US Patent 6,333,044: Scope, Claim Set, and US Landscape for Intranasal Analgesic/Anti-Inflammatory Liquids

US Patent 6,333,044 claims intranasal, transmucosally rapidly absorbable liquid analgesic/anti-inflammatory dosage forms designed to achieve systemic blood levels after nasal dosing, with multiple layers of formulation constraints (drug identity, dose ranges, promoters, viscosity behavior, and delivery format), plus corresponding treatment methods.

What is the core claimed invention and how is it positioned?

Drug and therapeutic function

The patent is anchored on an analgesic/anti-inflammatory active ingredient selected from:

racemic 5-benzoyl-2,3-dihydro-1H-pyrrolizine-1-carboxylic acid
optically active forms of that compound
pharmaceutically acceptable salts of the above

The claims also include dependent claim paths that narrow to ketorolac tromethamine (with water diluent and defined solution/excipient profiles).

Route and dosage form class

A central limitation across the dosage-form claims is:

intranasally administrable
transmucosally rapidly absorbable
achieves blood levels “effective for analgesic or anti-inflammatory use” after intranasal administration

A parallel class appears in the method claims:

treating inflammatory processes and pain of traumatic or pathologic origin via intranasal administration of the claimed dosage form.

Key formulation design constraints

Across the set, the most business-relevant formulation constraints are:

Non-thermosetting liquid dosage form (nasal)
Viscosity behavior: dosage form is free of polymers that produce low viscosity at room temperature but increased viscosity at body temperature
Active concentration ranges and exemplar concentrations
Mucosal absorption promoter options, including excipient bioadhesives
Single-dose vs solution/suspension structure
Specific plasma concentration target (dependent claims tied to a metabolite/linked analyte):
- “generate ... plasma concentration of 5-benzoyl-2,3-dihydro-1H-pyrrolizine-1-carboxylic acid within 0.3 and 5 mg/L”

What do the independent claims cover (and what do they exclude)?

US 6,333,044 includes multiple “independent-like” claim anchors (claim 1 and claim 21, plus method claims such as claim 11 and claim 14, which are independent in practical scope).

Claim 1 (dosage form)

An analgesic/anti-inflammatory liquid dosage form comprising:

systemically effective amount of the defined pyrrolizine-1-carboxylic acid (racemic or optically active forms or salts)
plus pharmaceutically acceptable excipient/diluent
non-thermosetting
intranasally administrable
transmucosally rapidly absorbable
achieves blood levels effective for analgesic/anti-inflammatory use after intranasal administration

Business implication: claim 1 is a formulation-and-performance claim for nasal systemic delivery of that active class in a liquid format.

Claim 11 (method)

Administration (intranasal) of a dosage form according to claim 1 for inflammatory pain (traumatic or pathologic origin).

Business implication: directly ties medical use scope to claim 1’s dosage-form limitations.

Claim 14 (method variant)

Same treatment objective, but explicitly recites a dosage form comprising the active (racemic/optical/salt) and repeating the performance features of intranasal liquid systemic delivery.

Business implication: keeps the method claim aligned with the same product definition.

Claim 21 (dosage form with polymer-viscosity exclusion)

A major scope-narrowing anchor:

same general drug class and nasal systemic liquid features
adds: dosage form is free of polymers providing:
- low viscosity at room temperature
- increased viscosity composition at body temperature

Dependent claims then narrow to solution/spray container and ketorolac embodiments.

Business implication: the “polymer viscosity behavior” negative limitation can carve out competitors using thermally thickening or temperature-responsive viscosity-increasing polymer systems.

What are the dependent claims that create practical “design-around” pressure?

Below, the most decision-relevant dependent claim clusters are mapped to formulation levers.

1) Active amount and concentration windows

Claim 2: 0.5 to 40 mg active ingredient
Claim 3: 2 to 20 mg
Claims 5, 7: 5-20% (w/v); example at 15% (w/v)
Claims 15-18 (method-linked): effective amount ranges mirroring the dosage-form ranges
Claims 24-25 (dosage form linked to claim 21): about 5-20% (w/v); example about 15% (w/v)
Claim 39-40 (method linked): about 5-20% (w/v); example about 15% (w/v)
Claim 51 (ketorolac bottle spray solution): about 5% to about 20% (w/v) ketorolac tromethamine

Business implication: if developing a competing intranasal ketorolac product, concentration outside these windows is a direct path to avoid literal infringement for concentration-restricted dependent claims (though claim 21/1 still have “systemically effective amount” language).

2) Physical form and delivery architecture

Claim 4: single-dose form
Claim 6: solution or suspension
Claim 22: dosage form is a solution
Claim 23: includes a container suitable for delivering a spray
Claim 34: includes an atomizer that administers liquid nasally as a spray
Claims 37-38, 43, 49: method claims aligned to solution/spray

Business implication: a nasal “spray” delivery device and atomization structure falls within claim framing; drops or gel systems may avoid the “spray” specific dependents but could still risk independent coverage if they satisfy liquid transmucosal rapid absorbability and systemic blood levels.

3) Excipients: bioadhesive and absorption promoters

Claim 8: excipient comprises a bioadhesive
Claim 9: further comprising an intranasal absorption promoter
Claim 10: promoters selected from:
- POE (9) lauryl alcohol
- sodium glycocholate
- lysophosphatidyl choline
Claim 13: mucosal absorption promoter is not a mucosal irritant

Business implication: promoters in this specific list (and bioadhesive systems) are explicitly inside the dependent claim scope. Using different promoter chemistry may reduce literal fit for these specific dependents, but the broader independent claim 1/21 still focuses on performance after intranasal administration.

4) Polymer viscosity behavior (negative limitation)

Claims 21 and 36: dosage forms are free of polymers that provide low viscosity at room temperature but increased viscosity at body temperature
Claims 51: repeats polymer exclusion for a ketorolac bottle spray solution

Business implication: this is the most explicit “negative ingredient limitation.” It impacts product design where formulator might use temperature-triggered viscosity enhancement (common in some mucoadhesion or controlled residence time approaches).

How far does the claim set extend from the pyrrolizine class to ketorolac?

The claim set builds a bridge:

The overall architecture starts with 5-benzoyl-2,3-dihydro-1H-pyrrolizine-1-carboxylic acid class (racemic/optical/salt).
Then, dependent claims 27-33 and 42-48 insert a ketorolac example, tying plasma concentration generation to the pyrrolizine-1-carboxylic acid analyte.

Key ketorolac-dependent chain:

Claim 27: active ingredient is ketorolac tromethamine, diluent water
Claims 29-30: ketorolac concentration about 5-20% (w/v); example about 15% (w/v)
Claims 31-32: “consisting essentially of” aqueous ketorolac tromethamine + optionally specified additives:
- humectant, isotonic agent, antioxidant, buffer, preservative, chelating agent
- specific narrowing includes optional chelating agent and optional preservative
Claim 33: sufficient ketorolac amount to generate plasma concentration of 5-benzoyl-2,3-dihydro-1H-pyrrolizine-1-carboxylic acid between 0.3 and 5 mg/L
Claims 34: atomizer spray
Claims 26, 41, 46-48: align “salt” and “consisting essentially of” and plasma concentration generation in the method chain

Business implication: ketorolac embodiments are explicitly claimed, but with a performance hook measuring a pyrrolizine-carboxylic acid plasma level, which can complicate regulatory/manufacturing translation because the clinical pharmacokinetic marker is defined in the claims.

What is the practical infringement surface (a claim-by-claim functional map)?

Dosage-form elements

A product faces the broadest risk if it satisfies all of the following simultaneously:

Liquid nasal formulation that is non-thermosetting
Active identity in claim 1/21 scope:
- pyrrolizine-1-carboxylic acid class (racemic/optical/salts), and/or ketorolac tromethamine for ketorolac dependents
Systemically effective amount achieving blood levels effective for analgesic/anti-inflammatory use after intranasal dosing
For narrower claim 21/36/51 coverage:
- formulation is free of certain thermally thickening viscosity polymers (low RT viscosity, increased body temperature viscosity)

Narrower “tight-lens” add-ons

Literal risk increases if the product also includes:

5-20% w/v concentration or ~15% w/v example
solution (not suspension) if positioned under solution dependents
single-dose configuration if sold in single-dose format
bioadhesive excipients
absorption promoter within the explicit list (POE (9) lauryl alcohol, sodium glycocholate, lysophosphatidyl choline)
a spray delivery system (bottle + atomizer)
“consisting essentially of” composition that allows only specific classes of aqueous additives

What treatments are claimed?

The therapeutic method scope is framed narrowly by etiology:

“treatment of inflammatory processes and pain of a traumatic or pathologic origin” (claims 11, 14, 36)

There is not a single named indication such as migraine, OA, postoperative pain, or rhinitis. Instead, it is category-based on pain/inflammation and etiology type.

Business implication: enforcement leverage likely centers on any clinical use asserted as traumatic/pathologic inflammatory pain.

How does the plasma concentration limitation function in scope?

Dependent claims include a quantified blood/plasma target:

0.3 to 5 mg/L of 5-benzoyl-2,3-dihydro-1H-pyrrolizine-1-carboxylic acid (claims 12, 33, 48)

This limitation appears where the method/dosage form is tied to ketorolac embodiments or human subjects. It creates a measurable performance boundary for at least the dependent claims.

Business implication: a product outside this exposure window could avoid those dependent claims even if it still meets other formulation/route limitations.

US Patent landscape analysis: what can be concluded from the claim set alone?

The provided materials include only the claims text for US 6,333,044, not the prosecution history, citations, assignee, publication number, filing dates, or maintenance/status data. Without those elements, an evidentiary, source-based US “patent landscape” (family size, priority chain, related continuations, common cited patents, litigation, or expiration status) cannot be produced accurately.

Result: The only defensible landscape conclusions are claim-structure-based: where competitors face narrower or broader exposure under this patent, based on the explicit limitations listed above.

Key “design-around” pressure points for a competitor (claim-construction driven)

Polymer viscosity exclusion (claims 21/36/51)
- Avoid formulations using polymers designed to be low viscosity at room temperature and increased viscosity at body temperature.
Concentration windows (claims 2-3-5-7-24-25-29-30-39-40-51)
- If launching with ketorolac, keep ketorolac tromethamine concentration outside the claimed ranges if literal coverage is targeted.
Promoter identity (claim 10)
- Avoid the explicit promoter list if aiming to reduce fit for claims 9-10.
Delivery format (claims 23/34/38/49)
- If marketed as a non-spray liquid (e.g., drops) may avoid some dependent claim structures, though independent claims may still capture “intranasally administrable transmucosally rapidly absorbable liquid dosage forms.”
Plasma exposure window dependents (claims 12/33/48)
- Ensure clinical exposure does not achieve the defined 0.3-5 mg/L target for the specified analyte if targeting to avoid those dependent claims.

Claim set snapshot table (what to watch in freedom-to-operate)

Claim cluster	Constraint type	Tight numerical/structural limits	Practical risk driver
Claims 1/11/14	Broad product concept	Nasal intranasal, non-thermosetting liquid, systemic blood levels for analgesic/anti-inflammatory	Any nasal liquid with systemic efficacy for same drug class
Claims 2-3	Dose (mg)	0.5-40 mg; 2-20 mg	Single-dose vs multi-dose product labeling and dosing
Claims 5-7 / 24-25 / 29-30 / 39-40 / 51	Concentration (w/v)	5-20% and example ~15%	Ketorolac concentration formulation selection
Claims 4/6/22/37	Physical form	Single-dose; solution or suspension; solution variants	Liquid physical state and packaging strategy
Claims 8-10 / 13	Excipients	Bioadhesive; promoter; promoter not mucosal irritant; explicit promoter list	Promoter chemistry and tolerability claim framing
Claims 21/36/51	Negative limitation	Free of polymers that raise viscosity at body temp	Avoid thermoresponsive viscosity-increasing polymers
Claims 23/34/38/49	Delivery hardware	Bottle for spray; atomizer spray	Nasal spray device integration
Claims 12/33/48	Plasma target (dependent)	0.3-5 mg/L of specified analyte	PK profile and dose-exposure alignment

Key Takeaways

US 6,333,044 claims intranasal, non-thermosetting liquid analgesic/anti-inflammatory formulations that achieve systemic blood levels after nasal dosing, with a major negative limitation on thermally thickening viscosity polymers (low RT viscosity, higher viscosity at body temperature).
The claim set uses tight dependent claim lenses on dose ranges, ketorolac tromethamine concentration (5-20% w/v), spray delivery, bioadhesive/promoter excipient selection, and a quantified plasma exposure target for the pyrrolizine-1-carboxylic acid analyte.
Ketorolac embodiments are explicitly claimed in dependent chains with water diluent and “consisting essentially of” aqueous solution compositions tied to optional additive classes and the defined plasma exposure range.
A credible US competitive risk screen from this patent alone focuses on avoiding the polymer viscosity behavior limitation and, for ketorolac, keeping formulation parameters and PK exposure outside the dependent claim windows.

FAQs

1) Is claim 1 limited to a specific drug concentration?

No. Claim 1 is limited by “systemically effective amount,” while multiple dependent claims add explicit mg and % (w/v) concentration ranges.

2) Does the patent require a spray delivery device?

Not in claim 1. Spray/atomizer language appears in dependent claims (notably claim 23 and claim 34) and in method dependents (claim 38 and claim 49).

3) What is the most important formulation exclusion in the claim set?

The dosage form being free of polymers that provide low viscosity at room temperature and increased viscosity at body temperature (claims 21, 36, and repeated in claim 51).

4) Are mucosal absorption promoters claimed by identity or by function?

Both. There is functional language (intranasal absorption promoter; not a mucosal irritant) and identity-specific dependent coverage (POE (9) lauryl alcohol, sodium glycocholate, lysophosphatidyl choline).

5) Does the patent include ketorolac tromethamine?

Yes. Dependent claims specify ketorolac tromethamine with water diluent and define concentration and “consisting essentially of” aqueous solution options, plus a plasma exposure requirement tied to the pyrrolizine-1-carboxylic acid analyte.

References

[1] United States Patent US 6,333,044, claims text provided by user (claims 1-51).

Foriegn Application Priority Data
Foreign Country	Foreign Patent Number	Foreign Patent Date
Italy	MI91A2024	Jul 22, 1991

Country	Patent Number	Estimated Expiration	Supplementary Protection Certificate	SPC Country	SPC Expiration
Austria	130758	⤷ Start Trial
Germany	69206345	⤷ Start Trial
Denmark	0524587	⤷ Start Trial
European Patent Office	0524587	⤷ Start Trial
Spain	2082288	⤷ Start Trial
Greece	3019012	⤷ Start Trial
Italy	1250691	⤷ Start Trial
>Country	>Patent Number	>Estimated Expiration	>Supplementary Protection Certificate	>SPC Country	>SPC Expiration

Details for Patent: 6,333,044

Summary for Patent: 6,333,044