Details for Patent: 6,500,456

Summary for Patent: 6,500,456

Title:	Compressed nitroglycerin tablet and its method of manufacture
Abstract:	The present invention is directed to a stable nitroglycerin containing pharmaceutical composition, preferably a tablet which is prepared by direct compression technology. The formulation closely replicates the properties of nitroglycerin molded sublingual tablets (e.g. adequate disintegration and sublingual absorption), while reducing the problems experienced with compressed tablets (e.g. friability and weight variations). The stable tablets are characterized by a decreased migration of nitroglycerin, decreased potency loss, excellent content uniformity when stored. The preferred combination of components are: nitroglycerin/lactose dilution, hydrous lactose, glyceril monostearate, fumed silica, pregelantinized starch and calcium stearate. The preferred process employs direct compression technology to yield composition showing adequate disintegration, bioavailability and improved stability.
Inventor(s):	Roberto L. Capella
Assignee:	Warner Lambert Co LLC
Application Number:	US09/508,705
Patent Claim Types: see list of patent claims	Composition; Process; Dosage form;

United States Patent 6,500,456: Scope, Claims, and U.S. Patent Landscape for a Nitroglycerin Sublingual Tablet Composition

What does US 6,500,456 claim, at the “core” level?

US 6,500,456 is directed to a stable solid oral dosage form and a stability-focused formulation process for nitroglycerin where nitroglycerin is the sole pharmacologically active agent. The claims concentrate on controlling chemical stability (keeping nitroglycerin from degrading) while meeting direct compression tablet performance targets (disintegration, friability, hardness, thickness, and weight/content uniformity).

Across the asserted claim set you provided, the patent’s protection is anchored to four pillars:

1. Composition architecture (mandatory elements)

   • Nitroglycerin as the only active
   • Lactose (specified as hydrous lactose in dependent claims)
   • Silica (specified as fumed silica in dependent claims)
   • Starch (specified as pregelatinized starch in dependent claims)
   • A stabilizer: glyceryl monostearate in about 0.5 to 10 wt%
   • A lubricant (specified as an alkali metal salt; calcium stearate in dependent claims)

2. Solid form constraints

   • Includes sublingual tablet and compressed tablet scopes.
   • “Consisting essentially of” appears in claim 12, tightening boundaries around allowed excipients.

3. Quantitative ranges tied to manufacturability and performance

   • Example dependent claim 7 gives a full compositional window:
     • Nitroglycerin 0.5 to 5 wt%
     • Lactose >90 wt% diluent
     • Silica 0.1 to 1 wt%
     • Calcium stearate 0.1 to 1 wt%
     • Starch 5 to 15 wt%
     • Glyceryl monostearate 0.5 to 10 wt%

4. Process protection through dry blending and compression

   • Claims 16 and 18 protect a process built around:
     • Creating a nitroglycerin dilution in lactose so that the active content is about 2% or less
     • Blending in silica, lubricant, glyceryl monostearate, starch, and optionally additional lactose
     • Direct compression
     • Recovering as a compressed product

The practical effect: the patent is designed to block substitutes that keep the same “stability system” (lactose + silica + glyceryl monostearate + starch + lubricant) and make it by the same direct compression route.

---

What is the actual claim scope: composition vs product vs process?

Composition claims (composition architecture + functional stability)

• Claim 1: A “stable composition” with:

  • Nitroglycerin + lactose + silica + starch + glyceryl monostearate (about 0.5 to 10 wt%) + lubricant
  • Nitro is sole pharmacologically active agent

• Claim 19: A second composition claim repeating the stabilizer concept:

  • “stabilizer consisting essentially of glyceryl monostearate” in 0.5 to 10 wt%
  • plus the same “nitroglycerin is sole pharmacologically active agent” structure

• Claim 12: A compressed tablet:

  • “stable compressed tablet consisting essentially of effective amounts” of nitroglycerin, lactose, silica, pregelatinized starch, glyceryl monostearate, and lubricant
  • nitroglycerin is sole active
    This is narrower than claim 1 because of “consisting essentially of” and because it fixes pregelatinized starch.

Product claims (form + performance parameters)

• Claim 2: Composition of claim 1 as a sublingual tablet
• Claim 8–10: The composition is tied to measurable specs:
  • Disintegration: about 20 to 30 seconds
  • Weight variation: about 1 to 2% RSD
  • Content variation: less than about 4% RSD
  • Friability: less than about 1%
  • Thickness: about 0.07 to 0.10 inch
  • Hardness: about 1 to 4 kp

These performance limitations can materially narrow infringement for designs that meet stability but miss tablet performance targets.

Dependent formulation identity constraints (material substitutions are controlled)

• Starch: pregelatinized starch (claim 3 and 17)
• Silica: fumed silica (claim 4 and 13)
• Lubricant: alkali metal salt (claim 5) and calcium stearate (claim 14)
• Lactose: hydrous lactose (claim 6 and 15)

This creates a “ladder” of claim coverage:

• Broad protection for any “starch” and “silica” in claim 1 (as written in your excerpt),
• With increasingly specific, easier-to-match infringements in dependent claims.

Process claims (dry, direct compression route)

• Claim 16: A dry compressed product process with steps:

  1. Commingling nitroglycerin with lactose to produce a dilution where nitroglycerin is about 2% or less
  2. Mixing the dilution with silica, lubricant, glyceryl monostearate, starch, and optionally more lactose, to form a blend
  3. Compressing
  4. Recovering as compressed product

• Claim 18: Expressly a “process for preparing” using the same step logic.

Process protection matters for “design-arounds” where the formulation might be similar but the manufacturing route differs.

---

What are the key quantitative boundaries that define the likely infringement perimeter?

Stabilizer boundary: glyceryl monostearate

• About 0.5 to 10 wt% appears in claim 1.
• In claim 19 it is “stabilizer consisting essentially of glyceryl monostearate” at about 0.5 to 10 wt%.

This makes glyceryl monostearate the core stabilizing excipient and restricts replacement with other mono-/diglycerides unless they are argued to fall within “consisting essentially of” territory (claim 19’s language).

Example full formulation window

Dependent claim 7 provides a full set of ranges that are likely used as the “engineering target” in prosecution and later commercial use:

Component	Claim 7 range / condition (wt%)
Nitroglycerin	0.5 to about 5
Lactose (diluent)	greater than about 90
Silica	0.1 to about 1
Lubricant (calcium stearate)	0.1 to about 1
Starch	5 to about 15
Glyceryl monostearate	0.5 to about 10

If a competitor’s formulation matches this tight grid and includes the same tablet performance parameters, they are in the highest-risk zone.

Tablet performance specs (narrowing limitation)

Parameter	Claims 8–10 range/spec
Disintegration	about 20 to about 30 seconds
Weight variation	about 1 to about 2% RSD
Content variation	less than about 4% RSD
Friability	less than about 1%
Thickness	about 0.07 to 0.10 inch
Hardness	about 1 to about 4 kp

These are not “typical” in a general excipient composition claim. They function as a measurable product identity constraint.

---

How does the “sole pharmacologically active agent” language affect the landscape?

The claim requirement that nitroglycerin is the sole pharmacologically active agent creates a direct boundary against:

• fixed-dose combinations in the same tablet (even if the added actives are at low dose),
• multi-active sublingual platforms that combine nitroglycerin with other drugs.

It does not stop combinations achieved by separate dosage forms (outside infringement scope depending on claim structure), but for tablet-level claims it is a hard line.

---

What is the practical “design-around” map implied by the claim structure?

Because US 6,500,456 mixes composition and process coverage, workarounds tend to fall into one of two buckets:

1. Formulation substitutions that escape one or more mandatory limitations

   • Replace glyceryl monostearate (hardest to avoid given its explicit stabilizer range and “consisting essentially of” language in claim 19).
   • Replace one of the functional excipient categories that are explicitly listed in claim 1 (lactose, silica, starch, lubricant).
   • Shift to a formulation where the stabilizer is not “about 0.5 to 10 wt% glyceryl monostearate” and can avoid “consisting essentially of” in claim 12/19.

2. Manufacturing-route changes

   • Claim 16/18 lock in a nitroglycerin-in-lactose dilution at about 2% or less, followed by blending/compression.
   • A route that materially differs in active dilution logic or does not involve the specified dilution step is a more plausible process design-around than a total formulation overhaul.

Performance specs in claims 8–10 are another escape hatch:

• If a competitor’s tablet does not meet the specified disintegration window or friability/hardness/thickness profile, the dependent claims anchored to those parameters are harder to assert.

---

Where is the likely patent landscape pressure in the U.S. market?

Without additional bibliographic data for US 6,500,456 (publication history, filing date, related family members, and cited art), the most reliable landscape view you can derive from your claim excerpt is mechanistic rather than bibliographic:

High-likelihood overlap zones (same excipient system)

Across U.S. solid dosage formulations for nitroglycerin or similar actives, competitive patents and formulations typically focus on:

• excipient selection for stability (especially against oxidative or decomposition pathways),
• lubricant and binder systems compatible with direct compression,
• tablet performance targets (disintegration, friability, hardness),
• controlling dose uniformity (RSD targets).

US 6,500,456’s claim language is concentrated on a specific stabilization system using lactose + silica + glyceryl monostearate in a high-lactose matrix, delivered via direct compression.

Risk concentration

Risk for a competitor rises when all three are true:

• formulation includes glyceryl monostearate at 0.5–10 wt%,
• formulation uses lactose (often hydrous), silica (often fumed), and pregelatinized starch,
• process includes active dilution in lactose to <=2% prior to blending.

---

Claim-by-claim scope snapshot (what each one covers)

Claim	Scope type	What must be present (from your excerpt)	Main narrowing lever
1	Composition	Nitro + lactose + silica + starch + glyceryl monostearate (0.5–10%) + lubricant; nitro sole active	Glyceryl monostearate range; sole active
2	Composition	Claim 1 as a sublingual tablet	Sublingual form
3	Composition	Starch is pregelatinized	Specific excipient identity
4	Composition	Silica is fumed	Specific excipient identity
5	Composition	Lubricant is alkali metal salt	Specific excipient identity
6	Composition	Lactose is hydrous	Specific excipient identity
7	Composition	Full numerical ranges (nitro, lactose, silica, Ca stearate, starch, glyceryl monostearate)	Tight composition grid
8	Composition	Disintegration 20–30 seconds	Tablet performance
9	Composition	Weight variation 1–2% RSD	Uniformity
10	Composition	Disintegration, RSDs, friability, thickness, hardness	Full performance profile
11	Composition	Compressed tablet	Form type
12	Product/Composition	“consisting essentially of” nitro + lactose + silica + pregelatinized starch + glyceryl monostearate + lubricant; nitro sole active	“consisting essentially of” and fixed excipient set
13	Product/Composition	Silica is fumed	Excipient identity
14	Product/Composition	Lubricant is calcium stearate	Excipient identity
15	Product/Composition	Lactose is hydrous	Excipient identity
16	Process	Dry product process with dilution step (nitro in lactose <=2%), blend with silica/lubricant/glyceryl monostearate/starch, compress	Active dilution step and dry direct compression sequence
17	Process	Starch is pregelatinized	Excipient identity in process
18	Process	Same steps as claim 16	Process coverage
19	Composition	Stabilizer consisting essentially of glyceryl monostearate (0.5–10%); nitro sole active	“consisting essentially of” for stabilizer

---

Key Takeaways

• US 6,500,456 is a nitroglycerin-only solid dosage patent that locks onto a specific stability system: lactose + silica + starch + glyceryl monostearate (0.5–10 wt%) + lubricant, with nitroglycerin as the sole pharmacologically active agent.
• The strongest competitive risk sits where a product uses glyceryl monostearate within the claimed range plus lactose/silica/starch that match the dependent specifications (hydrous lactose, fumed silica, pregelatinized starch).
• Dependent claims add tabular performance identity limits (disintegration 20–30 sec; friability <1%; thickness 0.07–0.10 inch; hardness 1–4 kp) that can materially affect infringement if not met.
• The process claims protect a dry, direct compression workflow with a defining step: nitroglycerin dilution in lactose at about 2% or less before blending with silica, lubricant, glyceryl monostearate, and starch.

---

FAQs

1. Does US 6,500,456 allow other actives in the tablet?
   No. The claims require that nitroglycerin is the sole pharmacologically active agent.

2. Which excipient is the central stabilizer in the claims?
   Glyceryl monostearate, at about 0.5 to 10 wt% (and “consisting essentially of” appears in claim 19).

3. What tablet performance limits are built into dependent claims?
   Disintegration about 20–30 seconds, weight variation about 1–2% RSD, content variation <4% RSD, friability <1%, thickness about 0.07–0.10 inch, and hardness about 1–4 kp.

4. How do the process claims differ from the formulation claims?
   Process claims (16 and 18) cover a manufacturing sequence built on active dilution in lactose (<=2%), then blending with specified excipients, followed by compression.

5. Which dependent claims most directly control excipient identity?
   Starch as pregelatinized (claims 3 and 17), silica as fumed silica (claims 4 and 13), lubricant as calcium stearate (claims 14), and lactose as hydrous lactose (claims 6 and 15).

---

References

1. United States Patent 6,500,456 (claims as provided by user).

Drugs Protected by US Patent 6,500,456

Applicant	Tradename	Generic Name	Dosage	NDA	Approval Date	TE	Type	RLD	RS	Patent No.	Patent Expiration	Product	Substance	Delist Req.	Patented / Exclusive Use	Submissiondate

Foreign Priority and PCT Information for Patent: 6,500,456

PCT Information
PCT Filed	September 16, 1998	PCT Application Number:	PCT/US98/19356
PCT Publication Date:	April 15, 1999	PCT Publication Number:	WO99/17766

International Family Members for US Patent 6,500,456

Country	Patent Number	Estimated Expiration	Supplementary Protection Certificate	SPC Country	SPC Expiration
Austria	209911
Australia	759018
Australia	9489398
Brazil	9812605
Canada	2299231
Germany	69802832
Denmark	1019039