement |
Claim 2 |
Claim 3 |
Claim 4 |
Claim 5 |
Claim 6 |
Claim 7 |
| Active |
itraconazole or saperconazole |
same |
same |
same |
same |
itraconazole |
itraconazole or saperconazole |
| HP-β-CD M.S. |
0.3 to 3 |
0.35 to 0.50 |
same |
same |
same |
60% (w/v) HP-β-CD |
40% (w/v) HP-β-CD |
| Unsubstituted β-CD impurity |
<5% |
<1.5% |
same |
same |
same |
not specified |
not specified |
| Acidic medium |
“aqueous acidic medium” |
same |
same |
pH 2.0 ± 0.1 |
pH implied |
pH 2.0 ± 0.1 |
pH 2.0 ± 0.1 |
| Alcohol co-solvent |
1% to 20% (v/v), ethanol/PG/glycerol |
same |
propylene glycol |
pH constraint independent |
same |
10% (v/v) propylene glycol |
10% (v/v) propylene glycol |
| Intense sweeteners |
category |
same |
same |
same |
saccharin / sodium saccharin / calcium saccharin |
sodium saccharin 0.08% (w/v) |
sodium saccharin 0.06% (w/v) |
| Bulk sweeteners |
category |
same |
same |
same |
sorbitol, mannitol, fructose, sucrose, maltose, glucose, caramel, honey |
(implied by flavors/other components; no explicit bulk sweetener listed) |
sorbitol 70% non-crystallizing 19% (v/v); plus carmel sweetener 0.02% (w/v) |
| Flavors |
category |
same |
same |
same |
same |
up to 1% (w/v) |
up to 1% (w/v) |
Numerical “anchor” embodiments
- Claim 6 anchors a high HP-β-CD loading formulation (60% w/v) at itraconazole 4% w/v, propylene glycol 10% v/v, sodium saccharin 0.08% w/v, pH 2.0 ± 0.1.
- Claim 7 anchors a lower HP-β-CD loading formulation (40% w/v) at active 1% w/v, with a bulk sweetener system based on sorbitol 70% solution (19% v/v), sodium saccharin 0.06% w/v, pH 2.0 ± 0.1.
What is the scope in practical business terms?
A. Product form
The patent targets oral administration and a “bulk liquid carrier” (aqueous acidic medium). This aligns to liquid oral formulations that need solubilization of itraconazole/saperconazole.
B. Key differentiator
It is the combination of:
- HP-β-CD with controlled M.S. and impurity level
- acidic aqueous medium
- defined alcohol co-solvent fraction
- sweetener and flavor system
The numeric constraints indicate the inventor treated cyclodextrin grade and acid/alcohol conditions as controlling parameters rather than incidental formulation choices.
C. Most likely commercial workstreams covered
- Liquid oral antifungal products for itraconazole and saperconazole, where the main formulation burden is solubilization and taste masking.
Key Takeaways
- Claim 1 covers oral itraconazole or saperconazole liquids built around HP-β-CD with M.S. 0.3 to 3 and <5% unsubstituted β-CD, in aqueous acidic media with 1% to 20% v/v alcohol (ethanol/propylene glycol/glycerol), plus sweeteners and flavors.
- The main enforcement levers are HP-β-CD grade/impurity and alcohol fraction, with pH 2.0 ± 0.1 and propylene glycol locked in dependent claims.
- Claims 6 and 7 are concrete embodiments with full percentage recipes that can guide both manufacturing design and prior-art comparisons.
FAQs
-
Which claim element most strongly controls “around” design?
The HP-β-CD specification: M.S. and the % unsubstituted β-cyclodextrin limits (Claim 1 and Claim 2).
-
Does swapping itraconazole to another antifungal avoid the patent?
Yes. The claims are limited to itraconazole or saperconazole.
-
Can a formulation with ethanol instead of propylene glycol still fall under Claim 1?
Yes, if ethanol is within 1% to 20% (v/v) and other Claim 1 requirements are met. Claim 3 specifically requires propylene glycol.
-
What is the tightest pH requirement in the claim set?
pH 2.0 ± 0.1 (Claim 4).
-
Do the dependent claims limit the sweetener system to specific items?
Yes for Claim 5, which enumerates allowed intense and bulk sweeteners. Claim 1 stays at category level.
References
- United States Patent 5,707,975. Claims 1-7 as provided in the prompt.
