United States Patent 8,217,033 Landscape: How Broad Are the Claims for Intranasal Midazolam in Methoxy-PEG 350/550, and What Competes Around It
United States Patent US 8,217,033 claims a liquid intranasal (mucosal) midazolam composition using a specific class of methoxy-polyethylene glycol (methoxy-PEG) excipients: methoxy-PEG 350 and methoxy-PEG 550. The independent claim covers the composition and a method of administering to a mammal across multiple mucosal sites, with added dependent claim limits on propylene glycol, water, ethyl alcohol, polyethylene glycol (PEG 400), midazolam concentration, dose volume, and pharmacokinetic timing (Tmax within 30 or 15 minutes).
A practical reading for freedom-to-operate (FTO) is that the claim set is most directly implicated by products that (1) are midazolam liquids intended for intranasal delivery, and (2) formulate with methoxy-PEG 350 or methoxy-PEG 550 as a key vehicle component.
What is US 8,217,033 claiming for intranasal midazolam with methoxy-PEG 350/550?
Claim 1 (composition) is the core capture:
A liquid pharmaceutical composition for intranasal administration comprising:
- Midazolam (or a pharmaceutically acceptable salt), and
- Methoxy-polyethylene glycol selected from methoxy-PEG 350 and methoxy-PEG 550.
How broad is Claim 1?
- Drug scope: midazolam is the active, not an interchangeable benzodiazepine. That narrows direct infringement risk to midazolam formulations.
- Dosage form: “liquid pharmaceutical composition formulated for intranasal administration” narrows to non-solid intranasal products.
- Excipient scope: methoxy-PEG must be one of exactly two molecular weight grades (350 or 550). The claim does not appear to cover other methoxy-PEG grades (e.g., 200, 1000).
What is included by general “comprising”?
The “comprising” open transition allows additional excipients beyond methoxy-PEG 350/550 and midazolam, subject to dependent claims that further specify optional co-solvents/agents.
Claim 15 (method of administration) and site breadth
Claim 15 extends coverage from composition to administration:
- Administer midazolam via a mucosal surface using a composition with midazolam + methoxy-PEG 350 or 550.
Mucosal site breadth (dependent claims 16–17):
- Claim 16 lists: nasal, buccal, pulmonal, ocular, rectal.
- Claim 17 narrows to nasal membrane.
Practical implication: Even though Claim 1 is written for intranasal, the method claim supports a wider “mucosal delivery” concept, though infringement still requires the presence of methoxy-PEG 350/550.
What dependent claim limits matter most for infringement risk?
Excipients that add claim specificity
The dependent claims carve in several optional additives:
| Claim |
Additional component(s) |
Constraint type |
| Claim 2 |
propylene glycol |
adds co-solvent requirement |
| Claim 3 |
water |
adds aqueous phase requirement |
| Claim 4 |
methoxy-PEG 350 (specifically) |
narrows methoxy-PEG grade |
| Claim 6 |
polyethylene glycol |
adds additional polymer excipient |
| Claim 7 |
polyethylene glycol (in context of claim set) |
duplicates with claim 6 but in dependent chain |
| Claim 8 |
ethyl alcohol |
adds co-solvent/solvent alcohol |
| Claim 9 |
PEG 400 as the specified polyethylene glycol |
narrows PEG grade |
| Claim 10 |
PEG 400 |
same grade narrowing in another chain |
| Claim 12 |
water |
redundant water limitation in another chain |
| Claim 14 |
methoxy-PEG 350 |
methoxy-PEG grade narrowing |
How to read these for claim coverage:
- If a product uses methoxy-PEG 350/550 but omits propylene glycol, water, ethyl alcohol, or PEG 400, it can still land in Claim 1/15 because those dependent features are not required for the independent claims.
- If a product includes those additives, it raises the likelihood of fitting multiple dependent claims, which can matter for infringement theories and claim construction in litigation.
Midazolam concentration range
- Claim 11: midazolam present at 0.001% (w/v) to 20% (w/v).
- Claim 13: repeats that concentration limitation in the methoxy-PEG 350 chain.
Impact: This is a very broad concentration range. For typical liquid intranasal midazolam concentrations, the range is likely to be satisfied in most marketed formulations and many clinical candidates.
Pharmacokinetic timing limitations
- Claim 18: Tmax within 30 minutes after administration.
- Claim 19: Tmax within 15 minutes.
Impact for infringement and FTO:
- These are performance/PK limitations. They can be harder to “see” from formulation alone and may depend on study conditions, sampling, and patient population.
- In litigation, these claims can drive disputes over whether the administered formulation produces the claimed Tmax window.
Dose volume limitation
- Claim 20: administered in a volume of 50 μl to 300 μl.
Impact: Intranasal dosing volumes for concentrated midazolam solutions often fall within or near this band, depending on concentration and delivery device. A device that delivers outside this range can avoid this dependent limitation, while still potentially infringing the independent composition/method claims.
How does the claim structure allocate coverage: composition vs administration?
Independent coverage split
- Claim 1: composition for intranasal use.
- Claim 15: method of administering to a mucosal surface with the same key excipient requirement.
Dependent claims create multiple “hooks”
- Excipient hooks (propylene glycol, water, ethyl alcohol, PEG 400)
- Parameter hooks (midazolam concentration; dose volume)
- Outcome hook (Tmax timing)
Infringement strategy implications (general):
- If a product matches midazolam + methoxy-PEG 350/550 in a liquid intranasal formulation, infringement can be asserted under Claim 1 without needing the dependent excipients or PK proof as a prerequisite for the independent claim theory.
- If the product instead avoids methoxy-PEG 350/550, it should fall outside these claims even if it uses other PEG variants or delivery polymers.
What patent estate risks exist around US 8,217,033 for intranasal midazolam?
Core risk driver: methoxy-PEG 350/550 in a midazolam liquid
The claim set is not generic “PEG” coverage. It is a targeted excipient selection:
- Methoxy-PEG 350
- Methoxy-PEG 550
That specificity is the main differentiator versus broader midazolam nasal formulations that use, for example, cyclodextrins, mucoadhesive polymers, or different PEG molecular weights.
Where competing formulations can still overlap
Even without knowing the entire patent record, common overlap scenarios for intranasal midazolam include:
- Same drug, different vehicle: If another patent claims midazolam + different solubilizer (cyclodextrins, polymers, surfactants) and avoids methoxy-PEG 350/550, it may not infringe the 8,217,033 claims.
- Same vehicle family with different grades: A formulation that uses methoxy-PEG 750, 1000, or non-methoxy PEG may be designed to avoid this claim selection.
- Hybrid formulations: Products sometimes use multiple PEG components (e.g., PEG 400 plus methoxy-PEG). If methoxy-PEG 350/550 is present, the “key” element for 8,217,033 may still be satisfied.
What other patents are typically in the same competitive zone as excipient-defined intranasal midazolam?
Without a complete US application family list and prosecution history for 8,217,033 and without the Orange Book listing(s) for specific intranasal midazolam products, a full mapping of “how many patents cover” cannot be completed accurately. What can be stated strictly from the claim text you provided is the following claim-driven search agenda:
Search clusters to locate overlapping/adjacent patents
- Midazolam intranasal liquid formulations
- Methoxy-PEG (and methoxy-polyethylene glycol) excipient grade-specific formulations (350 vs 550 vs other Mw)
- Co-solvent systems that include propylene glycol and/or ethyl alcohol
- PK/Tmax dependent method claims tied to intranasal dosing
- Dose volume and device-specific administration claims (50–300 μl)
These clusters are where you will typically find both:
- later reformulation patents trying to broaden vehicle grade scope, and
- earlier patents that argue that the use of methoxy-PEG in that formulation context was already known.
When does US 8,217,033 expire, and how does that affect generic entry risk?
A precise expiration timeline (filing date, priority date, PTA, terminal disclaimer status) requires the actual patent bibliographic record and any adjustments. With only the claim text and without the legal bibliographic data, an accurate exclusivity/expiration date cannot be produced.
From a practical litigation and FTO standpoint, the key question is not just the patent’s calendar life, but whether:
- the relevant drug approval (if any) lists this patent in the FDA Orange Book, and
- any enforcement is active via licensing or infringement suits.
These cannot be established from the claim text alone.
What “generic entry” design-arounds are implied by the claim language?
The claims’ technical pinch points suggest several design-around approaches:
1) Remove methoxy-PEG 350/550
- Avoid methoxy-PEG 350 and methoxy-PEG 550 entirely.
- Use alternative excipients or alternative PEG grades, while maintaining a liquid intranasal midazolam product.
This is the cleanest route because it avoids both Claim 1 and Claim 15.
2) Keep methoxy-PEG but use a different molecular weight range
- If methoxy-PEG 750 or other grades are used instead of 350/550, the literal scope of the excipient selection may be avoided.
3) Avoid intranasal/lower the mucosal intent
- Claim 1 is intranasal.
- Claim 15 is mucosal, including nasal among others.
A product intended strictly for a different route than the claimed mucosal sites can reduce risk, though that depends on what the claims are ultimately interpreted to cover.
4) Avoid additional dependent constraints
- If a product is close on excipient selection, it can still attempt to avoid dependent limitations:
- remove ethyl alcohol to avoid the ethyl-alcohol dependent claim hook
- adjust dosing volume outside 50–300 μl to avoid the volume dependent claim
- manage PK to avoid “Tmax within 15 or 30 minutes” dependent claims
These steps are less reliable for avoiding the independent claims, but can matter for narrowing the infringement theory.
How does US 8,217,033 compare with broader PEG-based midazolam nasal patents?
US 8,217,033 is excipient-grade specific. Many “PEG” patents in nasal drug delivery use PEG generally without locking the molecular weight, or they use non-methoxy PEG (e.g., PEG 400). Your claim set explicitly requires methoxy-PEG 350 or 550.
So the main distinction is:
- broad PEG patents risk covering many PEG-based vehicles, while
- this patent risks only those that use the methoxy-PEG 350/550 selection plus midazolam in a liquid intranasal/mucosal context.
Key takeaways on the scope and claim leverage of US 8,217,033
- Independent claim coverage hinges on two excipient grades: methoxy-PEG 350 or 550 plus midazolam in a liquid intranasal composition (Claim 1).
- Method claim extends to multiple mucosal sites (Claim 15), though it still requires the same excipient selection.
- Dependent claims add formulation and performance constraints (propylene glycol, water, ethyl alcohol, PEG 400, midazolam concentration, 50–300 μl volume, and Tmax within 15/30 minutes). These can strengthen infringement narratives but do not appear necessary to meet Claim 1/15.
- Design-around is strongly driven by excipient choice: avoiding methoxy-PEG 350/550 is the most direct path.
FAQs
1) What excipient grades are required to infringe US 8,217,033?
Methoxy-polyethylene glycol is limited to methoxy-PEG 350 or methoxy-PEG 550 under the independent claims.
2) Does US 8,217,033 cover midazolam salts or only freebase midazolam?
The claims cover midazolam or a pharmaceutically acceptable salt.
3) Is the claim limited to intranasal delivery or all mucosal routes?
Claim 1 is written for intranasal. Claim 15 covers mucosal administration and includes nasal, buccal, pulmonal, ocular, and rectal mucosa via dependent claims.
4) Do dependent claims require a specific midazolam concentration and dose volume?
Yes for the dependent chains: 0.001% to 20% (w/v) and 50 μl to 300 μl respectively, but these are not stated as prerequisites for the independent composition claim you provided.
5) Can a formulation avoid infringement by swapping methoxy-PEG 350/550 for PEG 400?
Yes in principle for literal scope avoidance, because the independent claims require methoxy-PEG 350/550, not just PEG 400.
References
No sources were provided or cited in the prompt beyond the claim text you included.
